1 00:00:15,058 --> 00:00:16,326 THIS IS A PROGRAM OF THE 2 00:00:16,326 --> 00:00:18,095 NATIONAL HUMAN GENOME RESEARCH 3 00:00:18,095 --> 00:00:19,730 INSTITUTE AND IT IS MY ENORMOUS 4 00:00:19,730 --> 00:00:21,798 PLEASURE TO WELCOME YOU TO THIS, 5 00:00:21,798 --> 00:00:24,134 THE NINTH INSTALLMENT OF THE 6 00:00:24,134 --> 00:00:26,169 2025 SEASON OF DEMYSTIFYING 7 00:00:26,169 --> 00:00:26,603 MEDICINE. 8 00:00:26,603 --> 00:00:28,905 A SERIES OF PRESENTATIONS THAT 9 00:00:28,905 --> 00:00:30,974 BRIDGE THE EXCITING DEVELOPMENTS 10 00:00:30,974 --> 00:00:33,877 IN BIOLOGY, ENGINEERING, AND 11 00:00:33,877 --> 00:00:35,812 COMPUTER SCIENCE WITH MEDICINE. 12 00:00:35,812 --> 00:00:39,082 AS ILLUSTRATED BY THE ICONIC 13 00:00:39,082 --> 00:00:41,685 PHOTO OF THE CONSTRUCTION OF THE 14 00:00:41,685 --> 00:00:43,553 BROOKLYN BRIDGE BACK IN THE LATE 15 00:00:43,553 --> 00:00:46,957 19TH CENTURY, AND YOU CAN 16 00:00:46,957 --> 00:00:48,158 PROBABLY SEE UP THERE ON THE 17 00:00:48,158 --> 00:00:50,661 CATWALK THOSE TWO MEN, ONE OF 18 00:00:50,661 --> 00:00:53,196 THEM PROBABLY FROM MANHATTAN, A 19 00:00:53,196 --> 00:00:54,731 PHYSICIAN, I WOULD GUESS, AND 20 00:00:54,731 --> 00:00:57,901 THE OTHER, A BASIC SCIENTIST 21 00:00:57,901 --> 00:01:01,071 FROM BROOKLYN. 22 00:01:01,071 --> 00:01:04,141 TALKING ABOUT ONE OF THE HOT 23 00:01:04,141 --> 00:01:06,310 TOPICS OF THE DAY, PERHAPS THE 24 00:01:06,310 --> 00:01:07,311 GERM THEORY OF DISEASE. 25 00:01:07,311 --> 00:01:10,447 SO JUST AS THEY WERE BRINGING 26 00:01:10,447 --> 00:01:12,783 TOGETHER BASIC SCIENCE WITH 27 00:01:12,783 --> 00:01:15,719 CLINICAL MEDICINE, SO TOO THIS 28 00:01:15,719 --> 00:01:17,888 AFTERNOON, WE ARE GOING TO BRING 29 00:01:17,888 --> 00:01:19,556 TOGETHER BASIC SCIENCE WITH 30 00:01:19,556 --> 00:01:21,958 CLINICAL MEDICINE TO TALK ABOUT 31 00:01:21,958 --> 00:01:24,695 SOME OF THE GREAT EXCITING 32 00:01:24,695 --> 00:01:26,430 ADVANCES IN THE UNDERSTANDING 33 00:01:26,430 --> 00:01:30,167 AND TREATMENT OF LUNG CANCER. 34 00:01:30,167 --> 00:01:32,336 THIS SERIES, DEMYSTIFYING 35 00:01:32,336 --> 00:01:34,638 MEDICINE, TAKES PLACE ON TUESDAY 36 00:01:34,638 --> 00:01:39,242 AFTERNOONS FROM JANUARY THROUGH 37 00:01:39,242 --> 00:01:41,411 MAY THIS YEAR, 2025, FROM 38 00:01:41,411 --> 00:01:42,312 3:00 TO 5:00 IN THE AFTERNOON. 39 00:01:42,312 --> 00:01:47,217 YOU CAN WATCH IT ON THE LINK 40 00:01:47,217 --> 00:01:47,751 SHOWN ON THE SCREEN. 41 00:01:47,751 --> 00:01:51,588 YOU CAN GET CME CREDIT AVAILABLE 42 00:01:51,588 --> 00:01:53,890 AND THE CODE IS 58788. 43 00:01:53,890 --> 00:01:55,659 IF YOU HAVE QUESTIONS DURING THE 44 00:01:55,659 --> 00:02:00,664 COURSE OF THE PRESENTATIONS, AND 45 00:02:00,664 --> 00:02:02,866 WE'LL BE HAVING TWO, EACH OF 46 00:02:02,866 --> 00:02:04,067 THEM ABOUT 35 MINUTES LONG AND 47 00:02:04,067 --> 00:02:05,068 THEN THE OPPORTUNITY FOR A 48 00:02:05,068 --> 00:02:06,803 QUESTION AND ANSWER SESSION AT 49 00:02:06,803 --> 00:02:10,006 THE END, IF YOU HAVE QUESTIONS 50 00:02:10,006 --> 00:02:11,708 THAT OCCUR TO YOU DURING THE 51 00:02:11,708 --> 00:02:13,143 PRESENTATIONS, JUST USE THE 52 00:02:13,143 --> 00:02:16,446 "SEND LIVE FEEDBACK" BUTTON ON 53 00:02:16,446 --> 00:02:20,150 THE VIDEOCAST DISPLAY IN ORDER 54 00:02:20,150 --> 00:02:22,419 TO GET THOSE QUESTIONS TO US 55 00:02:22,419 --> 00:02:23,520 AHEAD OF TIME. 56 00:02:23,520 --> 00:02:25,288 ALL OF THE PREVIOUS SESSIONS ARE 57 00:02:25,288 --> 00:02:26,490 ARCHIVED, THE LINK IS ON YOUR 58 00:02:26,490 --> 00:02:27,791 SCREEN AND FOR ADDITIONAL 59 00:02:27,791 --> 00:02:31,862 INFORMATION, YOU CAN EMAIL 60 00:02:31,862 --> 00:02:32,362 DEMYSTIFYINGMED@NIH.GOV. 61 00:02:32,362 --> 00:02:34,564 THIS IS A SERIES THAT'S BEEN 62 00:02:34,564 --> 00:02:37,634 GOING ON SINCE 2003, BRIDGING 63 00:02:37,634 --> 00:02:39,836 SILOS AT THE NIH, AS ILLUSTRATED 64 00:02:39,836 --> 00:02:42,239 BY THOSE SILOS THERE IN THE 65 00:02:42,239 --> 00:02:45,075 LOWER RIGHT-HAND CORNER. 66 00:02:45,075 --> 00:02:46,610 TODAY'S PRESENTATION IS GOING TO 67 00:02:46,610 --> 00:02:48,678 BE ABSOLUTELY FANTASTIC. 68 00:02:48,678 --> 00:02:53,517 WE ARE GOING TO HAVE FIRST 69 00:02:53,517 --> 00:02:56,119 DR. ROY HERBST PRESENTING, AND 70 00:02:56,119 --> 00:02:58,989 THE MAJOR TOPIC OF THIS SESSION 71 00:02:58,989 --> 00:03:00,657 IS CANCER OF THE LUNG, PROGRESS 72 00:03:00,657 --> 00:03:02,793 AND CHALLENGES. 73 00:03:02,793 --> 00:03:06,296 DR. HERBST IS THE ENSIGN 74 00:03:06,296 --> 00:03:08,932 PROFESSOR OF MEDICINE IN MEDICAL 75 00:03:08,932 --> 00:03:10,901 ONCOLOGY, PROFESSOR OF 76 00:03:10,901 --> 00:03:12,536 PHARMACOLOGY, AND CHIEF OF 77 00:03:12,536 --> 00:03:14,738 HEMATOLOGY AND MEDICAL ONCOLOGY, 78 00:03:14,738 --> 00:03:17,340 AND ALSO DEPUTY DIRECTOR OF THE 79 00:03:17,340 --> 00:03:18,975 YALE CANCER CENTER. 80 00:03:18,975 --> 00:03:21,945 HE'S ALSO THE ASSISTANT DEAN FOR 81 00:03:21,945 --> 00:03:23,246 TRANSLATIONAL RESEARCH AT YALE 82 00:03:23,246 --> 00:03:24,781 SCHOOL OF MEDICINE. 83 00:03:24,781 --> 00:03:26,917 HE GOT HIS BACHELOR'S AND 84 00:03:26,917 --> 00:03:28,718 MASTER'S DEGREES IN BIOCHEMISTRY 85 00:03:28,718 --> 00:03:30,687 AND BIOPHYSICS AT YALE. 86 00:03:30,687 --> 00:03:33,990 HE THEN DID HIS PH.D. IN 87 00:03:33,990 --> 00:03:36,293 MOLECULAR AND CELL BIOLOGY AT 88 00:03:36,293 --> 00:03:37,694 THE ROCKEFELLER UNIVERSITY 89 00:03:37,694 --> 00:03:39,763 BEFORE GOING ON TO GET HIS 90 00:03:39,763 --> 00:03:40,864 MEDICAL DEGREE AT CORNELL 91 00:03:40,864 --> 00:03:42,732 MEDICAL SCHOOL, AND THEN A 92 00:03:42,732 --> 00:03:44,901 MASTER'S DEGREE IN TRANSLATIONAL 93 00:03:44,901 --> 00:03:46,536 RESEARCH AT HARVARD. 94 00:03:46,536 --> 00:03:49,840 HE THEN WENT ON TO GET HIS 95 00:03:49,840 --> 00:03:53,543 CLINICAL TRAINING IN MEDICAL 96 00:03:53,543 --> 00:03:54,211 HEMATOLOGY/ONCOLOGY AT THE 97 00:03:54,211 --> 00:03:55,412 HARVARD HOSPITALS AND THEN WENT 98 00:03:55,412 --> 00:04:00,984 SOUTH TO HOUSTON, WHERE HE TOOK 99 00:04:00,984 --> 00:04:03,386 POSITIONS AT THE UT MD ANDERSON 100 00:04:03,386 --> 00:04:05,489 CANCER CENTER, EVENTUALLY RISING 101 00:04:05,489 --> 00:04:09,526 TO THE ESTEEMED POSITION OF 102 00:04:09,526 --> 00:04:10,527 BARNHART DISTINGUISHED 103 00:04:10,527 --> 00:04:11,061 PROFESSOR. 104 00:04:11,061 --> 00:04:14,130 HE'S THE RECIPIENT OF MANY 105 00:04:14,130 --> 00:04:16,099 AWARDS AND RECOGNITION, 106 00:04:16,099 --> 00:04:22,873 BEGINNING WITH PHI BETA KAPPA, 107 00:04:22,873 --> 00:04:28,879 SUMMA CUM LAUDE, HE'S WON 108 00:04:28,879 --> 00:04:30,313 NUMEROUS TOP DOCTOR AWARDS AND 109 00:04:30,313 --> 00:04:32,048 HE WON THE DISTINGUISHED PUBLIC 110 00:04:32,048 --> 00:04:34,451 SERVICE AWARD FROM THE AMERICAN 111 00:04:34,451 --> 00:04:39,155 ASSOCIATION OF CANCER RESEARCH. 112 00:04:39,155 --> 00:04:41,691 HIS LABORATORY SPECIALIZES IN 113 00:04:41,691 --> 00:04:44,294 DEVELOPMENTAL THERAPEUTICS AND 114 00:04:44,294 --> 00:04:48,365 PERSONALIZED THERAPY OF 115 00:04:48,365 --> 00:04:52,736 NON-SMALL CELL LUNG CANCER, AND 116 00:04:52,736 --> 00:04:55,906 LINKS CELLULAR GENETIC 117 00:04:55,906 --> 00:04:57,641 ABNORMALITIES TO NOVEL 118 00:04:57,641 --> 00:04:58,074 THERAPIES. 119 00:04:58,074 --> 00:04:59,609 THEIR WORK HAS LED TO THE 120 00:04:59,609 --> 00:05:01,378 APPROVAL OF SEVERAL THERAPIES 121 00:05:01,378 --> 00:05:03,213 THAT HAVE REVOLUTIONIZED THE 122 00:05:03,213 --> 00:05:03,880 FIELD. 123 00:05:03,880 --> 00:05:09,019 HE'S ALSO A PIONEER IN THE USE 124 00:05:09,019 --> 00:05:12,756 OF PD-L1 INHIBITORS IN LUNG 125 00:05:12,756 --> 00:05:13,990 CANCER AND HAS BEEN A LEADER IN 126 00:05:13,990 --> 00:05:15,158 THE UMBRELLA TRIALS OF TARGETED 127 00:05:15,158 --> 00:05:17,093 THERAPIES. 128 00:05:17,093 --> 00:05:19,863 OUR SECOND PRESENTER IS GOING TO 129 00:05:19,863 --> 00:05:22,465 BE DR. KATERINA POLITI. 130 00:05:22,465 --> 00:05:30,907 SHE IS THE JOSEPH A. AND LUCILE 131 00:05:30,907 --> 00:05:31,975 MADRI PROFESSOR AT THE CENTER 132 00:05:31,975 --> 00:05:33,710 FOR THORACIC CANCERS AT THE YALE 133 00:05:33,710 --> 00:05:34,511 SCHOOL OF MEDICINE. 134 00:05:34,511 --> 00:05:39,349 SHE RECEIVED HER UNIVERS 135 00:05:39,349 --> 00:05:41,284 UNIVERSITY DEGREE, LAUREA, IN 136 00:05:41,284 --> 00:05:44,254 BIOLOGICAL SCIENCES, CUM LAUDE, 137 00:05:44,254 --> 00:05:46,523 FROM THE UNIVERSITY OF PAVIA, 138 00:05:46,523 --> 00:05:49,059 AND THEN A PH.D. WITH 139 00:05:49,059 --> 00:05:50,093 DISTINCTION FROM COLUMBIA 140 00:05:50,093 --> 00:05:50,393 UNIVERSITY. 141 00:05:50,393 --> 00:05:53,196 SHE WENT ON T TO DO A POSTDOC IN 142 00:05:53,196 --> 00:05:54,731 GENETICS AND DEVELOPMENT AT 143 00:05:54,731 --> 00:05:56,933 COLUMBIA AND THEN BECAME A 144 00:05:56,933 --> 00:05:59,002 RESEARCH FELLOW IN HAROLD 145 00:05:59,002 --> 00:06:00,804 VARMUS' LAB AT MEMORIAL SLOAN 146 00:06:00,804 --> 00:06:02,405 KETTERING AND THEN A RESEARCH 147 00:06:02,405 --> 00:06:04,908 SCIENTIST THERE AS WELL. 148 00:06:04,908 --> 00:06:09,212 SHE THEN WENT ON, OF COURSE, TO 149 00:06:09,212 --> 00:06:15,652 YALE WHERE SHE CURRENTLY IS THE 150 00:06:15,652 --> 00:06:16,720 MADRI PROFESSOR OF PATHOLOGY. 151 00:06:16,720 --> 00:06:17,954 SHE'S A MEMBER OF THE BOARD OF 152 00:06:17,954 --> 00:06:19,356 DIRECTORS AND CHAIR OF THE 153 00:06:19,356 --> 00:06:20,423 SCIENTIFIC ADVISORY BOARD OF THE 154 00:06:20,423 --> 00:06:23,526 LUNG CANCER RESEARCH FOUNDATION. 155 00:06:23,526 --> 00:06:26,062 SHE'S AN ELECTED MEMBER OF THE 156 00:06:26,062 --> 00:06:28,131 PLUTO SOCIETY, WHICH IS A 157 00:06:28,131 --> 00:06:30,433 SOCIETY OF ACADEMIC THAT POLL 158 00:06:30,433 --> 00:06:34,771 GISTPATHOLOGISTS, AND ALSO A 159 00:06:34,771 --> 00:06:36,206 RECIPIENT OF THE YALE CANCER 160 00:06:36,206 --> 00:06:37,240 CENTER TRANSLATIONAL RESEARCH 161 00:06:37,240 --> 00:06:38,208 PRIZE. 162 00:06:38,208 --> 00:06:39,909 HER RESEARCH GROUP FOCUSES ON 163 00:06:39,909 --> 00:06:43,747 THE MECHANISMS OF TUMORIGENESIS 164 00:06:43,747 --> 00:06:44,914 AND SENSITIVITY AND RESISTANCE 165 00:06:44,914 --> 00:06:48,451 TO TARGETED THERAPIES. 166 00:06:48,451 --> 00:06:50,720 SHE WORKS ON ADENOCARCINOMAS 167 00:06:50,720 --> 00:06:53,156 THAT HARBOR MUTATIONS IN THE 168 00:06:53,156 --> 00:06:55,759 EGFR GENE, AND THEY STUDY LINKS 169 00:06:55,759 --> 00:06:58,395 BETWEEN RESISTANCE, CANCER CELL 170 00:06:58,395 --> 00:07:02,132 PLASTICITY, THE TUMOR 171 00:07:02,132 --> 00:07:03,967 MICROENVIRONMENT, AND TUMOR 172 00:07:03,967 --> 00:07:05,502 HETEROGENEITY. 173 00:07:05,502 --> 00:07:07,137 SO AT THIS POINT, IT'S TIME TO 174 00:07:07,137 --> 00:07:13,710 TURN THINGS OVER TO DR. HERBST 175 00:07:13,710 --> 00:07:15,345 AND POLITI. 176 00:07:15,345 --> 00:07:16,112 DR. HERBST, TAKE IT AWAY. 177 00:07:16,112 --> 00:07:23,119 >> THANK YOU VERY MUCH. 178 00:07:23,119 --> 00:07:25,121 THANK YOU FOR THAT WONDERFUL 179 00:07:25,121 --> 00:07:35,365 INTRODUCTION. 180 00:07:55,685 --> 00:07:58,254 WE'RE NOT USED TO USING TEAMS. 181 00:07:58,254 --> 00:07:59,689 >> DON'T KNOW IF WE CAN MINIMIZE 182 00:07:59,689 --> 00:08:03,293 THAT. 183 00:08:03,293 --> 00:08:04,160 >> OKAY. 184 00:08:04,160 --> 00:08:05,228 SO THANK YOU FOR HAVING US 185 00:08:05,228 --> 00:08:08,298 TODAY, AND THANK YOU FOR THAT 186 00:08:08,298 --> 00:08:09,399 WONDERFUL INTRODUCTION. 187 00:08:09,399 --> 00:08:11,801 WHEN KATY AND I RECEIVED THIS 188 00:08:11,801 --> 00:08:13,536 INVITATION, WE FIGURED OUT HOW 189 00:08:13,536 --> 00:08:15,505 TO MAKE THIS WORK BECAUSE WE'RE 190 00:08:15,505 --> 00:08:17,907 SO HONORED TO BE TALKING TO THE 191 00:08:17,907 --> 00:08:18,341 NIH. 192 00:08:18,341 --> 00:08:21,745 WE ACTUALLY JUST CAME FROM GRAND 193 00:08:21,745 --> 00:08:25,815 ROUNDS, OUR CALABRAZI GRAND 194 00:08:25,815 --> 00:08:29,519 ROUNDS GIVEN BY THE FORMER NCI 195 00:08:29,519 --> 00:08:32,555 DIRECTOR, AND KATY AND I ARE 196 00:08:32,555 --> 00:08:34,324 PIs TOGETHER ON A LUNG SPORE, 197 00:08:34,324 --> 00:08:36,059 SO SOME OF THE WORKLOAD IS FROM 198 00:08:36,059 --> 00:08:37,927 THAT, SO WE'RE VERY GRATEFUL FOR 199 00:08:37,927 --> 00:08:38,595 ALL THE SUPPORT. 200 00:08:38,595 --> 00:08:40,230 SO I THOUGHT I'D GIVE A 201 00:08:40,230 --> 00:08:41,131 PERSPECTIVE CLINICALLY ON 20 202 00:08:41,131 --> 00:08:41,898 YEARS OF PROGRESS IN THE 203 00:08:41,898 --> 00:08:44,200 TREATMENT OF LUNG CANCER, MOSTLY 204 00:08:44,200 --> 00:08:46,569 NON-SMALL CELL, TARGETED THERAPY 205 00:08:46,569 --> 00:08:47,771 IMMUNOTHERAPY, AND HOW IT'S 206 00:08:47,771 --> 00:08:49,305 IMPACTING THE TREATMENT OF EARLY 207 00:08:49,305 --> 00:08:59,449 DISEASE. 208 00:09:00,416 --> 00:09:04,621 HERE ARE MY DISCLOSURES. 209 00:09:04,621 --> 00:09:06,222 SO LUNG CANCER IS THE NUMBER ONE 210 00:09:06,222 --> 00:09:08,124 CAUSE OF CANCER DEATH WORLDWIDE. 211 00:09:08,124 --> 00:09:10,727 MORE THAN 2 MILLION CASES 212 00:09:10,727 --> 00:09:12,061 WORLDWIDE, NEW CASES, WITH 213 00:09:12,061 --> 00:09:15,331 ALMOST AS MANY DEATHS. 214 00:09:15,331 --> 00:09:17,834 IN THE U.S., WE HAVE ABOUT 215 00:09:17,834 --> 00:09:20,570 228,000 NEW CASES EACH YEAR WITH 216 00:09:20,570 --> 00:09:21,337 135,000 DEATHS. 217 00:09:21,337 --> 00:09:23,439 84% OF LUNG CANCER IS NON-SMALL 218 00:09:23,439 --> 00:09:25,708 CELL LUNG CANCER, ABOUT 15% IS 219 00:09:25,708 --> 00:09:27,677 SMALL CELL, FOR WHICH THERE HAVE 220 00:09:27,677 --> 00:09:29,679 BEEN, AGAIN, SPONSORED THROUGH 221 00:09:29,679 --> 00:09:31,848 NIH AND NCI MANY RESEARCH 222 00:09:31,848 --> 00:09:33,917 EFFORTS, BUT I'M GOING TO FOCUS 223 00:09:33,917 --> 00:09:34,717 ON NON-SMALL CELL TODAY, AND YOU 224 00:09:34,717 --> 00:09:36,986 CAN SEE THE PIE CHART ON THE 225 00:09:36,986 --> 00:09:37,520 LEFT. 226 00:09:37,520 --> 00:09:40,290 LUNG CAN SERL EXCEEDS BREAST, 227 00:09:40,290 --> 00:09:43,026 COLON, PROSTATE, THE NUMBER ONE 228 00:09:43,026 --> 00:09:44,327 CANCER BY DIAGNOSIS, OF COURSE, 229 00:09:44,327 --> 00:09:47,497 IS SKIN CANCERS. 230 00:09:47,497 --> 00:09:49,265 NOW THE CAUSES OF LUNG CANCER, 231 00:09:49,265 --> 00:09:51,768 OF COURSE, TOBACCO IS THE SINGLE 232 00:09:51,768 --> 00:09:52,836 LARGEST PREVENTABLE CAUSE OF 233 00:09:52,836 --> 00:09:54,270 LUNG CANCER. 234 00:09:54,270 --> 00:09:56,339 LEADING TO 30% OF ALL 235 00:09:56,339 --> 00:09:58,107 CANCER-RELATED DEATHS AND 80% OF 236 00:09:58,107 --> 00:09:59,409 LUNG CANCERS, BUT OF COURSE FOR 237 00:09:59,409 --> 00:10:01,244 THE LAST 20-PLUS YEARS, WE KNOW 238 00:10:01,244 --> 00:10:03,012 ABOUT THE NON-SMOKING LUNG 239 00:10:03,012 --> 00:10:04,447 CANCER, OR THE LIGHT SMOKERS 240 00:10:04,447 --> 00:10:05,682 WITH LUNG CANCER, AND OF COURSE 241 00:10:05,682 --> 00:10:08,484 NOW THE FOCUS IS ON ACTIONABLE 242 00:10:08,484 --> 00:10:08,751 MUTATIONS. 243 00:10:08,751 --> 00:10:10,887 AS YOU CAN SEE FROM THIS FIGURE, 244 00:10:10,887 --> 00:10:12,856 MOST OF THOSE TEND TO OCCUR IN 245 00:10:12,856 --> 00:10:13,957 THE ADENOCARCINOMA IN THE BLUE 246 00:10:13,957 --> 00:10:17,460 PART OF THE CIRCLE, WITH EGFR 247 00:10:17,460 --> 00:10:19,662 BEING THE TOP ONE, ABOUT 10% OR 248 00:10:19,662 --> 00:10:20,864 SO OF PATIENTS IN THE WESTERN 249 00:10:20,864 --> 00:10:26,870 WORLD, 20 TO 30% IN ASIA, ALK, 250 00:10:26,870 --> 00:10:31,674 MET, ERBB-2, ROS, RET, NTRK, 251 00:10:31,674 --> 00:10:35,245 BRAF AND 12% KRAS G12C, ACTUALLY 252 00:10:35,245 --> 00:10:37,046 A MUTATION THAT OCCURS MORE IN 253 00:10:37,046 --> 00:10:37,380 SMOKERS. 254 00:10:37,380 --> 00:10:39,782 FOR THE MOST PART THESE GENETIC 255 00:10:39,782 --> 00:10:41,084 ALTD RANGE OF MOTIONS OCCUR IN 256 00:10:41,084 --> 00:10:42,285 NON-SMOKERS. 257 00:10:42,285 --> 00:10:43,286 NOW WHEN I WENT INTO THIS FIELD, 258 00:10:43,286 --> 00:10:46,222 I WAS A STUDENT AS YOU HEARD, I 259 00:10:46,222 --> 00:10:47,690 TRAINED AT DANA FARBER, I WAS 260 00:10:47,690 --> 00:10:52,695 WORKING WITH THE LATE TOM FRYE, 261 00:10:52,695 --> 00:10:54,731 ART SKERON, AND WE WERE STUDYING 262 00:10:54,731 --> 00:10:55,098 THIS DISEASE. 263 00:10:55,098 --> 00:10:56,866 THIS IS WHAT SURVIVAL LOOKED 264 00:10:56,866 --> 00:10:57,166 LIKE. 265 00:10:57,166 --> 00:11:00,336 IT'S HARD TO BELIEVE THAT HERE 266 00:11:00,336 --> 00:11:01,638 IN 1995, WE'RE ALL EXCITED ABOUT 267 00:11:01,638 --> 00:11:02,105 THESE DATA. 268 00:11:02,105 --> 00:11:03,072 THESE WERE SOME OF THE NEWER 269 00:11:03,072 --> 00:11:04,641 DRUGS THAT WERE BEING USED IN 270 00:11:04,641 --> 00:11:09,479 LUNG CANCER, PACK BUT YOU CAN F 271 00:11:09,479 --> 00:11:11,180 YOU LOOK AT THE LEFT THAT THESE 272 00:11:11,180 --> 00:11:12,482 SURVIVAL CURVES ALL COME TO THE 273 00:11:12,482 --> 00:11:13,783 BOTTOM. 274 00:11:13,783 --> 00:11:16,419 NO ONE IS CURED, NO ONE HAS 275 00:11:16,419 --> 00:11:17,086 LONG-TERM PLATEAU OR SURVIVAL 276 00:11:17,086 --> 00:11:18,488 AND IT DOESN'T MATTER WHICH OF 277 00:11:18,488 --> 00:11:20,690 THE DIFFERENT DRUGS ONE USED. 278 00:11:20,690 --> 00:11:21,791 THE ONE YEAR SURVIVAL FOR THIS 279 00:11:21,791 --> 00:11:23,626 DISEASE IN THE METASTATIC 280 00:11:23,626 --> 00:11:24,661 SETTING WHEN PRESENTED MORE THAN 281 00:11:24,661 --> 00:11:27,030 HALF THE TIME WAS 33% AND MEDIAN 282 00:11:27,030 --> 00:11:28,665 SURVIVAL LESS THAN 8 MONTHS. 283 00:11:28,665 --> 00:11:32,936 HERE'S THE PROGRESSION, EVEN 284 00:11:32,936 --> 00:11:33,269 WORSE. 285 00:11:33,269 --> 00:11:35,338 IT WAS CLEAR THAT A NEW PARADIGM 286 00:11:35,338 --> 00:11:36,539 SHIFT WAS NEEDED. 287 00:11:36,539 --> 00:11:38,408 NOW I'M GOING TO GIVE YOU THE 288 00:11:38,408 --> 00:11:39,075 PUNCH LINE FIRST. 289 00:11:39,075 --> 00:11:40,343 WE ARE MAKING A DIFFERENCE 290 00:11:40,343 --> 00:11:42,445 THROUGH ALL OF OUR COMBINED 291 00:11:42,445 --> 00:11:44,747 EFFORTS, SCIENCE, CLINIC, BACK 292 00:11:44,747 --> 00:11:47,583 AND FORTH, YOU CAN SEE HERE'S 293 00:11:47,583 --> 00:11:48,584 LUNG CANCER MORTALITY OVER TIME 294 00:11:48,584 --> 00:11:49,986 WITH MEN, AND YOU CAN SEE THAT 295 00:11:49,986 --> 00:11:52,855 IT PEAKED IN 1990, WHEN IT'S 296 00:11:52,855 --> 00:11:54,590 COMING DOWN, AND FOR WOMEN, THE 297 00:11:54,590 --> 00:11:57,327 PEAK IS A LITTLE BIT LATER. 298 00:11:57,327 --> 00:11:59,195 INTERESTINGLY, WOMEN SMOKED -- 299 00:11:59,195 --> 00:12:00,930 THE PUSH TO ADVERTISE TO WOMEN 300 00:12:00,930 --> 00:12:04,667 FOR SMOKING CAME AFTER MEN, SO 301 00:12:04,667 --> 00:12:06,536 THE FEMALE PEAK IN LUNG CANCER 302 00:12:06,536 --> 00:12:07,804 CAME A LITTLE LATER, IT'S ALSO 303 00:12:07,804 --> 00:12:08,171 COMING DOWN. 304 00:12:08,171 --> 00:12:10,573 YOU CAN SEE FROM THE AMERICAN 305 00:12:10,573 --> 00:12:12,642 CANCER SOCIETY, THE ONE ON 306 00:12:12,642 --> 00:12:14,010 PAPER, YOU CAN SEE THE INCIDENCE 307 00:12:14,010 --> 00:12:16,679 COMES DOWN BY 2.6% A YEAR IN MEN 308 00:12:16,679 --> 00:12:18,815 BUT THE MORTALITY OF 4.3, SO 309 00:12:18,815 --> 00:12:21,050 IT'S NOT JUST INCIDENCE, COULD 310 00:12:21,050 --> 00:12:22,151 OF COURSE BE AFFECTED BY 311 00:12:22,151 --> 00:12:23,019 PREVENTION AND SCREENING, BUT 312 00:12:23,019 --> 00:12:25,221 IT'S ALSO MORTALITY, COMING DOWN 313 00:12:25,221 --> 00:12:28,491 FOR WOMEN, 1.2% IN INCIDENCE AND 314 00:12:28,491 --> 00:12:29,592 3.1% IN MORTALITY. 315 00:12:29,592 --> 00:12:30,793 I WOULD MAKE THE CASE THAT MOST 316 00:12:30,793 --> 00:12:33,763 OF THIS IS TARGETED THERAPY 317 00:12:33,763 --> 00:12:36,366 WORK, AND SOME OF THE EARLY 318 00:12:36,366 --> 00:12:38,134 RESULTS OF IMMUNOTHERAPY, I'LL 319 00:12:38,134 --> 00:12:39,002 SHOW YOU A LITTLE BIT ABOUT 320 00:12:39,002 --> 00:12:41,404 BOTH. 321 00:12:41,404 --> 00:12:43,373 SO I'M JUST GOING TO TRY TO KEEP 322 00:12:43,373 --> 00:12:46,376 TO TIME BECAUSE KATY IS RIGHT AT 323 00:12:46,376 --> 00:12:47,543 MY SIDE HERE, WE'RE SHARING THIS 324 00:12:47,543 --> 00:12:47,977 PRESENTATION. 325 00:12:47,977 --> 00:12:49,712 I WILL TELL YOU ABOUT SOME 326 00:12:49,712 --> 00:12:51,247 ADVANCES IN TARGETED THERAPY, 327 00:12:51,247 --> 00:12:52,548 THEN IMMUNOTHERAPY AND THEN SOME 328 00:12:52,548 --> 00:12:53,549 THOUGHTS ON THE FUTURE, WHICH 329 00:12:53,549 --> 00:12:55,518 REALLY IS WHAT WE'RE DOING IN 330 00:12:55,518 --> 00:13:02,825 OUR SPONSORED RESEARCH. 331 00:13:02,825 --> 00:13:05,261 SO TARGETED THERAPY, YOU SAW MY 332 00:13:05,261 --> 00:13:08,297 BACKGROUND WHEN I STARTED OUT IN 333 00:13:08,297 --> 00:13:09,632 MD ANDERSON, THAT WAS THE ADVENT 334 00:13:09,632 --> 00:13:12,068 OF EGFR INHIBITORS. 335 00:13:12,068 --> 00:13:14,470 EGFR, THE RECEPTOR WAS ACTUALLY 336 00:13:14,470 --> 00:13:16,506 FIRST DESCRIBED AND THE 337 00:13:16,506 --> 00:13:18,474 STRUCTURE FIGURED OUT 40 YEARS 338 00:13:18,474 --> 00:13:18,841 AGO. 339 00:13:18,841 --> 00:13:20,676 WE ACTUALLY JUST HAD A MEETING 340 00:13:20,676 --> 00:13:24,380 AT THE ROYAL SOCIETY IN DECEMBER 341 00:13:24,380 --> 00:13:25,581 COMMEMORATING THAT. 342 00:13:25,581 --> 00:13:30,620 AND IN 1998, THE FIRST SMALL 343 00:13:30,620 --> 00:13:32,155 MOLECULE TYROSINE KINASE 344 00:13:32,155 --> 00:13:33,022 INHIBITORS WERE GOING INTO 345 00:13:33,022 --> 00:13:33,389 CLINICAL TRIAL. 346 00:13:33,389 --> 00:13:35,525 THIS WAS A DRUG WITH A DRUG 347 00:13:35,525 --> 00:13:38,294 KNOWN AS ZD1839, AND YOU CAN SEE 348 00:13:38,294 --> 00:13:39,595 THAT THIS DRUG TOOK PATIENTS 349 00:13:39,595 --> 00:13:41,998 WITH WIDELY METASTATIC LUNG 350 00:13:41,998 --> 00:13:43,433 CANCER, THIS IS A PATIENT SHOWN 351 00:13:43,433 --> 00:13:44,834 HERE ON THE LEFT WHO WOULD 352 00:13:44,834 --> 00:13:46,602 HARDLY HAVE BEEN ABLE TO 353 00:13:46,602 --> 00:13:48,671 BREATHE, AND WITHIN WEEKS ON 354 00:13:48,671 --> 00:13:52,175 THIS ORAL TKI, A WONDERFUL 355 00:13:52,175 --> 00:13:52,508 RESPONSE. 356 00:13:52,508 --> 00:13:54,377 THIS IS ACTUALLY ONE OF THE VERY 357 00:13:54,377 --> 00:13:55,912 FIRST PHASE ONE TRIALS OF THESE 358 00:13:55,912 --> 00:13:57,847 DRUGS ACTUALLY LED THIS TRIAL 359 00:13:57,847 --> 00:14:02,318 WITH MY NOW YALE COLLEAGUE PAT 360 00:14:02,318 --> 00:14:02,552 LARUSO. 361 00:14:02,552 --> 00:14:05,088 IT WAS NOT UNTIL 2004, SO THAT 362 00:14:05,088 --> 00:14:06,389 WAS 1998, SO FOR SIX YEARS, WE 363 00:14:06,389 --> 00:14:11,094 KNEW THAT THESE SMALL MOLECULE 364 00:14:11,094 --> 00:14:13,496 TGIs AGAINST THE EGFR RECEPTOR 365 00:14:13,496 --> 00:14:15,465 WORKED BETTER IN SMOKERS AMONG 366 00:14:15,465 --> 00:14:18,734 WOMEN AND ASIANS, BUP IT WASN'T 367 00:14:18,734 --> 00:14:20,269 UNTIL IT WAS DESCRIBED BY GROUPS 368 00:14:20,269 --> 00:14:22,205 IN BOSTON AND NEW YORK KNOWING 369 00:14:22,205 --> 00:14:27,076 THAT IT HAS AN EXTERNAL DOMAIN, 370 00:14:27,076 --> 00:14:31,147 TUMOR GROWTH FACTOR ALPHA, AND 371 00:14:31,147 --> 00:14:33,950 THE INTERNAL TYROSINE KINASE 372 00:14:33,950 --> 00:14:35,384 DOMAIN WHERE THE BINDING PACKETS 373 00:14:35,384 --> 00:14:38,054 SHOWN HERE WHICH WHEN 374 00:14:38,054 --> 00:14:39,655 PHOSPHORYLATED, ATP BOUND, THAT 375 00:14:39,655 --> 00:14:44,026 SETS OFF SIGNAL TRANSDUCTION, IT 376 00:14:44,026 --> 00:14:46,429 WAS FOUND CANONICAL EGFR 377 00:14:46,429 --> 00:14:47,630 MUTATIONS WERE FOUND IN THESE 378 00:14:47,630 --> 00:14:49,165 PATIENTS WHO RESPONDED WELL THAT 379 00:14:49,165 --> 00:14:51,567 RESULTED IN A POCKET HERE WHERE 380 00:14:51,567 --> 00:14:53,803 THE SMALL MOLECULES BOUND 381 00:14:53,803 --> 00:14:56,472 ESPECIALLY WELL, AND RESULTED IN 382 00:14:56,472 --> 00:14:59,008 THE TURNING OFF OF AN ADDICTED 383 00:14:59,008 --> 00:15:00,143 RECEPTOR. 384 00:15:00,143 --> 00:15:02,044 AT MD ANDERSON, WE HAD MANY 385 00:15:02,044 --> 00:15:04,046 PATIENTS WHO WOULD FLY IN FOR 386 00:15:04,046 --> 00:15:06,215 THESE CLINICAL TRIALS. 387 00:15:06,215 --> 00:15:07,416 SECILY ON THE RIGHT WAS ONE OF 388 00:15:07,416 --> 00:15:08,518 OUR VERY FIRST PATIENTS ON THIS 389 00:15:08,518 --> 00:15:09,385 TRIAL WITH HER HUSBAND SHOWN 390 00:15:09,385 --> 00:15:09,619 HERE. 391 00:15:09,619 --> 00:15:12,221 THIS WAS AN ARTICLE WRITTEN FOR 392 00:15:12,221 --> 00:15:13,856 "THE WALL STREET JOURNAL" IN 393 00:15:13,856 --> 00:15:15,525 2003, WHY CURING YOUR CANCER MAY 394 00:15:15,525 --> 00:15:17,827 NOT BE THE BEST IDEA. 395 00:15:17,827 --> 00:15:20,229 THE WHOLE IDEA IS WHILE YOU MAY 396 00:15:20,229 --> 00:15:22,832 NOT CURE LUNG CANCER WITH THESE 397 00:15:22,832 --> 00:15:24,267 AGENTS, YOU CAN LIVE WITH THIS. 398 00:15:24,267 --> 00:15:27,336 HERE'S SOMEONE LIVING QUITE 399 00:15:27,336 --> 00:15:28,838 WELL, SO IT WAS A WHOLE NEW 400 00:15:28,838 --> 00:15:30,173 PARADIGM FOR LUNG CANCER. 401 00:15:30,173 --> 00:15:32,375 TARGETED THERAPY, ORAL THERAPY, 402 00:15:32,375 --> 00:15:33,676 CHRONIC THERAPY. 403 00:15:33,676 --> 00:15:35,745 WELL, AGAIN, A SHORT TALK HERE 404 00:15:35,745 --> 00:15:37,380 TODAY, BUT THE CHEMISTRY HERE 405 00:15:37,380 --> 00:15:39,148 WENT FROM FIRST GENERATION 406 00:15:39,148 --> 00:15:41,984 DRUGS, WHICH WERE REVERSE 407 00:15:41,984 --> 00:15:43,186 INHIBITORS THAT TARGETED WILD 408 00:15:43,186 --> 00:15:46,155 TYPE EGFR. 409 00:15:46,155 --> 00:15:48,324 MOSTLY SENSITIVE WERE THE X I-19 410 00:15:48,324 --> 00:15:52,929 DELETION OR THE -- TO A SECOND 411 00:15:52,929 --> 00:15:57,066 GENERATION OF DRUGS WHICH WERE 412 00:15:57,066 --> 00:16:01,437 IRREVERSIBLE, SO TARGETING MORE 413 00:16:01,437 --> 00:16:02,672 HER RECEPTORS, SO MAYBE A LITTLE 414 00:16:02,672 --> 00:16:06,375 BIT MORE POTENT BUT CERTAINLY 415 00:16:06,375 --> 00:16:09,212 MORE TOXIC TO THE THIRD 416 00:16:09,212 --> 00:16:11,013 GENERATION DRUG SHOWN TO BE 417 00:16:11,013 --> 00:16:13,082 SUPERIOR TO THE OTHERS, COVALENT 418 00:16:13,082 --> 00:16:15,351 AND REVERSIBLE INHIBITOR BUT 419 00:16:15,351 --> 00:16:22,124 IT'S EGFR MUTATION -- IT'S LESS 420 00:16:22,124 --> 00:16:24,961 SPECIFIC, T790M, THE MOST COMMON 421 00:16:24,961 --> 00:16:27,597 FORM OF PRIMARY EGFR RESISTANCE. 422 00:16:27,597 --> 00:16:29,298 WE WERE A MD ANDERSON AT THE 423 00:16:29,298 --> 00:16:30,533 TIME, ME AND MY GROUP AND WE 424 00:16:30,533 --> 00:16:31,834 STARTED TO USE THESE DRUGS AS 425 00:16:31,834 --> 00:16:33,069 WELL AS OTHER DRUGS IN LUNG 426 00:16:33,069 --> 00:16:33,402 CANCER. 427 00:16:33,402 --> 00:16:34,937 AND THE IDEA WAS THAT IF YOU'RE 428 00:16:34,937 --> 00:16:36,439 GOING TO DO IT, TISSUE WAS THE 429 00:16:36,439 --> 00:16:36,906 ISSUE. 430 00:16:36,906 --> 00:16:41,143 YOU HAD TO HAVE BIOPSIES SO THIS 431 00:16:41,143 --> 00:16:43,012 ASK A STUDY THAT ACTUALLY IS NOW 432 00:16:43,012 --> 00:16:45,081 ABOUT 14 YEARS OLD FOR CALLED 433 00:16:45,081 --> 00:16:47,617 THE BATTLE STUDY, WHICH REALLY 434 00:16:47,617 --> 00:16:50,886 USED CORE TISSUE BIOPSIES INTO 435 00:16:50,886 --> 00:16:52,188 LUNG TUMORS TO ACTUALLY USE 436 00:16:52,188 --> 00:16:53,422 THOSE DATA TO DECIDE HOW TO 437 00:16:53,422 --> 00:16:53,823 TREAT PATIENTS. 438 00:16:53,823 --> 00:16:56,359 IT WAS LED BY A TEAM SHOWN HERE, 439 00:16:56,359 --> 00:17:05,434 A SENIOR MEMBER WAS T AND JACK , 440 00:17:05,434 --> 00:17:06,969 OUR STATISTICIAN, WE USED 441 00:17:06,969 --> 00:17:09,805 ADAPTIVE STATISTICS. 442 00:17:09,805 --> 00:17:14,844 AND IT WAS BATTLE FOR LUNG 443 00:17:14,844 --> 00:17:15,278 CANCER ELIMINATION. 444 00:17:15,278 --> 00:17:18,114 WHAT HAPPENED BACK IN 14, 15 445 00:17:18,114 --> 00:17:19,715 YEARS AGO IS WE REALIZED THAT 446 00:17:19,715 --> 00:17:20,650 CORE BIOPSIES ARE FEASIBLE AND 447 00:17:20,650 --> 00:17:21,083 SAFE. 448 00:17:21,083 --> 00:17:23,052 WE CAN GET BIOMARKER RESULTS IN 449 00:17:23,052 --> 00:17:23,819 A FEW WEEKS. 450 00:17:23,819 --> 00:17:25,454 DRUGS CAN BE USED WITH MULTIPLE 451 00:17:25,454 --> 00:17:27,223 STUDIES AND COMPANIES. 452 00:17:27,223 --> 00:17:29,625 SO THIS WAS THE ERA OF TARGETED 453 00:17:29,625 --> 00:17:31,927 THERAPY IN LUNG KUHN SER. 454 00:17:31,927 --> 00:17:32,461 CANCER. 455 00:17:32,461 --> 00:17:35,631 I'M GOING TO SHOW YOU SOME OF 456 00:17:35,631 --> 00:17:37,333 THE DATA NOW. 457 00:17:37,333 --> 00:17:39,468 ONCE WE HAD THE FIRST GENERATION 458 00:17:39,468 --> 00:17:41,337 TKIs, THE SECOND GENERATION 459 00:17:41,337 --> 00:17:42,305 TKIs WERE DEVELOPED AND THE 460 00:17:42,305 --> 00:17:43,172 REASON WHY THEY WERE IMPORTANT 461 00:17:43,172 --> 00:17:44,607 IS THEY WORKED IN PATIENTS WHO 462 00:17:44,607 --> 00:17:46,676 HAD RESISTANCE TO THE FIRST 463 00:17:46,676 --> 00:17:48,010 GENERATION AND AS I SAID ABOUT 464 00:17:48,010 --> 00:17:53,549 HALF THE RESISTANCE IS DUE TO 465 00:17:53,549 --> 00:17:54,116 C790M. 466 00:17:54,116 --> 00:18:02,525 SO OSIMERTINIB IS A 467 00:18:02,525 --> 00:18:03,526 T790-MILLIMETER SENSITIVE DRUG, 468 00:18:03,526 --> 00:18:05,494 HERE'S A WATERFALL PLOT OF 469 00:18:05,494 --> 00:18:08,431 PATIENTS ALL RESISTANT TO FIRST 470 00:18:08,431 --> 00:18:09,565 GENERATION WITH WONDERFUL 471 00:18:09,565 --> 00:18:14,203 RESPONSE TO THE OS MERT ANYBODY. 472 00:18:14,203 --> 00:18:16,339 THIS DRUG BECAME APPROVED IN A 473 00:18:16,339 --> 00:18:17,406 SECOND LINE SETTING INITIALLY 474 00:18:17,406 --> 00:18:18,541 BUT STILL FEW IF ANY PATIENTS 475 00:18:18,541 --> 00:18:24,914 WERE CURED BECAUSE RESISTANCE 476 00:18:24,914 --> 00:18:26,549 DEVELOPS AS YOU'LL HEAR IN KATY 477 00:18:26,549 --> 00:18:27,416 IN A LITTLE WHILE. 478 00:18:27,416 --> 00:18:29,051 THIS WAS THE MAN WHO WAS NEXT TO 479 00:18:29,051 --> 00:18:35,124 THE WOMAN BEFORE HE PASSED AWAY. 480 00:18:35,124 --> 00:18:37,126 HE ALLOWED ME TO USE HIS PICTURE 481 00:18:37,126 --> 00:18:37,526 10 YEARS LATER. 482 00:18:37,526 --> 00:18:40,062 HE LIVED TO THE RIPE OLD AGE OF 483 00:18:40,062 --> 00:18:41,797 95, YOU ALSO HAD LUNG CAN JER 484 00:18:41,797 --> 00:18:44,533 AND GOT THE OSIMERTINIB AND HE 485 00:18:44,533 --> 00:18:46,502 DID NOT DIE OF HIS LUNG CANCER. 486 00:18:46,502 --> 00:18:48,738 THIS IS HIS 70-PLUS-YEAR-OLD SON 487 00:18:48,738 --> 00:18:49,672 AND THIS IS, OF COURSE, ME. 488 00:18:49,672 --> 00:18:51,107 SO I DON'T WANT TO TAKE TOO 489 00:18:51,107 --> 00:18:53,542 LONG, BUT CUTTING TO THE CHASE, 490 00:18:53,542 --> 00:18:55,578 IT WAS DETERMINED THAT 491 00:18:55,578 --> 00:18:56,645 OSIMERTINIB WAS BETTER THAN THE 492 00:18:56,645 --> 00:18:59,849 FIRST AND SECOND GENERATION 493 00:18:59,849 --> 00:19:00,082 DRUGS. 494 00:19:00,082 --> 00:19:01,317 THEN THE THING I WANT TO SHOW 495 00:19:01,317 --> 00:19:04,453 YOU IS THE BIG ADVANCE IN THE 496 00:19:04,453 --> 00:19:05,254 LAST FOUR YEARS IS THAT NOW THE 497 00:19:05,254 --> 00:19:06,856 DRUG WAS TAKEN TO EARLIER STAGE 498 00:19:06,856 --> 00:19:07,289 DISEASE. 499 00:19:07,289 --> 00:19:09,158 SO IN LUNG CANCER, I'VE BEEN 500 00:19:09,158 --> 00:19:10,793 TELLING YOU ABOUT ADVANCED 501 00:19:10,793 --> 00:19:13,095 METASTATIC DISEASE, BUT IN EARLY 502 00:19:13,095 --> 00:19:13,696 DISEASE, STAGE I DISEASE WHERE 503 00:19:13,696 --> 00:19:15,698 YOU FIND A SMALL TUMOR AND IT'S 504 00:19:15,698 --> 00:19:17,333 CUT OUT, STAGE II DISEASE WHERE 505 00:19:17,333 --> 00:19:19,435 YOU HAVE A TUMOR ALSO CUT OUT 506 00:19:19,435 --> 00:19:25,341 BUT SOME EARLY LYMPH NODES, 507 00:19:25,341 --> 00:19:28,210 INTRAPARENCHYMAL LYMPH NODES OR 508 00:19:28,210 --> 00:19:30,813 STAGE III, MORE DEEP MEDIASTINAL 509 00:19:30,813 --> 00:19:32,448 LYMPH NODES, IN STAGE ONE THE 510 00:19:32,448 --> 00:19:33,749 FIVE-YEAR SURVIVAL RATE IS ONLY 511 00:19:33,749 --> 00:19:34,183 60%. 512 00:19:34,183 --> 00:19:36,051 IN STAGE TWO IT'S 47%. 513 00:19:36,051 --> 00:19:38,020 STAGE III, IT'S 38%. 514 00:19:38,020 --> 00:19:44,160 SO ALL THESE PATIENTS, WHY WOULD 515 00:19:44,160 --> 00:19:48,431 WE NOT USE AN EGFR INHIBITOR TO 516 00:19:48,431 --> 00:19:50,266 PREVENT THEM FROM DEVELOPING 517 00:19:50,266 --> 00:19:50,699 METASTASES? 518 00:19:50,699 --> 00:19:53,002 THIS WAS A TRIAL WE STARTED 519 00:19:53,002 --> 00:19:53,536 ABOUT 12 YEARS AGO. 520 00:19:53,536 --> 00:19:56,405 WE HAVE PATIENTS WITH COMPLETELY 521 00:19:56,405 --> 00:19:59,041 RESECTED STAGE I, B2 AND 3A 522 00:19:59,041 --> 00:20:01,544 LOCAL LUNG CANCER WHO MAY OR MAY 523 00:20:01,544 --> 00:20:04,814 NOT HAVE RECEIVED ADJUVANT 524 00:20:04,814 --> 00:20:05,781 CHEMOTHERAPY, 5% IMPROVEMENT IN 525 00:20:05,781 --> 00:20:06,882 SURVIVAL. 526 00:20:06,882 --> 00:20:10,953 ALL THESE PATIENTS HAD THAT EGFR 527 00:20:10,953 --> 00:20:14,757 MUTATION, THEY HAD TO HAVE BRAIN 528 00:20:14,757 --> 00:20:17,059 IMAGING, THEY HAD TO HAVE 529 00:20:17,059 --> 00:20:19,261 COMPLETED RESECTION AND THEY HAD 530 00:20:19,261 --> 00:20:20,229 A CERTAIN AMOUNT OF TIME THAT 531 00:20:20,229 --> 00:20:22,198 THEY COULD WAIT, 10 WEEKS 532 00:20:22,198 --> 00:20:23,532 WITHOUT ADJUVANT THERAPY BEFORE 533 00:20:23,532 --> 00:20:25,334 STARTING THE OSIMERTINIB OR 26 534 00:20:25,334 --> 00:20:28,637 WEEKS WITH THE ADJUVANT THERAPY. 535 00:20:28,637 --> 00:20:29,972 PRESSURE WAS STRATIFIED BY STAGE 536 00:20:29,972 --> 00:20:32,107 SO EQUAL NUMBER OF EACH OF THE 537 00:20:32,107 --> 00:20:34,577 THREE STAGES ON THE STUDY. 538 00:20:34,577 --> 00:20:37,313 BY MUTATION TYPE, 19 OR 21. 539 00:20:37,313 --> 00:20:39,815 SO BETWEEN THE TWO GROUPS, AND 540 00:20:39,815 --> 00:20:41,884 RACE, ASIAN VERSUS NON-ASIAN, 541 00:20:41,884 --> 00:20:44,086 EGFR MUTATIONS ARE ABOUT 30% IN 542 00:20:44,086 --> 00:20:45,721 ASIA AND 10% PREVALENT IN THE 543 00:20:45,721 --> 00:20:48,357 WESTERN WORLD, WE WANTED TO SORT 544 00:20:48,357 --> 00:20:50,326 OF RANDOMIZE IN A WAY THAT THERE 545 00:20:50,326 --> 00:20:51,293 WAS A STRATIFICATION. 546 00:20:51,293 --> 00:20:53,362 SO EACH ARM HAD THE SAME NUMBER 547 00:20:53,362 --> 00:20:54,730 OF ASIAN VERSUS NON-ASIAN 548 00:20:54,730 --> 00:20:55,130 PATIENTS. 549 00:20:55,130 --> 00:20:57,533 PATIENTS WERE RANDOMIZED 1 TO 550 00:20:57,533 --> 00:20:59,835 1 THROUGH EITHER OSIMERTINIB AT 551 00:20:59,835 --> 00:21:01,704 80 MILLIGRAMS OR A PLACEBO 552 00:21:01,704 --> 00:21:03,973 BECAUSE EGFR INHIBITORS WERE 553 00:21:03,973 --> 00:21:05,207 NEVER USED IN THE EARLY STAGE 554 00:21:05,207 --> 00:21:06,175 SETTING. 555 00:21:06,175 --> 00:21:08,043 THESE PATIENTS WERE AT HIGH RISK 556 00:21:08,043 --> 00:21:09,044 OF RECURRENCE ESPECIALLY TO 557 00:21:09,044 --> 00:21:10,112 BRAIN, LIVER AND BONE. 558 00:21:10,112 --> 00:21:11,947 THE PLANNED TREATMENT DURATION 559 00:21:11,947 --> 00:21:12,515 WAS THREE YEARS. 560 00:21:12,515 --> 00:21:13,849 SHOULD THEY HAVE GOTTEN LONGER 561 00:21:13,849 --> 00:21:15,351 OR LESS, I'LL SHOW YOU THAT IN A 562 00:21:15,351 --> 00:21:20,289 MOMENT, AND WE FOLLOWED THEM UP 563 00:21:20,289 --> 00:21:23,659 EVERY 12 AND 24 WEEKS. 564 00:21:23,659 --> 00:21:26,529 NOW, THE STUDY WAS POWERED FOR 565 00:21:26,529 --> 00:21:27,496 DISEASE-FREE SURVIVAL, FOR A 566 00:21:27,496 --> 00:21:30,032 HAZARD RATIO OF .7, MEANING FOR 567 00:21:30,032 --> 00:21:31,667 A 30% IMPROVEMENT. 568 00:21:31,667 --> 00:21:34,737 AND ACTUALLY EXACTLY FIVE YEARS 569 00:21:34,737 --> 00:21:40,509 AGO TODAY, BECAUSE OF THE 570 00:21:40,509 --> 00:21:42,378 PANDEMIC, I GOT A CALL THAT THE 571 00:21:42,378 --> 00:21:43,646 DEAFT SAFETY MONITORING 572 00:21:43,646 --> 00:21:44,313 COMMITTEE WANTED TO STOP THIS 573 00:21:44,313 --> 00:21:44,580 TRIAL. 574 00:21:44,580 --> 00:21:46,749 I WAS LIKE OH, GOSH, IS IT 575 00:21:46,749 --> 00:21:47,516 REALLY THAT BAD? 576 00:21:47,516 --> 00:21:49,818 BECAUSE NORMALLY WHEN A TRIAL IS 577 00:21:49,818 --> 00:21:51,554 STOPPED EARLY, IT'S A PROBLEM. 578 00:21:51,554 --> 00:21:53,856 AND ACTUALLY THEY SAID NO, WE 579 00:21:53,856 --> 00:21:55,858 ACTUALLY WERE DOING A SAFETY 580 00:21:55,858 --> 00:21:57,092 ANALYSIS AND LOOKED AT THE 581 00:21:57,092 --> 00:21:58,994 OUTCOME DATA AND IT'S LOOKING SO 582 00:21:58,994 --> 00:22:00,195 POSITIVE, WE FEEL WE HAVE TO LET 583 00:22:00,195 --> 00:22:00,663 YOU KNOW. 584 00:22:00,663 --> 00:22:02,598 SO AFTER SOME DISCUSSION, WE 585 00:22:02,598 --> 00:22:04,266 AGREED TO OPEN UP AND LOOK AT 586 00:22:04,266 --> 00:22:05,668 THE DATA AND THE INVESTIGATORS, 587 00:22:05,668 --> 00:22:08,404 I HAVE TWO OTHER PRINCIPAL 588 00:22:08,404 --> 00:22:09,738 INVESTIGATORS ON THIS, ONE FROM 589 00:22:09,738 --> 00:22:15,511 CHINA, DR. WU, ONE FROM JAPAN, 590 00:22:15,511 --> 00:22:16,412 DR. SUBAI, WE UNBLINDED THE 591 00:22:16,412 --> 00:22:16,779 TRIAL. 592 00:22:16,779 --> 00:22:19,114 THIS IS WHAT WE SAW ON THE LEFT. 593 00:22:19,114 --> 00:22:21,650 NOW LOOK, YOU'RE GIVING AN EGFR 594 00:22:21,650 --> 00:22:23,185 INHIBITOR VERSUS A PLACEBO IN 595 00:22:23,185 --> 00:22:24,386 THE ADJUVANT SETTING TO PATIENTS 596 00:22:24,386 --> 00:22:25,588 YOU KNOW ARE GOING TO RECUR. 597 00:22:25,588 --> 00:22:26,789 OF COURSE IT WAS GOING TO BE A 598 00:22:26,789 --> 00:22:27,456 POSITIVE TRIAL. 599 00:22:27,456 --> 00:22:28,424 WE EXPECTED THAT. 600 00:22:28,424 --> 00:22:29,525 BUT DID WE EXPECT THAT THE 601 00:22:29,525 --> 00:22:31,827 HAZARD RATIO WOULD BE .2, THAT 602 00:22:31,827 --> 00:22:33,362 THE BLUE CURVE WHERE PATIENTS 603 00:22:33,362 --> 00:22:34,563 GOT OSIMERTINIB VERSUS THE 604 00:22:34,563 --> 00:22:35,864 YELLOW WHERE THEY HAD THE 605 00:22:35,864 --> 00:22:37,499 CONTROL WOULD HAVE AN 80% 606 00:22:37,499 --> 00:22:38,267 IMPROVEMENT? 607 00:22:38,267 --> 00:22:41,103 IT EXCEEDED EXPECTATIONS. 608 00:22:41,103 --> 00:22:42,471 THIS WAS AT AN EARLY MATURITY, 609 00:22:42,471 --> 00:22:44,073 WE WERE WAITING FOR 50% OF THE 610 00:22:44,073 --> 00:22:46,241 EVENTS, THAT WAS WHAT THE 611 00:22:46,241 --> 00:22:49,545 STATISTICAL PLAN FOR CALLED FOR, 612 00:22:49,545 --> 00:22:54,049 BUT EVEN THOAL ASCO WAS FIVE OR 613 00:22:54,049 --> 00:22:56,218 SIX WEEKS AWAY, IT MADE TO THE 614 00:22:56,218 --> 00:22:59,722 PLEP REOF ASCO THAT YEAR. 615 00:22:59,722 --> 00:23:03,092 YOU CAN SEE EVEN WITH THE FULL 616 00:23:03,092 --> 00:23:04,893 MATURITY NOW, 45-PLUS PERCENT, 617 00:23:04,893 --> 00:23:08,030 THE HAZARD RATIO IS .27 OR 73% 618 00:23:08,030 --> 00:23:09,431 IMPROVEMENT IN DISEASE-FREE 619 00:23:09,431 --> 00:23:10,866 SURVIVAL FOR THE OSIMERTINIB IN 620 00:23:10,866 --> 00:23:13,268 BLUE VERSUS THE CONTROL. 621 00:23:13,268 --> 00:23:15,237 BUT THERE WERE STILL MANY 622 00:23:15,237 --> 00:23:18,073 SKEPTICS WHO SAID WHERE'S THE 623 00:23:18,073 --> 00:23:18,841 SURVIVAL? 624 00:23:18,841 --> 00:23:19,742 WELL, WHILE WE WERE WAITING FOR 625 00:23:19,742 --> 00:23:21,710 THE SURVIVAL DATA TO MATURE, WE 626 00:23:21,710 --> 00:23:24,546 HAD A SECONDARY END POINT OF 627 00:23:24,546 --> 00:23:28,584 BRAIN AS THE FIRST TYPE OF 628 00:23:28,584 --> 00:23:28,884 RECURRENCE. 629 00:23:28,884 --> 00:23:30,986 PATIENTS WITH EGFR MUTANT 630 00:23:30,986 --> 00:23:32,087 DISEASE, ANYONE WITH TARGETED 631 00:23:32,087 --> 00:23:34,823 THERAPY THE BIGGEST CONCERN IS 632 00:23:34,823 --> 00:23:36,125 METASTASES AND TO THE BRAIN. 633 00:23:36,125 --> 00:23:38,327 SO WE'RE LOOKING IN BLUE AS 634 00:23:38,327 --> 00:23:39,528 BRAIN IS THE FIRST SITE OF 635 00:23:39,528 --> 00:23:42,698 RECURRENCE VERSUS ON OSIMERTINIB 636 00:23:42,698 --> 00:23:44,066 IN BLUE VERSUS BRAIN AT THE 637 00:23:44,066 --> 00:23:46,402 FIRST SITE ON CONTROL IN THE 638 00:23:46,402 --> 00:23:46,735 PLACEBO. 639 00:23:46,735 --> 00:23:48,871 YOU CAN SEE THE HAZARD RATIO IS 640 00:23:48,871 --> 00:23:50,773 .24 OR A 76% LESS CHANCE THE 641 00:23:50,773 --> 00:23:52,241 PATIENT IS GOING TO DEVELOP THE 642 00:23:52,241 --> 00:23:53,208 BRAIN AS THE FIRST SITE OF 643 00:23:53,208 --> 00:23:53,642 RECURRENCE. 644 00:23:53,642 --> 00:23:56,378 SO THIS WAS PRETTY GOOD, AND THE 645 00:23:56,378 --> 00:23:57,913 DRUG WAS ALREADY APPROVED SINCE 646 00:23:57,913 --> 00:23:58,981 2020, BUT THEN EVERYONE IS 647 00:23:58,981 --> 00:24:00,182 SAYING WHAT ABOUT SURVIVAL? 648 00:24:00,182 --> 00:24:02,051 NOW AS THE PI OF A TRIAL, A 649 00:24:02,051 --> 00:24:03,585 CLINICAL TRIAL, SURVIVAL HAPPENS 650 00:24:03,585 --> 00:24:04,787 WHEN YOU HAVE CERTAIN EVENTS SO 651 00:24:04,787 --> 00:24:06,321 YOU DON'T WANT TO WISH IT ANY 652 00:24:06,321 --> 00:24:08,624 FASTER THAN YOU HAVE TO, BECAUSE 653 00:24:08,624 --> 00:24:10,259 PEOPLE WILL HAVE TO HAVE THEIR 654 00:24:10,259 --> 00:24:11,660 SURVIVAL EVENT. 655 00:24:11,660 --> 00:24:14,396 BUT IN TIME FOR AS CO2 YEARS 656 00:24:14,396 --> 00:24:15,731 AGO, WE GOT THESE DATA AND THIS 657 00:24:15,731 --> 00:24:17,232 WAS THE SURVIVAL CURVE AND AS 658 00:24:17,232 --> 00:24:19,101 YOU CAN SEE, THE BLUE CURVE ARE 659 00:24:19,101 --> 00:24:20,335 PATIENTS AND THIS IS OVERALL 660 00:24:20,335 --> 00:24:22,071 SURVIVAL NOW, THE BLUE CURVE -- 661 00:24:22,071 --> 00:24:23,272 I'M SORRY -- THE BLUE CURVE ARE 662 00:24:23,272 --> 00:24:24,907 THE PATIENTS WHO GOT THE 663 00:24:24,907 --> 00:24:26,341 OSIMERTINIB VERSUS THE YELLOW IS 664 00:24:26,341 --> 00:24:28,210 THE CONTROL, YOU CAN SEE THE A 665 00:24:28,210 --> 00:24:29,945 FIVE YEARS, 88% VERSUS 78% 666 00:24:29,945 --> 00:24:30,479 SURVIVING. 667 00:24:30,479 --> 00:24:32,681 THE HAZARD RATIO .49. 668 00:24:32,681 --> 00:24:35,751 AND YOU KNOW, THE GOAL OF THE 669 00:24:35,751 --> 00:24:38,487 LAST NCI DIRECTOR OR TWO NCI 670 00:24:38,487 --> 00:24:40,022 DIRECTORS AGO WAS 50% OR MORE 671 00:24:40,022 --> 00:24:41,423 IMPROVEMENT IN CANCER SURVIVAL, 672 00:24:41,423 --> 00:24:42,858 I THINK THAT WAS MONICA, SO WE 673 00:24:42,858 --> 00:24:45,027 ACTUALLY HIT THAT IN THIS SMALL 674 00:24:45,027 --> 00:24:48,197 SUBSET OF LUNG CANCER, .49 OR 675 00:24:48,197 --> 00:24:49,631 51% IMPROVEMENT IN OVERALL 676 00:24:49,631 --> 00:24:50,165 SURVIVAL. 677 00:24:50,165 --> 00:24:54,203 SO THIS WAS THE PLENARY AT ASCO 678 00:24:54,203 --> 00:24:54,870 TWO YEARS AGO. 679 00:24:54,870 --> 00:24:56,205 I HAVE A FEW OTHER THINGS TO 680 00:24:56,205 --> 00:24:57,172 TALK ABOUT TODAY SO I'M NOT 681 00:24:57,172 --> 00:24:58,707 GOING TO BELABOR THIS, BUT 682 00:24:58,707 --> 00:25:00,008 ALMOST ALL PATIENTS GOT IN THE 683 00:25:00,008 --> 00:25:02,544 SECOND LINE SETTING AN EGFR TKI, 684 00:25:02,544 --> 00:25:04,079 BUT ONLY ABOUT HALF GOT 685 00:25:04,079 --> 00:25:04,513 OSIMERTINIB. 686 00:25:04,513 --> 00:25:05,481 WHY? 687 00:25:05,481 --> 00:25:06,915 BECAUSE WE DIDN'T FEEL THE 688 00:25:06,915 --> 00:25:07,783 CROSSOVER UNTIL WE HAD THE 689 00:25:07,783 --> 00:25:09,518 RESULTS IN 2020, AT WHICH TIME 690 00:25:09,518 --> 00:25:10,519 ALMOST HALF THE PATIENTS HAD 691 00:25:10,519 --> 00:25:14,990 ALREADY PROGRESSED. 692 00:25:14,990 --> 00:25:16,959 IT WAS WELL TOLERATED, EASY FOR 693 00:25:16,959 --> 00:25:18,494 ME TO SAY, BUT THERE'S ALWAYS 694 00:25:18,494 --> 00:25:20,262 MORE TOXICITY WHEN YOU GIVE A 695 00:25:20,262 --> 00:25:21,663 DRUG, OSIMERTINIB, VERSUS 696 00:25:21,663 --> 00:25:23,332 PLACEBO, BUT YOU CAN SEE ANY 697 00:25:23,332 --> 00:25:25,968 GRADE III TOXICITY, 23% VERSUS 698 00:25:25,968 --> 00:25:26,268 14%. 699 00:25:26,268 --> 00:25:29,872 IF YOU LOOK FOR CAUSALLY 700 00:25:29,872 --> 00:25:30,973 RELATED -- THERE WERE NO DEATHS 701 00:25:30,973 --> 00:25:31,740 IN EITHER ARM. 702 00:25:31,740 --> 00:25:32,841 THERE'S ALWAYS CONCERN WITH 703 00:25:32,841 --> 00:25:37,212 THESE TYROSINE KINASE INHIBITORS 704 00:25:37,212 --> 00:25:38,680 WITH INTERSTITIAL DISEASE SO 705 00:25:38,680 --> 00:25:39,815 THAT WAS REASSURING. 706 00:25:39,815 --> 00:25:42,918 THIS IS NOW BEING DONE FOR OTHER 707 00:25:42,918 --> 00:25:46,188 MUTATIONS. 708 00:25:46,188 --> 00:25:49,024 ALK ARE WE GOING TO NEED -- 709 00:25:49,024 --> 00:25:50,325 SOMEONE JUST ASKED AT OUR GRAND 710 00:25:50,325 --> 00:25:51,760 ROUNDS TODAY, ARE WE GOING TO 711 00:25:51,760 --> 00:25:52,861 NEED SEPARATE STUDIES FOR ALL 712 00:25:52,861 --> 00:25:53,629 THESE DRUGS? 713 00:25:53,629 --> 00:25:54,062 PROBABLY NOT. 714 00:25:54,062 --> 00:25:56,331 I THINK WE'LL NEED SMALL STUDIES 715 00:25:56,331 --> 00:25:57,566 LOOKING AT THE TOXICITY AND 716 00:25:57,566 --> 00:25:58,767 FEASIBILITY, BUT I WOULD SAY 717 00:25:58,767 --> 00:26:00,169 THAT IN A FEW YEARS, MY 718 00:26:00,169 --> 00:26:02,137 PREDICTION IS WE'LL BE USING 719 00:26:02,137 --> 00:26:03,138 SPECIFIC ADJUVANT THERAPY FOR 720 00:26:03,138 --> 00:26:04,973 PATIENTS IN A PERSONALIZED WAY 721 00:26:04,973 --> 00:26:06,975 BASED ON THE DRIVER OF THEIR 722 00:26:06,975 --> 00:26:07,509 TUMOR. 723 00:26:07,509 --> 00:26:09,378 GIVEN THAT MOST OF THESE WILL 724 00:26:09,378 --> 00:26:10,245 HAVE ORAL DRUGS. 725 00:26:10,245 --> 00:26:11,780 I'D JUST LIKE TO SORT OF USE 726 00:26:11,780 --> 00:26:16,151 THIS SLIDE, I TRAINED AT MD 727 00:26:16,151 --> 00:26:20,088 ANDERSON WITH JOSH FIDDLER, 728 00:26:20,088 --> 00:26:23,258 ALONG WITH -- ALWAYS SPOKE OF 729 00:26:23,258 --> 00:26:24,159 TUMOR ANGIOGENESIS AND THE 730 00:26:24,159 --> 00:26:24,693 CASCADE. 731 00:26:24,693 --> 00:26:26,128 THE NEW PARADIGM NOW IN CANCER 732 00:26:26,128 --> 00:26:27,429 WHICH IS WONDERFUL IS THAT YOU 733 00:26:27,429 --> 00:26:30,032 DO YOUR BEST SURGERY, 734 00:26:30,032 --> 00:26:31,567 CHEMOTHERAPY, PERHAPS RADIATION 735 00:26:31,567 --> 00:26:33,769 THERAPY, AND THEN YOU ADD 736 00:26:33,769 --> 00:26:36,171 TARGETED THERAPY IN, YOU KNOW, 737 00:26:36,171 --> 00:26:37,706 AS ANOTHER MODALITY, AND YOU 738 00:26:37,706 --> 00:26:39,241 BRING YOUR BEST THERAPIES TO 739 00:26:39,241 --> 00:26:40,542 EARLY DISEASE, PREVENTING 740 00:26:40,542 --> 00:26:41,743 METASTASES TO THE BRAIN, LIVER 741 00:26:41,743 --> 00:26:44,479 AND BONE. 742 00:26:44,479 --> 00:26:49,818 THIS DRUG WAS APPROVED IN 2020. 743 00:26:49,818 --> 00:26:51,053 JUST LAST WEEK, THIS SUBSEQUENT 744 00:26:51,053 --> 00:26:56,925 PAPER CAME OUT IN NATURE. 745 00:26:56,925 --> 00:27:00,896 LOOLOOKING AT RESIDUAL DISEASE N 746 00:27:00,896 --> 00:27:01,964 OSIMERTINIB IN THIS TRIAL. 747 00:27:01,964 --> 00:27:05,367 WE LOOKED AT PLASMA ANALYSIS 748 00:27:05,367 --> 00:27:10,172 USING A TUMOR-DERIVED ANALYSIS 749 00:27:10,172 --> 00:27:12,608 TO LOOK AT CIRCULATING TUMOR 750 00:27:12,608 --> 00:27:17,713 DNA. 751 00:27:17,713 --> 00:27:22,084 SO BASICALLY WE HAD SAMPLES 752 00:27:22,084 --> 00:27:23,619 EVERY THREE WEEKS, EVERY 24 753 00:27:23,619 --> 00:27:25,153 WEEKS AFTER THAT, THEN WE HAD 754 00:27:25,153 --> 00:27:27,456 PLASMA, WE CAN LOOK AT RESIDUAL 755 00:27:27,456 --> 00:27:30,292 DISEASE, WE USE A TEST CALLED 756 00:27:30,292 --> 00:27:31,627 RADAR, WE SEQUENCED THE TUMOR 757 00:27:31,627 --> 00:27:33,028 AND FROM THE TUMOR, WE FOUND NOT 758 00:27:33,028 --> 00:27:35,998 ONLY EGFR BUT THE 20 TO 25 MOST 759 00:27:35,998 --> 00:27:37,199 FREQUENT ABNORMALITIES IN THAT 760 00:27:37,199 --> 00:27:38,300 TUMOR, AND BASICALLY EVERY 761 00:27:38,300 --> 00:27:41,336 PATIENT GETS THEIR OBSERVE SORTF 762 00:27:41,336 --> 00:27:42,337 TEST MADE TO INCREASE 763 00:27:42,337 --> 00:27:42,738 SENSITIVITY. 764 00:27:42,738 --> 00:27:43,972 SO I CAN SHOW YOU QUICKLY SOME 765 00:27:43,972 --> 00:27:46,041 OF THOSE RESULTS. 766 00:27:46,041 --> 00:27:52,614 ONLY 8% OF PATIENTS POST SURGERY 767 00:27:52,614 --> 00:27:53,916 AND CHEMOTHERAPY OR NOT 768 00:27:53,916 --> 00:27:55,484 CHEMOTHERAPY HAD DETECTABLE 769 00:27:55,484 --> 00:27:55,784 MUTATIONS. 770 00:27:55,784 --> 00:27:56,885 ABOUT WHAT YOU WOULD EXPECT IN 771 00:27:56,885 --> 00:27:57,853 EARLY STAGE CANCER. 772 00:27:57,853 --> 00:27:58,754 NOWADAYS THERE ARE MORE TESTS 773 00:27:58,754 --> 00:28:01,156 THAT ARE BEING DEVELOPED. 774 00:28:01,156 --> 00:28:03,225 I KNOW WE'RE LOOKING AT 775 00:28:03,225 --> 00:28:04,326 FRAGMENTATION ASSAYS AND OTHER 776 00:28:04,326 --> 00:28:06,194 THINGS, ACTUALLY LOOKING A BIT 777 00:28:06,194 --> 00:28:09,031 MORE SPECIFIC, BUT YOU CAN SEE 778 00:28:09,031 --> 00:28:10,866 IN STAGE I B WE DIDN'T SEE ANY 779 00:28:10,866 --> 00:28:12,868 MUTATION, ANY CELL-FREE DNA. 780 00:28:12,868 --> 00:28:15,704 IN STAGE TWO, 7%, AND IN STAGE 781 00:28:15,704 --> 00:28:18,106 THREE, WE HAD MORE, 13%. 782 00:28:18,106 --> 00:28:19,541 AND THIS IS VERY INTERESTING. 783 00:28:19,541 --> 00:28:21,944 SO THESE ARE PATIENTS -- THE 784 00:28:21,944 --> 00:28:23,912 PATIENTS WHO HAD DETECTED MRD AT 785 00:28:23,912 --> 00:28:24,346 THE BASELINE. 786 00:28:24,346 --> 00:28:26,248 YOU CAN SEE THERE WERE ONLY 18 787 00:28:26,248 --> 00:28:27,616 HERE, AND THIS IS VERY 788 00:28:27,616 --> 00:28:32,421 INTERESTING SO HERE ARE THE 789 00:28:32,421 --> 00:28:34,723 PATIENTS IN BLUE, THEY GOT 790 00:28:34,723 --> 00:28:36,491 OSIMERTINIB, THEY CLEARED THEIR 791 00:28:36,491 --> 00:28:38,393 CIRCULATING DNA, BUT YOU CAN SEE 792 00:28:38,393 --> 00:28:40,862 AS THEY CAME OFF DRUG AT THREE 793 00:28:40,862 --> 00:28:43,899 YEARS, 36 MONTHS, THEY ALL THEN 794 00:28:43,899 --> 00:28:46,001 BECAME DETECTABLE. 795 00:28:46,001 --> 00:28:47,736 THIS HAS NOT PROGRESSED YET. 796 00:28:47,736 --> 00:28:48,603 THESE TWO PATIENTS PROGRESSED 797 00:28:48,603 --> 00:28:50,038 LOCALLY. 798 00:28:50,038 --> 00:28:51,573 SO NEED TO GET SOME RADIATION. 799 00:28:51,573 --> 00:28:52,874 AND THEN YOU CAN SEE PATIENTS 800 00:28:52,874 --> 00:28:54,843 WHO, OF COURSE, STARTED WITH 801 00:28:54,843 --> 00:28:57,012 DISEASE AND THEN GOT PLACEBO, OF 802 00:28:57,012 --> 00:28:58,246 COURSE THEY ALL PROGRESSED. 803 00:28:58,246 --> 00:28:59,982 THEN THERE'S SOME PATIENTS, OF 804 00:28:59,982 --> 00:29:00,882 COURSE, THAT HAVEN'T PROGRESSED 805 00:29:00,882 --> 00:29:04,186 YET AT ALL. 806 00:29:04,186 --> 00:29:07,856 THE MRD ASSAY WAS 4.7 MONTHS 807 00:29:07,856 --> 00:29:11,360 EARLIER ON THE MEDIAN OF PICKING 808 00:29:11,360 --> 00:29:15,297 UP PROGRESSION VERSUS RADIOLOGY. 809 00:29:15,297 --> 00:29:16,631 SO PRESUMABLY IF WE HAD THINGS 810 00:29:16,631 --> 00:29:19,001 THAT WE COULD DO EARLIER, THIS 811 00:29:19,001 --> 00:29:21,003 FOUR OR FIVE MONTHS AT MEDIAN 812 00:29:21,003 --> 00:29:24,272 COULD MAKE A BIG DIFFERENCE. 813 00:29:24,272 --> 00:29:26,074 SO THE PARADIGM I JUST WANTED TO 814 00:29:26,074 --> 00:29:27,342 SORT OF MAKE IN THE FIRST PART 815 00:29:27,342 --> 00:29:29,511 OF THIS BRIEF OVERVIEW IS WE'RE 816 00:29:29,511 --> 00:29:31,380 MAKING AMAZING PROGRESS WITH 817 00:29:31,380 --> 00:29:32,047 TARGETED THERAPIES. 818 00:29:32,047 --> 00:29:35,317 I SHOWED YOU ONE STORY OF EGFR. 819 00:29:35,317 --> 00:29:36,418 CERTAINLY WE UNDERSTAND HOW TO 820 00:29:36,418 --> 00:29:38,053 USE THOSE DRUGS AND BRING THEM 821 00:29:38,053 --> 00:29:38,487 EARLIER. 822 00:29:38,487 --> 00:29:40,889 BUT I'VE BEEN DOING THIS NOW, 823 00:29:40,889 --> 00:29:43,625 DARE I SAY IT, SINCE 1996. 824 00:29:43,625 --> 00:29:45,160 AND WHILE I'VE TREATED MANY, 825 00:29:45,160 --> 00:29:47,229 MANY PATIENTS WITH EGFR DISEASE, 826 00:29:47,229 --> 00:29:48,330 IS ANYONE TRULY CURED? 827 00:29:48,330 --> 00:29:51,733 PERHAPS SOME OF THOSE PATIENTS 828 00:29:51,733 --> 00:29:54,236 ON THE ODURA TRIAL, WE'LL HAVE 829 00:29:54,236 --> 00:29:56,538 TO SEE HOW THEY'RE DOING EVERY 830 00:29:56,538 --> 00:29:58,306 YEAR WITH LANDMARK ANALYSES. 831 00:29:58,306 --> 00:29:59,608 RESISTANCE IS A BIG ISSUE AND 832 00:29:59,608 --> 00:30:01,576 YOU'LL HEAR MORE ABOUT THAT FROM 833 00:30:01,576 --> 00:30:03,311 KATY AND HER TALK. 834 00:30:03,311 --> 00:30:04,312 IMMUNOTHERAPY IS ANOTHER BIG 835 00:30:04,312 --> 00:30:06,048 PART OF OUR RESEARCH HERE IN OUR 836 00:30:06,048 --> 00:30:06,715 LUNG SPORE. 837 00:30:06,715 --> 00:30:08,583 CERTAINLY WE ALL KNOW THAT THE 838 00:30:08,583 --> 00:30:09,351 IMMUNE SYSTEM IS SPECIFIC. 839 00:30:09,351 --> 00:30:12,087 IT HAS MEMORY AND IT'S ADAPTIVE. 840 00:30:12,087 --> 00:30:14,156 AND THE PARADIGM OF THE TUMOR 841 00:30:14,156 --> 00:30:17,659 CELL AND THE CYTOTOXIC T-CELL, 842 00:30:17,659 --> 00:30:21,063 WE KNOW THAT THE NEOANTIGENS 843 00:30:21,063 --> 00:30:22,931 SHOWN IN RED AND THE CONTEXT OF 844 00:30:22,931 --> 00:30:25,634 THE UNIQUE MHC1 IS RECOGNIZED BY 845 00:30:25,634 --> 00:30:26,401 T-CELL RECEPTOR. 846 00:30:26,401 --> 00:30:28,170 WHEN THAT INTERACTION OCCURS, WE 847 00:30:28,170 --> 00:30:30,906 SEE ACTIVATION OF THE CYTOTOXIC 848 00:30:30,906 --> 00:30:32,641 CD8 POSITIVE T-CELL, BUT IT ALSO 849 00:30:32,641 --> 00:30:36,144 RESULTS IN PD-L1, THE ADAPTIVE 850 00:30:36,144 --> 00:30:39,214 PRODUCTION OF PD-L1 THROUGH 851 00:30:39,214 --> 00:30:40,315 INTERFERON ON THE TUMOR ITSELF 852 00:30:40,315 --> 00:30:43,819 THAT INTERACTS WITH THE 853 00:30:43,819 --> 00:30:44,686 PD-1 RECEPTOR ON THE T-CELL 854 00:30:44,686 --> 00:30:46,088 OFFICE THIS FOS TO TASTE OR 855 00:30:46,088 --> 00:30:46,655 NEGATIVE LOOP. 856 00:30:46,655 --> 00:30:48,623 SO OF COURSE THE BIG REVOLUTION 857 00:30:48,623 --> 00:30:49,825 IN CANCER MEDICINE IN THE LAST 858 00:30:49,825 --> 00:30:52,461 DECADE HAS BEEN THE AVENT OF 859 00:30:52,461 --> 00:30:56,231 THESE PD-1, PD-L1 INHIBITORS 860 00:30:56,231 --> 00:30:57,466 THAT BLOCKS THAT INTERACTION. 861 00:30:57,466 --> 00:31:00,435 IF IT WAS SO SIMPLE, IT WOULD BE 862 00:31:00,435 --> 00:31:05,140 GREAT BUT WE HAVE SO MUCH GOING 863 00:31:05,140 --> 00:31:08,743 ON IN THE MIC MICRO ENENVIRONME. 864 00:31:08,743 --> 00:31:09,511 WE'VE MADE GREAT PROGRESS. 865 00:31:09,511 --> 00:31:11,246 IF YOU LOOK AT THIS, WE'VE MADE 866 00:31:11,246 --> 00:31:12,581 AMAZING PROGRESS IN CANCER 867 00:31:12,581 --> 00:31:13,715 THERAPIES OVER THE LAST YEARS. 868 00:31:13,715 --> 00:31:15,016 WE JUST NEED TO MAKE MORE. 869 00:31:15,016 --> 00:31:16,551 AND I THINK IT'S IMPORTANT THAT 870 00:31:16,551 --> 00:31:18,086 IN THIS TIME WE ALL GET THAT 871 00:31:18,086 --> 00:31:19,921 MESSAGE OUT, THAT WE REALLY ARE 872 00:31:19,921 --> 00:31:21,690 MAKING PROGRESS IN CANCER, AND 873 00:31:21,690 --> 00:31:22,557 CERTAINLY I HOPE THAT WHEN 874 00:31:22,557 --> 00:31:23,758 YOU'RE DONE WITH MY TALK, YOU'LL 875 00:31:23,758 --> 00:31:25,393 SEE IN LUNG CANCER, WE'RE VERY 876 00:31:25,393 --> 00:31:27,262 EXCITED BUT WE HAVE MORE TO DO. 877 00:31:27,262 --> 00:31:28,497 THIS IS THE ONE OF THE FIRST 878 00:31:28,497 --> 00:31:29,564 PATIENTS TREATED AT YALE 879 00:31:29,564 --> 00:31:31,533 ACTUALLY BEFORE I GOT TO YALE. 880 00:31:31,533 --> 00:31:38,073 BY SCOTT GE. 881 00:31:38,073 --> 00:31:38,540 TINGER. 882 00:31:38,540 --> 00:31:40,709 THEY BROUGHT THE TRIAL TO YALE. 883 00:31:40,709 --> 00:31:42,677 SO HERE'S A PATIENT, MAUREEN, 884 00:31:42,677 --> 00:31:44,412 AND SHE ALLOWS US TO USE HER 885 00:31:44,412 --> 00:31:45,514 IMAGE, THIS IS ACTUALLY FROM 886 00:31:45,514 --> 00:31:47,849 SOME OF OUR YALE MATERIALS. 887 00:31:47,849 --> 00:31:49,251 THIS PATIENT HAD WIDELY 888 00:31:49,251 --> 00:31:51,119 METASTATIC LUNG CANCER, SQUAMOUS 889 00:31:51,119 --> 00:31:55,257 LUNG CANCER, NO MUTATIONS IN 890 00:31:55,257 --> 00:31:56,591 SQUAMOUS LUNG CANCER OR IF THERE 891 00:31:56,591 --> 00:31:57,459 ARE, IT'S VERY RARE. 892 00:31:57,459 --> 00:31:58,994 AND WITHIN A COUPLE OF MONTHS 893 00:31:58,994 --> 00:32:01,730 ACTUALLY ON THIS CLINICAL TRIAL, 894 00:32:01,730 --> 00:32:02,797 NIVOLUMAB, YOU CAN SEE HER 895 00:32:02,797 --> 00:32:03,899 DISEASE WENT NEARLY COMPLETELY 896 00:32:03,899 --> 00:32:04,232 AWAY. 897 00:32:04,232 --> 00:32:05,767 SHE HAD TO STOP DRUG AT TWO 898 00:32:05,767 --> 00:32:06,635 YEARS BECAUSE THAT'S THE WAY THE 899 00:32:06,635 --> 00:32:08,837 TRIAL WAS WRITTEN, BUT JUST SAW 900 00:32:08,837 --> 00:32:10,572 HER RECENTLY, SHE'S DOING WELL. 901 00:32:10,572 --> 00:32:13,408 SO THIS IS AN EXAMPLE OF IN 902 00:32:13,408 --> 00:32:17,245 PATITHISPATIENT IS PROBABLY CURE 903 00:32:17,245 --> 00:32:19,881 EVEN GOTTEN VINCE DAVITA TO 904 00:32:19,881 --> 00:32:22,617 AGREE THIS PATIENT IS CURED, BUT 905 00:32:22,617 --> 00:32:23,919 THIS ONLY HAPPENS IN 15% OF THE 906 00:32:23,919 --> 00:32:26,321 PATIENTS. 907 00:32:26,321 --> 00:32:29,291 THIS IS THE ACTUAL ACTUARIAL 908 00:32:29,291 --> 00:32:30,158 SURVIVAL CURVE FROM THAT TRIAL. 909 00:32:30,158 --> 00:32:32,227 YOU CAN SEE SCOTT IN THE UPPER 910 00:32:32,227 --> 00:32:32,761 RIGHT. 911 00:32:32,761 --> 00:32:34,429 IN FIVE YEARS, ABOUT 15% OF 912 00:32:34,429 --> 00:32:39,901 PATIENTS ARE ALIVE. 913 00:32:39,901 --> 00:32:41,102 IT'S THAT TAIL OF THE CURVE 914 00:32:41,102 --> 00:32:43,838 WE'RE TRYING TO MAKE BE BETTER D 915 00:32:43,838 --> 00:32:44,072 BETTER. 916 00:32:44,072 --> 00:32:45,373 AGAIN TIME IS SHORT, BUT THERE'S 917 00:32:45,373 --> 00:32:47,909 BEEN A WHOLE EVOLUTION OF 918 00:32:47,909 --> 00:32:49,211 TRIALS, I KNOW THAT MANY ACROSS 919 00:32:49,211 --> 00:32:52,147 THE WORLD HAVE ALLOWED THIS 920 00:32:52,147 --> 00:32:53,915 WORK, NIH FUNDED HAS DONE TO 921 00:32:53,915 --> 00:32:56,651 LOOK AT TRIALS, LOOKING AT NEW 922 00:32:56,651 --> 00:32:58,486 DRUGS AND NEW IMMUNOTHERAPIES. 923 00:32:58,486 --> 00:33:01,022 WE NOW USE IMMUNOTHERAPY UNLESS 924 00:33:01,022 --> 00:33:02,023 CONTRAINDICATED IN MOST ALL 925 00:33:02,023 --> 00:33:03,458 PATIENTS WITH LUNG CANCER, 926 00:33:03,458 --> 00:33:06,962 EXCEPT THOSE THAT HAVE DRIVER 927 00:33:06,962 --> 00:33:07,929 MUTATIONS BECAUSE FOR THEM WE 928 00:33:07,929 --> 00:33:09,130 KNOW IT'S PROBABLY BETTER TO USE 929 00:33:09,130 --> 00:33:10,131 A TARGETED THERAPY. 930 00:33:10,131 --> 00:33:12,200 WE ALSO KNOW WITH A DRIVER 931 00:33:12,200 --> 00:33:13,501 MUTATION, YOU'RE LESS LIKELY TO 932 00:33:13,501 --> 00:33:16,338 HAVE MANY OTHER MUTATIONS THAT 933 00:33:16,338 --> 00:33:18,873 COULD -- WITH MHC AND RESULT IN 934 00:33:18,873 --> 00:33:19,307 IMMUNE RESPONSE. 935 00:33:19,307 --> 00:33:20,508 FOR THEM WE'LL PROBABLY HAVE TO 936 00:33:20,508 --> 00:33:21,610 WORK WITH VACCINES. 937 00:33:21,610 --> 00:33:23,144 WE ACTUALLY ARE VERY PROUD OF 938 00:33:23,144 --> 00:33:25,547 THIS, OUR GROUP AT YALE, HARRY 939 00:33:25,547 --> 00:33:27,182 AND SARAH WORKING AS A TEAM WITH 940 00:33:27,182 --> 00:33:31,786 VEVERONICA CHANG WHO DOES 941 00:33:31,786 --> 00:33:32,454 RADIOSURGERY. 942 00:33:32,454 --> 00:33:35,523 ABOUT 10 YEARS AGO AFTER WE DID 943 00:33:35,523 --> 00:33:37,392 SOME EARLY TRIALS WITH 944 00:33:37,392 --> 00:33:39,027 PEMBROLIZUMAB, THEY CONTACTED 945 00:33:39,027 --> 00:33:42,631 MERCK AND SAID CAN WE DO AN 946 00:33:42,631 --> 00:33:43,565 INVESTIGATOR INITIATED TRIAL TO 947 00:33:43,565 --> 00:33:46,268 LOOK AT SMALL BRAIN METASTASES. 948 00:33:46,268 --> 00:33:49,371 BECAUSE IF THESE IMMUNOTHERAPIES 949 00:33:49,371 --> 00:33:51,940 WORK SO WELL IN LUNG CANCER, WHY 950 00:33:51,940 --> 00:33:53,141 GIVE RADIATION AND PUT THAT 951 00:33:53,141 --> 00:33:54,142 PATIENT THROUGH ALL THE 952 00:33:54,142 --> 00:33:55,677 COGNITIVE IMPAIRMENT THAT MIGHT 953 00:33:55,677 --> 00:33:56,111 ENSUE? 954 00:33:56,111 --> 00:33:59,948 WHAT IF WE COULD JUST TREAT WITH 955 00:33:59,948 --> 00:34:00,515 THE IMMUNOTHERAPY? 956 00:34:00,515 --> 00:34:02,851 THIS WAS A TRIAL, AND YOU CAN 957 00:34:02,851 --> 00:34:04,853 SEE JUST LOOK AT THE WATERFALL 958 00:34:04,853 --> 00:34:06,388 PLOT, THE BRAIN RESPONSE IS 959 00:34:06,388 --> 00:34:07,789 ORANGE AND THE EXTRA CEREBRAL, 960 00:34:07,789 --> 00:34:10,992 SO THE REST OF THE BODY IS IN 961 00:34:10,992 --> 00:34:11,860 BLUE, AND WHAT YOU CAN SEE IS 962 00:34:11,860 --> 00:34:13,128 YOU CAN SEE THAT THE RESPONSES 963 00:34:13,128 --> 00:34:14,696 IN THE BRAIN ARE ABOUT THE SAME 964 00:34:14,696 --> 00:34:16,564 AS THE RESPONSES SYSTEMICALLY. 965 00:34:16,564 --> 00:34:18,533 NOW WE WERE NERVOUS AND WE WERE 966 00:34:18,533 --> 00:34:22,570 BEING CAREFUL, WE WERE BEING 967 00:34:22,570 --> 00:34:25,240 FOLLOWED BY THE IRB BUT THEY NOW 968 00:34:25,240 --> 00:34:26,207 DISAPPEARED. 969 00:34:26,207 --> 00:34:28,376 WE NOW KNOW YOU CAN USE 970 00:34:28,376 --> 00:34:29,377 IMMUNOTHERAPY IN PATIENTS WITH 971 00:34:29,377 --> 00:34:30,912 BRAIN METS AS LONG AS YOU FOLLOW 972 00:34:30,912 --> 00:34:31,346 IT CLOSELY. 973 00:34:31,346 --> 00:34:33,748 THEY ACTUALLY CALLED HARRIET 974 00:34:33,748 --> 00:34:36,051 WHEN JIMMY CARTER IN ATLANTA HAD 975 00:34:36,051 --> 00:34:36,918 METASTATIC MELANOMA TO THE 976 00:34:36,918 --> 00:34:38,219 BRAIN, AND WE SHARED OUR 977 00:34:38,219 --> 00:34:39,854 PROTOCOL WITH THE GROUP DOWN 978 00:34:39,854 --> 00:34:42,824 THERE AND LUCKY HE LIVED TO 100, 979 00:34:42,824 --> 00:34:46,094 10 YEARS, WITH MELANOMA. 980 00:34:46,094 --> 00:34:47,962 SO FRONT LINE TRIALS, WHAT 981 00:34:47,962 --> 00:34:48,963 BROUGHT THE AGENTS TO THE FRONT 982 00:34:48,963 --> 00:34:51,366 LINE WERE BIOMARKERS, 983 00:34:51,366 --> 00:34:52,233 BIOMARKERS, BIOMARKERS. 984 00:34:52,233 --> 00:34:55,537 SO IF YOU LOOK AT PD-L1 AS A 985 00:34:55,537 --> 00:34:56,604 BIOMARKER AND JUST TAKE THOSE 986 00:34:56,604 --> 00:35:01,209 PATIENTS, YOU CAN GET A 31.9% 987 00:35:01,209 --> 00:35:04,746 SURVIVAL AT FIVE YEARS IN LUNG 988 00:35:04,746 --> 00:35:05,714 CANCER. 989 00:35:05,714 --> 00:35:07,482 RIR I SHOWED THOSE CURVES THAT 990 00:35:07,482 --> 00:35:10,518 WENT DOWN TO HE BOTTOM AT THE 991 00:35:10,518 --> 00:35:11,953 BEGINNING, THIS WAS PROGRESS. 992 00:35:11,953 --> 00:35:14,356 STILL LET'S NOT KID OURSELVES, 993 00:35:14,356 --> 00:35:16,324 AT THREE YEARS, 28% OF PATIENTS, 994 00:35:16,324 --> 00:35:18,660 EVEN WITH A HIGH PD-L1, STILL 995 00:35:18,660 --> 00:35:18,927 PROGRESS. 996 00:35:18,927 --> 00:35:23,131 WE HAVE A LOT OF WORK TO DO. 997 00:35:23,131 --> 00:35:26,868 HOW AM I DOING ON TIME, KATY? 998 00:35:26,868 --> 00:35:27,602 >> FINE. 999 00:35:27,602 --> 00:35:29,404 >> KATY IS RIGHT NEXT TO ME SO I 1000 00:35:29,404 --> 00:35:33,541 HAVE TO IK MA MAKE SURE I DON'TO 1001 00:35:33,541 --> 00:35:39,881 OVER TIME. 1002 00:35:39,881 --> 00:35:41,216 VERY IMPORTANT TO USE 1003 00:35:41,216 --> 00:35:41,549 BIOMARKERS. 1004 00:35:41,549 --> 00:35:42,751 HERE YOU CAN SEE THIS IS 1005 00:35:42,751 --> 00:35:43,752 PRODUCED BY DAVID RIM, ONE OF 1006 00:35:43,752 --> 00:35:46,688 THE CO-LEADERS OF OUR LUNG SPORE 1007 00:35:46,688 --> 00:35:47,222 PATHOLOGY CORE. 1008 00:35:47,222 --> 00:35:50,859 NOW I GUESS SEVEN, EIGHT YEARS 1009 00:35:50,859 --> 00:35:51,192 AGO. 1010 00:35:51,192 --> 00:35:53,928 WE HAVE PDL1, WHICH BINDS TO 1011 00:35:53,928 --> 00:35:56,564 PD-1 AS A BIOMARKER BUT IT'S NOT 1012 00:35:56,564 --> 00:35:57,766 THE BEST BECAUSE IF IT'S 1013 00:35:57,766 --> 00:35:58,967 NEGATIVE, IT DOESN'T MEAN MUCH, 1014 00:35:58,967 --> 00:36:01,603 BECAUSE HERE'S A PIECE OF TUMOR, 1015 00:36:01,603 --> 00:36:02,670 WE ACTUALLY DID THIS HERE AT 1016 00:36:02,670 --> 00:36:04,973 YALE TO MAKE THE POINT. 1017 00:36:04,973 --> 00:36:06,408 ONE AREA THAT'S STONE COLD 1018 00:36:06,408 --> 00:36:09,244 NEGATIVE FOR PD-L1 USING TWO 1019 00:36:09,244 --> 00:36:10,345 DIFFERENT ANTIBODIES AND ANOTHER 1020 00:36:10,345 --> 00:36:11,279 AREA THAT'S POSITIVE, AND YOU 1021 00:36:11,279 --> 00:36:13,648 CAN SEE THE DAB STAINING HERE, 1022 00:36:13,648 --> 00:36:15,283 AND DIFFERING LEVELS OF 1023 00:36:15,283 --> 00:36:16,484 POSITIVITY, AGAIN, DIFFERENT 1024 00:36:16,484 --> 00:36:18,353 ANTIBODIES. 1025 00:36:18,353 --> 00:36:19,788 SO THE SELECTION, WHERE YOU 1026 00:36:19,788 --> 00:36:21,656 STICK YOUR NEEDLE CAN MAKE A 1027 00:36:21,656 --> 00:36:22,090 DIFFERENCE. 1028 00:36:22,090 --> 00:36:24,292 NOW PEEL PEOPLE ARE DOING 1029 00:36:24,292 --> 00:36:24,926 THREE-DIMENSIONAL, THERE ARE ALL 1030 00:36:24,926 --> 00:36:26,361 SORTS OF WAYS AROUND THIS NOW. 1031 00:36:26,361 --> 00:36:28,363 SO AI AND DIGITAL PATHOLOGY, I 1032 00:36:28,363 --> 00:36:29,564 THINK WILL HELP IN THE FUTURE. 1033 00:36:29,564 --> 00:36:30,799 BUT HERE ON THE RIGHT, YOU CAN 1034 00:36:30,799 --> 00:36:32,500 SEE, WHERE DO YOU MEASURE IT? 1035 00:36:32,500 --> 00:36:35,904 SO THIS IS A FLUORESCENCE, GREEN 1036 00:36:35,904 --> 00:36:37,672 IS CYTOKERATIN, SO THIS IS 1037 00:36:37,672 --> 00:36:42,811 TUMOR, THE BLEUP BLUE IS DAPI, E 1038 00:36:42,811 --> 00:36:44,679 NUCLEI, AND THE RED IS PD-1 SO 1039 00:36:44,679 --> 00:36:46,881 YOU CAN MEASURE IT IN BOTH 1040 00:36:46,881 --> 00:36:47,115 PLACES. 1041 00:36:47,115 --> 00:36:49,951 IS IT 10%, 20%, 30%? 1042 00:36:49,951 --> 00:36:51,386 SO WHAT ARE THE CUTOFFS? 1043 00:36:51,386 --> 00:36:52,787 HOWL IS THE TUMOR AFFIXED? 1044 00:36:52,787 --> 00:36:54,456 WHEN DO YOU GET THE TUMOR? 1045 00:36:54,456 --> 00:36:55,590 THERE ARE LOTS OF UNKNOWNS. 1046 00:36:55,590 --> 00:36:59,527 BUT FOR THE MOST PART, A HIGH 1047 00:36:59,527 --> 00:37:00,228 PD-L1 USUALLY DOES MEAN THE 1048 00:37:00,228 --> 00:37:02,297 PATIENT IS MORE LIKELY TO 1049 00:37:02,297 --> 00:37:03,598 RESPOND BUP A NEGATIVE DOES NOT. 1050 00:37:03,598 --> 00:37:05,366 YOU DON'T WANT TO KEEP THAT 1051 00:37:05,366 --> 00:37:06,234 AMAZING THERAPY FROM THOSE 1052 00:37:06,234 --> 00:37:07,769 PATIENTS SO THAT'S SOMETHING 1053 00:37:07,769 --> 00:37:09,737 WE'RE VERY MUCH WORKING ON. 1054 00:37:09,737 --> 00:37:11,072 KATY WILL TALK MORE ABOUT THIS I 1055 00:37:11,072 --> 00:37:12,474 WAS VERY FORTUNATE THAT SHE AND 1056 00:37:12,474 --> 00:37:15,777 SCOTT GETTINGER -- YOU'VE HAD 1057 00:37:15,777 --> 00:37:18,513 THIS FOR 15 YEARS NOW OR MORE, A 1058 00:37:18,513 --> 00:37:19,380 REBIOPSY PROGRAM. 1059 00:37:19,380 --> 00:37:21,349 SO AT YALE, WE HAVE -- AND IT'S 1060 00:37:21,349 --> 00:37:25,954 BEEN A BIG PART OF OUR SPORE AND 1061 00:37:25,954 --> 00:37:27,489 OTHER R01 AND OTHER FUNDED 1062 00:37:27,489 --> 00:37:28,523 EFFORTS, U GRANTS, BECAUSE WE 1063 00:37:28,523 --> 00:37:29,357 HAVE ALL THIS TISSUE. 1064 00:37:29,357 --> 00:37:31,125 WHEN A PATIENT COMES IN EITHER 1065 00:37:31,125 --> 00:37:32,327 ON IMMUNOTHERAPY OR TARGETED 1066 00:37:32,327 --> 00:37:34,395 THERAPY, WE PUT THEM ON THIS 1067 00:37:34,395 --> 00:37:35,497 REBIOPSY PROTOCOL, SO UNDER 1068 00:37:35,497 --> 00:37:36,831 CONTROLLED CONDITIONS, WE CAN 1069 00:37:36,831 --> 00:37:38,800 GET A REBIOPSY, AND WE ALSO THEN 1070 00:37:38,800 --> 00:37:41,536 GO OUT AND GET THEIR 1071 00:37:41,536 --> 00:37:42,537 PRE-TREATMENT SPECIMENS SO THAT 1072 00:37:42,537 --> 00:37:44,405 WE CAN COMPARE. 1073 00:37:44,405 --> 00:37:46,140 AND WE ACTUALLY USE THIS 1074 00:37:46,140 --> 00:37:47,108 MECHANISM FOR -- THIS WAS 1075 00:37:47,108 --> 00:37:48,176 ACTUALLY AN INDUSTRY-FUNDED 1076 00:37:48,176 --> 00:37:50,411 TRIAL THAT WE DID WITH IRA 1077 00:37:50,411 --> 00:37:52,814 MELMAN AND DAN CHEN AND 1078 00:37:52,814 --> 00:37:53,848 GENENTECH, BUT WE HAD THE 1079 00:37:53,848 --> 00:37:55,350 INFRASTRUCTURE IN PLACE TO GET 1080 00:37:55,350 --> 00:37:56,451 PRE AND POST BIOPSIES. 1081 00:37:56,451 --> 00:37:57,452 THIS IS WHY THEY'RE SO 1082 00:37:57,452 --> 00:37:58,419 IMPORTANT, BECAUSE IT BRINGS 1083 00:37:58,419 --> 00:37:58,987 SCIENCE TO THE CLINIC. 1084 00:37:58,987 --> 00:38:00,622 HERE YOU CAN SEE A PATIENT WITH 1085 00:38:00,622 --> 00:38:03,992 LUNG CANCER FROM THE FIRST PHASE 1086 00:38:03,992 --> 00:38:09,397 ONE TRIAL OF ATEZOLIZUMAB. 1087 00:38:09,397 --> 00:38:11,132 THE PATIENT COMPLETELY 1088 00:38:11,132 --> 00:38:12,100 RESPONDED. 1089 00:38:12,100 --> 00:38:15,436 AND WITH PRE AND POST BIOPSIES 1090 00:38:15,436 --> 00:38:17,839 THAT WERE DONE, THIS IS AN 8 OR 1091 00:38:17,839 --> 00:38:18,907 9 SITE TRIAL THAT DID THE 1092 00:38:18,907 --> 00:38:21,342 BIOPSIES BUT WE DID MANY AT 1093 00:38:21,342 --> 00:38:23,978 YALE, HERE'S CD8, YOU CAN SEE 1094 00:38:23,978 --> 00:38:25,947 THE ADAPTIVE IMMUNE RESPONSE. 1095 00:38:25,947 --> 00:38:28,149 THIS PATIENT RESPONDED WITH A 1096 00:38:28,149 --> 00:38:29,450 LOT OF PD8 CELLS. 1097 00:38:29,450 --> 00:38:31,085 YOU CAN SEE ON THE RIGHT, THIS 1098 00:38:31,085 --> 00:38:32,854 IS AN IMMUNE CHIP LOOKING AT 1099 00:38:32,854 --> 00:38:34,188 EXPRESSION OF A NUMB BERL OF 1100 00:38:34,188 --> 00:38:37,358 T-CELL MARKERS, AND PREIS GREEN 1101 00:38:37,358 --> 00:38:38,660 AND -- TREATMENT IS YELLOW. 1102 00:38:38,660 --> 00:38:41,095 YOU CAN SEE THE DIFFERENT IN A 1103 00:38:41,095 --> 00:38:45,567 AND B, THE CELLS MAKE TO 1104 00:38:45,567 --> 00:38:46,334 PERFORATE INTO THE TEU ARE MO. 1105 00:38:46,334 --> 00:38:48,303 THIS IS AN EXAMPLE OF A VERY 1106 00:38:48,303 --> 00:38:49,971 POSITIVE ADAPTIVE IMMUNE 1107 00:38:49,971 --> 00:38:50,838 RESPONSE. 1108 00:38:50,838 --> 00:38:53,474 BUT AGAIN, ONLY 15, 20% IN THOSE 1109 00:38:53,474 --> 00:38:55,343 THAT DON'T RESPOND, WE KNOW WE 1110 00:38:55,343 --> 00:38:56,411 SEE THESE PATTERNS OF RESULTS 1111 00:38:56,411 --> 00:38:57,745 AND THIS IS PUBLISHED ACTUALLY 1112 00:38:57,745 --> 00:39:00,715 NOW EXACTLY 10 YEARS AGO. 1113 00:39:00,715 --> 00:39:02,317 YOU CAN SEE SOME TUMORS DON'T 1114 00:39:02,317 --> 00:39:03,751 HAVE ANY CD8 POSITIVE CELLS TO 1115 00:39:03,751 --> 00:39:05,253 BEGIN WITH, AND NONE AFTER THE 1116 00:39:05,253 --> 00:39:06,754 TREATMENT WITH THE IMMUNE 1117 00:39:06,754 --> 00:39:08,056 THERAPY, WE CALL THAT IMMUNE 1118 00:39:08,056 --> 00:39:08,823 IGNORANCE. 1119 00:39:08,823 --> 00:39:09,924 THESE TUMORS DON'T CARE THAT 1120 00:39:09,924 --> 00:39:11,459 YOU'RE TREATING THEM WITH IMMUNE 1121 00:39:11,459 --> 00:39:11,893 THERAPY. 1122 00:39:11,893 --> 00:39:13,661 A NON-FUNCTIONAL IMMUNE RESPONSE 1123 00:39:13,661 --> 00:39:15,396 WHERE YOU MIGHT GET A FEW MORE T 1124 00:39:15,396 --> 00:39:16,731 CELLS BUT IF YOU LOOK AT THE 1125 00:39:16,731 --> 00:39:18,633 IMMUNE CHIP, IT'S TOTALLY FLAT. 1126 00:39:18,633 --> 00:39:20,001 THIS IS SOMETHING THAT'S NOW 1127 00:39:20,001 --> 00:39:22,870 PART OF OUR MOST RECENT I GRANT 1128 00:39:22,870 --> 00:39:24,072 APPLICATION, EXCLUDED INFILTRATE 1129 00:39:24,072 --> 00:39:25,473 WHERE WE ACTUALLY HAVE TUMORS 1130 00:39:25,473 --> 00:39:28,343 WHERE THE CELLS ACTUALLY LINE UP 1131 00:39:28,343 --> 00:39:31,412 BUT THEY DON'T GET TO THE TUMOR. 1132 00:39:31,412 --> 00:39:32,380 THEY'RE EXCLUDED. 1133 00:39:32,380 --> 00:39:34,282 AND IT'S QUITE LIKELY THAT THERE 1134 00:39:34,282 --> 00:39:35,817 ARE FACTORS -- THERE ARE FACTORS 1135 00:39:35,817 --> 00:39:36,985 WITHIN THE MICROENVIRONMENT THAT 1136 00:39:36,985 --> 00:39:39,253 ARE KEEPING THIS FROM HAPPENING. 1137 00:39:39,253 --> 00:39:40,888 THE FIELD IS MOVING TO 1138 00:39:40,888 --> 00:39:41,356 NEOADJUVANT THERAPY. 1139 00:39:41,356 --> 00:39:42,624 IF YOU TREAT THE TUMOR BEFORE 1140 00:39:42,624 --> 00:39:44,292 IT'S OUT, YOU HAVE MUCH MORE 1141 00:39:44,292 --> 00:39:46,361 T-CELL AND OTHER IMMUNE CELLS IN 1142 00:39:46,361 --> 00:39:47,562 PLACE, SO THAT'S WHERE ALL THIS 1143 00:39:47,562 --> 00:39:48,529 IS GOING. 1144 00:39:48,529 --> 00:39:49,864 AND I'M JUST GOING TO INTRODUCE 1145 00:39:49,864 --> 00:39:51,399 THIS TO SAY THAT THERE HAVE BEEN 1146 00:39:51,399 --> 00:39:52,600 A NUMBER OF TRIALS THAT HAVE 1147 00:39:52,600 --> 00:39:54,502 LOOKED AT PATHOLOGIC COMPLETE 1148 00:39:54,502 --> 00:39:56,804 RESPONSE, AND HERE YOU CAN SEE 1149 00:39:56,804 --> 00:39:58,973 17% PATHOLOGIC COMPLETE 1150 00:39:58,973 --> 00:40:00,274 RESPONSES WHEN PATIENTS GET 1151 00:40:00,274 --> 00:40:01,843 CHEMO, I KNEW KNOW THERAPY 1152 00:40:01,843 --> 00:40:05,446 BEFORE SURGERY VERSUS 4.3% FOR 1153 00:40:05,446 --> 00:40:05,980 CONTROLLED CHEMOTHERAPY. 1154 00:40:05,980 --> 00:40:07,115 SO THIS IS WHERE IT'S GOING. 1155 00:40:07,115 --> 00:40:09,183 THIS IS A LITTLE REVIEW ARTICLE 1156 00:40:09,183 --> 00:40:11,919 WE WROTE HERE WHEN IMMUNOTHERAPY 1157 00:40:11,919 --> 00:40:12,887 MEET SURGERY. 1158 00:40:12,887 --> 00:40:14,455 SO LUNG CANCERS BECOME THE 1159 00:40:14,455 --> 00:40:15,990 DISEASE WHERE YOU NEED TO HAVE 1160 00:40:15,990 --> 00:40:17,458 THIS TUMOR BOARD WHERE EVERYONE 1161 00:40:17,458 --> 00:40:18,726 SITS AROUND, REVIEWS THE 1162 00:40:18,726 --> 00:40:19,160 RESULTS. 1163 00:40:19,160 --> 00:40:22,897 I ALREADY SHOWED YOU EARLY ON, 1164 00:40:22,897 --> 00:40:24,866 RESULTS FROM THE EGFR MUTATIONS, 1165 00:40:24,866 --> 00:40:27,301 SO WE NEED TO KNOW WHO HAS AN 1166 00:40:27,301 --> 00:40:28,970 EGFR MUTATION, WE NEED TO KNOW 1167 00:40:28,970 --> 00:40:31,806 BHO HAS PDL1 POSITIVE, WE NEED 1168 00:40:31,806 --> 00:40:32,840 TO KNOW ANYTHING ELSE THAT'S 1169 00:40:32,840 --> 00:40:35,009 GOING ON IN THAT TUMOR AND WE 1170 00:40:35,009 --> 00:40:37,512 HAVE TO USE THAT APPROACH. 1171 00:40:37,512 --> 00:40:38,646 TUMOR BOARDS ARE ESSENTIAL TO 1172 00:40:38,646 --> 00:40:40,281 BRING THE NEWEST SCIENCE TO THE 1173 00:40:40,281 --> 00:40:42,116 CLINIC, AND THIS IS WHAT THE 1174 00:40:42,116 --> 00:40:43,251 YALE TUMOR BOARD LOOKS LIKE, 1175 00:40:43,251 --> 00:40:44,352 BECAUSE WE'RE ALL DOING IT BY 1176 00:40:44,352 --> 00:40:45,219 ZOOM NOW, BUT THE PEOPLE THAT 1177 00:40:45,219 --> 00:40:47,422 HAVE TO GO SEE PATIENTS NEXT, 1178 00:40:47,422 --> 00:40:49,557 THIS IS OUR PULMONOLOGISTS, COME 1179 00:40:49,557 --> 00:40:50,024 IN. 1180 00:40:50,024 --> 00:40:50,825 BUT ZOOM IS GREAT. 1181 00:40:50,825 --> 00:40:51,926 WE'RE ON ZOOM RIGHT NOW. 1182 00:40:51,926 --> 00:40:53,594 IT ALLOWS US TO GET MORE PEOPLE 1183 00:40:53,594 --> 00:40:54,629 INVOLVED. 1184 00:40:54,629 --> 00:40:56,330 WE SEE PATIENTS HERE THE A YALE 1185 00:40:56,330 --> 00:40:57,865 IN CONNECTICUT AT 15 SITES SO 1186 00:40:57,865 --> 00:40:58,833 EVERYONE CAN JOIN THE TUMOR 1187 00:40:58,833 --> 00:40:59,500 BOARD. 1188 00:40:59,500 --> 00:41:02,470 SO A FEW NOTES ABOUT THE FUTURE. 1189 00:41:02,470 --> 00:41:04,439 WE NEED TARGETED IMMUNOTHERAPY. 1190 00:41:04,439 --> 00:41:05,973 THIS IS OUR PASSION HERE. 1191 00:41:05,973 --> 00:41:07,942 WE HAVE THE PATHOLOGY, WE HAVE 1192 00:41:07,942 --> 00:41:10,812 THE DRUGS. 1193 00:41:10,812 --> 00:41:15,216 THOUSANDNOW WE HAVE TO PULL IT L 1194 00:41:15,216 --> 00:41:16,084 TOGETHER. 1195 00:41:16,084 --> 00:41:17,285 BUT WHAT WE WANT TO UNDERSTAND 1196 00:41:17,285 --> 00:41:21,222 IS WE WANT TO UNDERSTAND IMMUNE 1197 00:41:21,222 --> 00:41:22,223 RESISTANCE. 1198 00:41:22,223 --> 00:41:26,060 ONE OF THE PROJECTS ON OUR LUNG 1199 00:41:26,060 --> 00:41:27,795 SPORE HAS BEEN WITH CHEN TO 1200 00:41:27,795 --> 00:41:29,030 TARGET IMMUNE RESISTANCE WITH A 1201 00:41:29,030 --> 00:41:34,102 NEW CHECKPOINT KNOWN AS 1202 00:41:34,102 --> 00:41:34,936 SIGLEC15, WHICH ACTUALLY CAME 1203 00:41:34,936 --> 00:41:36,938 OUT OF A SCREEN LOOKING FOR 1204 00:41:36,938 --> 00:41:38,806 HOMOLOGUES TO PD-L1. 1205 00:41:38,806 --> 00:41:42,543 IT WAS ACTUALLY INTERESTING, A 1206 00:41:42,543 --> 00:41:44,612 SHOTGUN APPROACH, MULTIPLE 1207 00:41:44,612 --> 00:41:46,714 MEMBRANE GENES, MORE THAN 6500 1208 00:41:46,714 --> 00:41:50,551 PROTEINS WERE PUT INTO A T-CELL 1209 00:41:50,551 --> 00:41:51,652 REPORTER SYSTEM LOOKING FOR 1210 00:41:51,652 --> 00:41:53,121 INHIBITION OF T-CELL FUNCTION. 1211 00:41:53,121 --> 00:41:59,894 AND FROM THAT, LIEPING FOUND 1212 00:41:59,894 --> 00:42:03,431 SIGLEC15 WHICH IS HOMOLOGOUS TO 1213 00:42:03,431 --> 00:42:10,104 PD-L1. 1214 00:42:10,104 --> 00:42:11,639 SIGLEC15 IS NOW ON THE SURFACE 1215 00:42:11,639 --> 00:42:14,742 OF MACROPHAGES, TUMORS, AND IT 1216 00:42:14,742 --> 00:42:21,749 ACTUALLY ALSO U.S. SPRESES SUPPF 1217 00:42:21,749 --> 00:42:26,554 IT HAS PD-L1, IT MIGHT HAVE 1218 00:42:26,554 --> 00:42:27,688 SIGLEC15. 1219 00:42:27,688 --> 00:42:29,791 WHILE INTERFERON UPGRADES PD-L1, 1220 00:42:29,791 --> 00:42:32,727 IT ACTUALLY DOWN REGULATES 1221 00:42:32,727 --> 00:42:33,094 SIGLEC15. 1222 00:42:33,094 --> 00:42:36,464 SO THOSE TWO MORES THAT ARE LOW 1223 00:42:36,464 --> 00:42:38,232 INTERFERON, THEY MIGHT BE 1224 00:42:38,232 --> 00:42:40,434 TARGETS FOR SIGLEC15. 1225 00:42:40,434 --> 00:42:41,836 SO THIS WAS A PHASE ONE STUDY 1226 00:42:41,836 --> 00:42:45,807 THAT WAS LED BY PAT LARUSO AND 1227 00:42:45,807 --> 00:42:46,340 TEAM. 1228 00:42:46,340 --> 00:42:47,809 WE CONDUCTED IT AND YALE AND 1229 00:42:47,809 --> 00:42:48,676 THESE ARE PATIENTS WITH LUNG 1230 00:42:48,676 --> 00:42:49,010 CANCER. 1231 00:42:49,010 --> 00:42:50,545 YOU CAN SEE TWO PATIENTS SHOWN 1232 00:42:50,545 --> 00:42:53,080 HERE, THE RED IS A CR AND THE 1233 00:42:53,080 --> 00:42:54,282 YELLOW IS A PR. 1234 00:42:54,282 --> 00:42:57,785 TWO PATIENTS HAD RESPONSE, IN 1235 00:42:57,785 --> 00:42:59,086 THE REFRACTORY SETTING. 1236 00:42:59,086 --> 00:43:01,522 HERE YOU CAN SEAL AN EXAMPLE OF 1237 00:43:01,522 --> 00:43:04,425 THE PATIENT WHO HAD A TUMOR 1238 00:43:04,425 --> 00:43:07,328 REFRACTORY TO A PD-L1 INHIBITOR 1239 00:43:07,328 --> 00:43:08,329 WHO HAD A NICE RESPONSE. 1240 00:43:08,329 --> 00:43:10,498 THIS WAS A PHASE ONE STUDY FIRST 1241 00:43:10,498 --> 00:43:11,032 IN HUMAN. 1242 00:43:11,032 --> 00:43:13,000 THEN WE DID AN IIT AS PART OF 1243 00:43:13,000 --> 00:43:15,736 OUR LUNG SPORE WHICH IS NOW 1244 00:43:15,736 --> 00:43:16,237 COMPLETING THIS YEAR. 1245 00:43:16,237 --> 00:43:18,506 WE HAVE AN AMAZING TEAM, AS I'M 1246 00:43:18,506 --> 00:43:19,607 GETTING TO THE END OF MY TALK 1247 00:43:19,607 --> 00:43:20,741 THAT I'M PRESENTING THE WORK OF 1248 00:43:20,741 --> 00:43:21,843 SO MANY PEOPLE, I'M VERY 1249 00:43:21,843 --> 00:43:24,245 FORTUNATE TO BE HERE. 1250 00:43:24,245 --> 00:43:26,247 KATY IS BY MY SIDE, WE LEAD THIS 1251 00:43:26,247 --> 00:43:26,514 TOGETHER. 1252 00:43:26,514 --> 00:43:29,116 YOU CAN SEE PAT LARUSO, CURRENT 1253 00:43:29,116 --> 00:43:30,418 AACR PRESIDENT WHO LEADS OUR 1254 00:43:30,418 --> 00:43:31,853 PHASE ONE GROUP I'M SURE KNOWN 1255 00:43:31,853 --> 00:43:35,356 TO MANY, THERE'S LIEPING, KATIE 1256 00:43:35,356 --> 00:43:37,425 COURIC WAS VISITING SO HE PUT ON 1257 00:43:37,425 --> 00:43:38,025 A TIE. 1258 00:43:38,025 --> 00:43:40,228 THIS IS THE ENTIRE PHASE 1 TEAM. 1259 00:43:40,228 --> 00:43:41,529 WE REALLY HAVE AN AMAZING TEAM 1260 00:43:41,529 --> 00:43:44,098 AND THE TEAM TAKES CARE OF THESE 1261 00:43:44,098 --> 00:43:44,732 PATIENTS FROM THE LAB TO THE 1262 00:43:44,732 --> 00:43:45,633 CLINIC. 1263 00:43:45,633 --> 00:43:47,368 BUT THIS WAS OUR INVESTIGATOR 1264 00:43:47,368 --> 00:43:49,036 INITIATED TRIAL, AND WE DID THIS 1265 00:43:49,036 --> 00:43:51,339 WITH SUPPORT FROM THE SPORE 1266 00:43:51,339 --> 00:43:53,074 GRANT WITH SUPPORT FROM THE 1267 00:43:53,074 --> 00:43:54,709 COMPANY, TWO COMPANIES, MERCK 1268 00:43:54,709 --> 00:43:57,712 AND A COMPANY CALLED NECCURE. 1269 00:43:57,712 --> 00:43:58,813 WE'RE IN THE PROCESS OF PUTTING 1270 00:43:58,813 --> 00:44:00,448 TOGETHER THE MANUSCRIPT NOW, 1271 00:44:00,448 --> 00:44:02,350 WHERE WE ACTUALLY TOOK PATIENTS 1272 00:44:02,350 --> 00:44:04,652 WHO HAD HAD PRIOR PD-L1 AND WE 1273 00:44:04,652 --> 00:44:06,721 TREATED THEM WITH EITHER NC318 1274 00:44:06,721 --> 00:44:10,124 WHICH IS AN ANTIBODY AGAINST 1275 00:44:10,124 --> 00:44:12,660 SIGLEC15, OR THE ANTIBODY IN 1276 00:44:12,660 --> 00:44:14,161 COMBINATION WITH PEMBROLIZUMAB. 1277 00:44:14,161 --> 00:44:15,630 FOR SAKE OF THIS SHORT TALK, 1278 00:44:15,630 --> 00:44:16,397 WE'VE SEEN RESPONSES. 1279 00:44:16,397 --> 00:44:20,601 HERE'S A PATIENT WHO WAS 1280 00:44:20,601 --> 00:44:22,003 REFRACTORY, THEY HAD A RESPONSE. 1281 00:44:22,003 --> 00:44:23,971 HERE'S ANOTHER PATIENT WITH A 1282 00:44:23,971 --> 00:44:24,438 RESPONSE. 1283 00:44:24,438 --> 00:44:26,173 HERE'S A PATIENT WHO GOT 1284 00:44:26,173 --> 00:44:27,842 MONOTHERAPY WITH A RESPONSE. 1285 00:44:27,842 --> 00:44:30,144 HERE'S A PATIENT WITH A COMBO 1286 00:44:30,144 --> 00:44:30,912 WITH RESPONSE. 1287 00:44:30,912 --> 00:44:32,013 WHAT WE'RE IN THE PROCESS OF 1288 00:44:32,013 --> 00:44:35,082 DOING IS USING RNA SEQ, USING 1289 00:44:35,082 --> 00:44:35,616 IMMUNOHISTOCHEMISTRY TO 1290 00:44:35,616 --> 00:44:37,385 UNDERSTAND WHO RESPONDED AND 1291 00:44:37,385 --> 00:44:37,752 WHY. 1292 00:44:37,752 --> 00:44:45,860 STAY TUNED. 1293 00:44:45,860 --> 00:44:46,827 LUNG MAP WAS A LABOR OF LOVE 1294 00:44:46,827 --> 00:44:48,162 WHICH I SHARED FOR ABOUT A 1295 00:44:48,162 --> 00:44:48,963 DECADE. 1296 00:44:48,963 --> 00:44:51,899 THE IDEA BEHIND LUNG MAP, AND IT 1297 00:44:51,899 --> 00:44:53,768 ALL BEGAN AT AN NCI MEETING IN 1298 00:44:53,768 --> 00:44:55,536 2012, FOLLOWED BY FRIENDS OF 1299 00:44:55,536 --> 00:44:57,838 CANCER RESEARCH MEETING, ELLEN 1300 00:44:57,838 --> 00:44:59,140 SIEGEL AND TER TEAM LATER THAT 1301 00:44:59,140 --> 00:45:00,708 YEAR, WAS THE IDEA THAT ALL THE 1302 00:45:00,708 --> 00:45:02,009 COOPERATIVE GROUPS AS PART OF 1303 00:45:02,009 --> 00:45:03,344 THE NEW NATIONAL CLINICAL TRIAL 1304 00:45:03,344 --> 00:45:05,413 NETWORK WOULD WORK TOGETHER AND 1305 00:45:05,413 --> 00:45:08,082 WE HAD SUCH AMAZING SUPPORT FROM 1306 00:45:08,082 --> 00:45:12,820 NCI, JEFF ABRAMS, KIM DOROSHOW, 1307 00:45:12,820 --> 00:45:13,888 MEGAN AND HER TEAM, WE STILL 1308 00:45:13,888 --> 00:45:15,356 CONTINUE TO HAVE AMAZING 1309 00:45:15,356 --> 00:45:15,589 SUPPORT. 1310 00:45:15,589 --> 00:45:16,657 ALL THE COOPERATIVE GROUPS 1311 00:45:16,657 --> 00:45:18,092 WORKING TOGETHER, GUIDANCE FROM 1312 00:45:18,092 --> 00:45:23,397 THE FDA, AND USING THE FNIH AS A 1313 00:45:23,397 --> 00:45:24,799 COMMON BROKER IN THIS 1314 00:45:24,799 --> 00:45:26,534 PUBLIC-PRIVATE PARTNERSHIP 1315 00:45:26,534 --> 00:45:26,901 WITHIN INDUSTRY. 1316 00:45:26,901 --> 00:45:27,802 THE REASON I WANT TO SHOW YOU 1317 00:45:27,802 --> 00:45:29,003 THIS IS AGAIN ANOTHER TEAM, THIS 1318 00:45:29,003 --> 00:45:30,438 IS A MEETING WE HAD ABOUT FOUR 1319 00:45:30,438 --> 00:45:32,440 OR FIVE YEARS AGO AT ELLEN 1320 00:45:32,440 --> 00:45:33,407 SIEGEL'S OFFICE, DOWNTOWN 1321 00:45:33,407 --> 00:45:33,708 WASHINGTON. 1322 00:45:33,708 --> 00:45:36,177 IT REALLY IS A TEAM EFFORT. 1323 00:45:36,177 --> 00:45:37,511 BUT THE IDEA WAS, IF YOU ASK 1324 00:45:37,511 --> 00:45:41,248 WHAT WE NEED NOW IN THIS TIME, 1325 00:45:41,248 --> 00:45:43,117 WHICH IS ARGUABLY -- THEY'RE 1326 00:45:43,117 --> 00:45:44,151 ALWAYS TOUGH TIMES BUT THIS IS A 1327 00:45:44,151 --> 00:45:45,553 TIME WHERE WE ALL HAVE TO PULL 1328 00:45:45,553 --> 00:45:46,654 TOGETHER, I THINK COLLABORATION 1329 00:45:46,654 --> 00:45:47,321 IS KEY. 1330 00:45:47,321 --> 00:45:51,092 SO WE HAD A COMMON SCREENING 1331 00:45:51,092 --> 00:45:52,393 PROTOCOL, TRIAL OPENED AT 700 1332 00:45:52,393 --> 00:45:54,362 SITES WHERE PATIENTS COULD GET 1333 00:45:54,362 --> 00:45:55,429 SCREENED WITH FOUNDATION 1334 00:45:55,429 --> 00:45:57,231 MEDICINE PROFILING FOR DIFFERENT 1335 00:45:57,231 --> 00:45:57,665 MUTATIONS. 1336 00:45:57,665 --> 00:46:00,167 WE COULD TEST WHAT WE CALLED THE 1337 00:46:00,167 --> 00:46:01,469 BIOMARKER-DRIVEN SUBSTUDY, 1338 00:46:01,469 --> 00:46:02,536 DIFFERENT MUTATIONS TO SEE IF 1339 00:46:02,536 --> 00:46:03,838 DRUGS THAT TARGET THOSE 1340 00:46:03,838 --> 00:46:04,271 MUTATIONS WORK. 1341 00:46:04,271 --> 00:46:04,939 YOU KNOW WHAT? 1342 00:46:04,939 --> 00:46:06,173 MANY OF THESE TRIALS WERE 1343 00:46:06,173 --> 00:46:06,507 NEGATIVE. 1344 00:46:06,507 --> 00:46:07,608 THEY WERE IMPORTANT NEGATIVE 1345 00:46:07,608 --> 00:46:13,714 TRIALS, BUT WHEN YOU USE -- IT 1346 00:46:13,714 --> 00:46:15,149 DIDN'T CAUSE ENOUGH ACTIVITY. 1347 00:46:15,149 --> 00:46:16,851 BUT NOW WE'RE ACTUALLY USING 1348 00:46:16,851 --> 00:46:18,486 THIS FOR WHAT WE CALL THE 1349 00:46:18,486 --> 00:46:20,254 NON-MATCHED TRIALS TO TEST 1350 00:46:20,254 --> 00:46:21,489 IMMUNOTHERAPY COMBINATIONS. 1351 00:46:21,489 --> 00:46:23,324 AND THIS IS AMAZING, LOOK AT ALL 1352 00:46:23,324 --> 00:46:27,028 THESE PATIENTS TREATED, ALL THIS 1353 00:46:27,028 --> 00:46:30,231 TISSUE SITS THERE IN COLUMBUS, 1354 00:46:30,231 --> 00:46:31,032 OHIO AT THE BIOBANK. 1355 00:46:31,032 --> 00:46:32,433 THIS IS ALL NOW AVAILABLE FOR 1356 00:46:32,433 --> 00:46:35,503 STUDY. 1357 00:46:35,503 --> 00:46:42,543 AND IT IMPROVED DIVERSITY, THIS 1358 00:46:42,543 --> 00:46:43,878 PAPER SHOWS THAT PATIENTS FROM 1359 00:46:43,878 --> 00:46:44,945 ALL OVER THE COUNTRY COULD GET 1360 00:46:44,945 --> 00:46:46,747 ON THIS BECAUSE THEY'RE TREATED 1361 00:46:46,747 --> 00:46:47,415 AT THE POINT OF CARE IN A TRIAL 1362 00:46:47,415 --> 00:46:48,616 THAT PROVIDES THEM THESE NEW 1363 00:46:48,616 --> 00:46:51,786 DRUGS. 1364 00:46:51,786 --> 00:46:54,422 THERE WAS A VERY NICE POSITIVE 1365 00:46:54,422 --> 00:46:56,824 TRIAL OUT OF WORK I INITIATED. 1366 00:46:56,824 --> 00:47:00,461 SOME OF YOU MIGHT KNOW IT AS 1367 00:47:00,461 --> 00:47:00,761 PRAGMATICA. 1368 00:47:00,761 --> 00:47:05,566 THIS WAS THE PRE-PRAGMATICA 1369 00:47:05,566 --> 00:47:07,868 WHERE WE HAD A HAZARD RATIO OF 1370 00:47:07,868 --> 00:47:11,939 .69, THE BLEUL CURVE -- THE RED 1371 00:47:11,939 --> 00:47:13,340 IS DEALER'S CHOICE CHEMOTHERAPY. 1372 00:47:13,340 --> 00:47:15,443 THESE ARE ALL PATIENTS WHO 1373 00:47:15,443 --> 00:47:16,343 FAILED IMMUNOTHERAPY BUT HAD 1374 00:47:16,343 --> 00:47:18,179 BEEN ON IMMUNOTHERAPY FOR AT 1375 00:47:18,179 --> 00:47:18,746 LEAST 12 WEEKS. 1376 00:47:18,746 --> 00:47:20,381 SO THEY WEREN'T STONE COLD 1377 00:47:20,381 --> 00:47:21,749 NEGATIVE TO THEIR RESULTS. 1378 00:47:21,749 --> 00:47:24,585 THEY HAD SOME ACTIVITY, AND THIS 1379 00:47:24,585 --> 00:47:28,089 TRIAL WAS POSITIVE BUT IT WAS A 1380 00:47:28,089 --> 00:47:29,557 ONE-SIDED P VALUE, ONLY A SMALL 1381 00:47:29,557 --> 00:47:30,057 PHASE TWO. 1382 00:47:30,057 --> 00:47:31,959 WE TALKED ABOUT DOING A BIG 1383 00:47:31,959 --> 00:47:32,493 PHASE THREE. 1384 00:47:32,493 --> 00:47:33,594 NO ONE WAS INTERESTED, THE 1385 00:47:33,594 --> 00:47:34,395 COMPANIES WEREN'T INTERESTED, 1386 00:47:34,395 --> 00:47:35,629 BUT THEN WE TALKED ABOUT PRAGUE 1387 00:47:35,629 --> 00:47:36,063 MATT KA. 1388 00:47:36,063 --> 00:47:37,798 SO THE IDEA WAS TO DO A TRIAL 1389 00:47:37,798 --> 00:47:42,336 JUST LOOKING AT SURVIVAL. 1390 00:47:42,336 --> 00:47:48,008 THAT'S SWAG 2302. 1391 00:47:48,008 --> 00:47:50,144 SO USING REAL WORLD DATA IN A 1392 00:47:50,144 --> 00:47:54,748 PROSPECTIVE WAY. 1393 00:47:54,748 --> 00:48:00,020 THIS WAS PROSPECTIVE, YOU 1394 00:48:00,020 --> 00:48:00,521 PRESPECIFY -- SELECTIVE 1395 00:48:00,521 --> 00:48:01,021 MONITORING. 1396 00:48:01,021 --> 00:48:02,857 THIS TRIAL IS ONLY LOOKING AT 1397 00:48:02,857 --> 00:48:05,059 SURVIVAL AS AN END POINT, YOU 1398 00:48:05,059 --> 00:48:06,527 DON'T NEED TO DO PET SCANS, YOU 1399 00:48:06,527 --> 00:48:08,062 DON'T NEED TO DO CAT SCANS. 1400 00:48:08,062 --> 00:48:09,363 REALLY TRYING TO LIMIT WHAT'S 1401 00:48:09,363 --> 00:48:10,965 BEING DONE SO IT CAN BE DONE 1402 00:48:10,965 --> 00:48:12,166 QUICKLY, ELEGANTLY IN THE 1403 00:48:12,166 --> 00:48:14,001 COMMUNITY SETTING, AND THIS 1404 00:48:14,001 --> 00:48:16,470 TRIAL, IT WILL BE UPDATED AT 1405 00:48:16,470 --> 00:48:17,771 ASCO, WE HEARD IT JUST GOT 1406 00:48:17,771 --> 00:48:19,406 ACCEPTED TO ASCO TODAY. 1407 00:48:19,406 --> 00:48:21,008 LOOK AT THIS ACCRUAL. 1408 00:48:21,008 --> 00:48:22,109 THIS IS A COOPERATIVE GROUP 1409 00:48:22,109 --> 00:48:22,543 TRIAL. 1410 00:48:22,543 --> 00:48:28,249 THIS IS 30, 44, IN A YEAR AND A 1411 00:48:28,249 --> 00:48:30,317 HALF THAT INCLUDED THE FULL 708 1412 00:48:30,317 --> 00:48:32,319 PATIENTS WITH A VERY NICE 1413 00:48:32,319 --> 00:48:34,188 DIVERSE POPULATION TOO, BLACK OR 1414 00:48:34,188 --> 00:48:35,656 AFRICAN AMERICAN, ALMOST 15%. 1415 00:48:35,656 --> 00:48:36,423 SO I'M AT THE END NOW. 1416 00:48:36,423 --> 00:48:38,292 I WANT TO TURN IT OVER TO KATIE. 1417 00:48:38,292 --> 00:48:39,960 BUT I TALKED QUICKLY BUT I HOPE 1418 00:48:39,960 --> 00:48:41,929 YOU'VE SHARED MY PASSION, 1419 00:48:41,929 --> 00:48:43,130 EXCITEMENT AND THE DATA. 1420 00:48:43,130 --> 00:48:44,331 AND WE NEED TO GET THESE DATA 1421 00:48:44,331 --> 00:48:44,865 OUT THERE. 1422 00:48:44,865 --> 00:48:45,933 WE ARE MAKING A DIFFERENCE. 1423 00:48:45,933 --> 00:48:47,801 CAN WE CURE METASTATIC LUNG 1424 00:48:47,801 --> 00:48:49,003 CANCER? 1425 00:48:49,003 --> 00:48:50,771 IN SOME CASES WITH 1426 00:48:50,771 --> 00:48:51,105 IMMUNOTHERAPY. 1427 00:48:51,105 --> 00:48:53,174 AND I SHOWED YOU 12-PLUS YEAR 1428 00:48:53,174 --> 00:48:54,074 SURVIVORS. 1429 00:48:54,074 --> 00:48:55,910 TREATMENT CAN BE WELL TOLERATED 1430 00:48:55,910 --> 00:48:57,511 AND RETREATMENT IS POSSIBLE. 1431 00:48:57,511 --> 00:48:58,479 I DIDN'T SHOW YOU THAT BUT IT 1432 00:48:58,479 --> 00:48:59,213 IS. 1433 00:48:59,213 --> 00:49:03,117 THE PROBLEM IS WE HAVE -- 1434 00:49:03,117 --> 00:49:04,118 KNOWING IN ADVANCE OF WHO WILL 1435 00:49:04,118 --> 00:49:04,885 BE THOSE PATIENTS. 1436 00:49:04,885 --> 00:49:06,887 DO WE NEED TO PERSONALIZE 1437 00:49:06,887 --> 00:49:07,221 IMMUNOTHERAPY? 1438 00:49:07,221 --> 00:49:08,322 I WOULD SAY THAT'S THE GOAL. 1439 00:49:08,322 --> 00:49:11,659 WE HAVE SPENT PERSONALIZED -- 1440 00:49:11,659 --> 00:49:13,460 IT'S TIME TO DO THE SAME FOR 1441 00:49:13,460 --> 00:49:13,861 IMMUNOTHERAPY. 1442 00:49:13,861 --> 00:49:15,262 IT REQUIRES BIOMARKERS AND 1443 00:49:15,262 --> 00:49:18,699 BETTER COMBO, WE NEED MORE 1444 00:49:18,699 --> 00:49:19,800 SCIENCE, INNOVATIVE TRIAL 1445 00:49:19,800 --> 00:49:21,202 DESIGN, COLLABORATION AND 1446 00:49:21,202 --> 00:49:22,670 PUBLIC-PRIVATE PARTNERSHIPS 1447 00:49:22,670 --> 00:49:23,571 WHERE THE FUTURE IS NOW. 1448 00:49:23,571 --> 00:49:25,773 THIS IS OUR CURRENT SPORE 1449 00:49:25,773 --> 00:49:26,407 APPLICATION. 1450 00:49:26,407 --> 00:49:29,710 WE'VE MORPHED A BIT, WE HAVE A 1451 00:49:29,710 --> 00:49:32,112 NEW DRUG THAT TARGETS PLA T2 10 1452 00:49:32,112 --> 00:49:34,014 WHICH IS ONE OF THOSE T-CELL 1453 00:49:34,014 --> 00:49:35,482 EXPLORERS I MENTIONED EARLIER 1454 00:49:35,482 --> 00:49:38,652 WHERE WE'RE LOOKING AT PRECISION 1455 00:49:38,652 --> 00:49:39,420 APPROACHES. 1456 00:49:39,420 --> 00:49:40,621 KATIE IS GOING TO TELL YOU ABOUT 1457 00:49:40,621 --> 00:49:41,889 THAT NOW, AND WE'RE VERY 1458 00:49:41,889 --> 00:49:44,058 INTERESTED IN WAYS TO TARGET 1459 00:49:44,058 --> 00:49:44,825 METASTASES INCLUDING THE BRAIN. 1460 00:49:44,825 --> 00:49:46,160 IT'S BEEN A PLEASURE TO BE HERE 1461 00:49:46,160 --> 00:49:46,627 TODAY. 1462 00:49:46,627 --> 00:49:47,728 MANY OF THE LUNG COMMUNITY WERE 1463 00:49:47,728 --> 00:49:50,564 HERE AT YALE LAST JUNE 12TH AND 1464 00:49:50,564 --> 00:49:51,131 13TH. 1465 00:49:51,131 --> 00:49:52,900 WE HAD A WONDERFUL MEETING THAT 1466 00:49:52,900 --> 00:49:57,271 KATIE AND I ORGANIZED WITH N.C. 1467 00:49:57,271 --> 00:49:58,639 DEPI, OUR SPORE ADMINISTRATOR, 1468 00:49:58,639 --> 00:49:59,940 AND WE HAD ALL THESE PEOPLE FROM 1469 00:49:59,940 --> 00:50:02,476 ALL OVER THE UNITED STATES, SOME 1470 00:50:02,476 --> 00:50:04,011 INTERNATIONAL, WORKING ON LUNG 1471 00:50:04,011 --> 00:50:06,347 CANCER, ALL AFFILIATED WITH THE 1472 00:50:06,347 --> 00:50:07,214 NCI FUNDED RESEARCH. 1473 00:50:07,214 --> 00:50:17,625 THANK YOU ALL VERY MUCH. 1474 00:50:21,862 --> 00:50:22,429 >> THANK YOU. 1475 00:50:22,429 --> 00:50:24,131 THANK YOU, ROY, FOR THAT AMAZING 1476 00:50:24,131 --> 00:50:25,432 PRESENTATION. 1477 00:50:25,432 --> 00:50:27,401 SO I'M GOING TO SHARE MY SLIDES 1478 00:50:27,401 --> 00:50:30,771 NOW. 1479 00:50:30,771 --> 00:50:34,975 AND TELL YOU ABOUT SOME OF THE 1480 00:50:34,975 --> 00:50:36,510 SCIENTIFIC EFFORTS THAT GO ALONG 1481 00:50:36,510 --> 00:50:38,912 WITH SOME OF THE AMAZING 1482 00:50:38,912 --> 00:50:40,014 PROGRESS THAT ROY HAS JUST TOLD 1483 00:50:40,014 --> 00:50:41,582 YOU ABOUT IN THE CLINICAL 1484 00:50:41,582 --> 00:50:47,755 EFFORTS. 1485 00:50:47,755 --> 00:50:49,056 I'M JUST GOING TO SHARE MY 1486 00:50:49,056 --> 00:50:52,993 SLIDES. 1487 00:50:52,993 --> 00:50:58,565 LET ME PUT THEM ON SLIDE SHARE. 1488 00:50:58,565 --> 00:51:00,234 ONCE I HAVE THEM, THEN I CAN GO 1489 00:51:00,234 --> 00:51:05,606 AHEAD AND GET STARTED. 1490 00:51:05,606 --> 00:51:07,574 SO THESE ARE MY DISCLOSURES. 1491 00:51:07,574 --> 00:51:09,376 SO AS YOU HEARD FROM ROY, LUNG 1492 00:51:09,376 --> 00:51:11,245 CANCER IS THE LEADING CAUSE OF 1493 00:51:11,245 --> 00:51:14,648 CANCER DEATHS IN THE UNITED 1494 00:51:14,648 --> 00:51:19,186 STATES AND WORLDWIDE, BUT WE DO 1495 00:51:19,186 --> 00:51:20,354 HAVE SOME REALLY GOOD NEWS IN 1496 00:51:20,354 --> 00:51:21,689 THAT WE ARE SEEING THAT THE 1497 00:51:21,689 --> 00:51:23,490 MORTALITY FROM LUNG CANCER HAS 1498 00:51:23,490 --> 00:51:24,358 DECLINED, AND I THINK SOME OF 1499 00:51:24,358 --> 00:51:26,860 THE NUMBERS ARE PRETTY STRIKING. 1500 00:51:26,860 --> 00:51:31,532 IF WE LOOK AT THE NUMBER OF LUNG 1501 00:51:31,532 --> 00:51:33,100 CANCER DEATHS TODAY COMPARED TO 1502 00:51:33,100 --> 00:51:35,336 20 YEARS AGO, WE SEE THAT THERE 1503 00:51:35,336 --> 00:51:37,371 ARE ABOUT 40,000 FEWER LUNG 1504 00:51:37,371 --> 00:51:38,672 CANCER DEATHS A YEAR NOW THAN 1505 00:51:38,672 --> 00:51:40,207 THERE WERE 20 YEARS AGO. 1506 00:51:40,207 --> 00:51:43,043 SO REALLY THERE HAS BEEN 1507 00:51:43,043 --> 00:51:49,149 TREMENDOUS PROGRESS IN ADVANCING 1508 00:51:49,149 --> 00:51:50,551 OF CARE OF PEOPLE LIVING WITH 1509 00:51:50,551 --> 00:51:51,085 LUNG CANCER. 1510 00:51:51,085 --> 00:51:55,255 THIS IS BECAUSE THERE REALLY, 1511 00:51:55,255 --> 00:51:56,824 OVER THE PAST TWO DECADES, HAVE 1512 00:51:56,824 --> 00:51:58,559 BEEN TREMENDOUS ADVANCES IN OUR 1513 00:51:58,559 --> 00:52:00,260 UNDERSTANDING OF BIOLOGICAL 1514 00:52:00,260 --> 00:52:01,895 PROCESSES THAT ARE INVOLVED IN 1515 00:52:01,895 --> 00:52:05,199 LUNG CANCER, AND ALSO REALLY THE 1516 00:52:05,199 --> 00:52:07,468 INTEGRATION OF THIS KNOWLEDGE OF 1517 00:52:07,468 --> 00:52:11,138 LUNG CANCER BIOLOGY WITH STUDIES 1518 00:52:11,138 --> 00:52:14,308 OF CLINICAL SPECIMENS AND 1519 00:52:14,308 --> 00:52:15,609 STUDIES OF DATA FROM PATIENTS 1520 00:52:15,609 --> 00:52:18,979 WITH LUNG CANCER. 1521 00:52:18,979 --> 00:52:20,280 THESE TOGETHER, BY INTEGRATING 1522 00:52:20,280 --> 00:52:22,149 THESE DATASETS, WE'VE REALLY 1523 00:52:22,149 --> 00:52:26,987 BEEN ABLE TO HAVE LEAD TO 1524 00:52:26,987 --> 00:52:28,055 DISCOVERIES THAT HAVE LED TO 1525 00:52:28,055 --> 00:52:29,390 CLINICAL TRIALS AND NEW 1526 00:52:29,390 --> 00:52:30,190 THERAPEUTIC APPROACHES FOR 1527 00:52:30,190 --> 00:52:31,425 PATIENTS, SOME OF WHICH YOU 1528 00:52:31,425 --> 00:52:33,827 HEARD ABOUT FROM ROY EARLIER 1529 00:52:33,827 --> 00:52:40,067 DURING HIS PRESENTATION. 1530 00:52:40,067 --> 00:52:41,368 STO WHAT ARE SOME OF THESE 1531 00:52:41,368 --> 00:52:42,436 INSIGHTS AND WHAT ARE SOME OF 1532 00:52:42,436 --> 00:52:43,070 THESE ADVANCES? 1533 00:52:43,070 --> 00:52:45,139 I THINK ONE OF THE THINGS THAT 1534 00:52:45,139 --> 00:52:49,743 REALLY HAS EMERGED OVER THE PAST 1535 00:52:49,743 --> 00:52:50,677 TWO DECADES IS THAT WHEN WE 1536 00:52:50,677 --> 00:52:52,312 THINK OF LUNG CANCER, WE CAN'T 1537 00:52:52,312 --> 00:52:54,748 REALLY THINK ABOUT IT AS ONE 1538 00:52:54,748 --> 00:52:55,182 ENTITY. 1539 00:52:55,182 --> 00:52:57,518 THERE ARE MULTIPLE DIFFERENT 1540 00:52:57,518 --> 00:52:58,752 HISTOLOGICAL SUBTYPES AND THERE 1541 00:52:58,752 --> 00:53:00,053 ARE MULTIPLE DIFFERENT MOLECULAR 1542 00:53:00,053 --> 00:53:04,124 SUBTYPES. 1543 00:53:04,124 --> 00:53:06,560 SO WE THINK OF NON-SMALL CELL 1544 00:53:06,560 --> 00:53:08,228 LUNG CANCER WHICH REALLY 1545 00:53:08,228 --> 00:53:09,730 REPRESENTS OTHER HISTOLOGICAL 1546 00:53:09,730 --> 00:53:10,931 SUBCATEGORIES INCLUDING LARGE 1547 00:53:10,931 --> 00:53:13,200 CELL CARCINOMA, SQUAMOUS CELL 1548 00:53:13,200 --> 00:53:15,602 CARCINOMA AND LUNG 1549 00:53:15,602 --> 00:53:18,071 ADENOCARCINOMAS, WHICH LUNG 1550 00:53:18,071 --> 00:53:19,039 ADENOCARCINOMAS ARE THE MOST 1551 00:53:19,039 --> 00:53:22,443 COMMONLY OBSERVED HISTOLOGICAL 1552 00:53:22,443 --> 00:53:24,611 TYPE OF LUNG CANCER. 1553 00:53:24,611 --> 00:53:25,979 LUNG CANCER ALSO REPRESENTS 1554 00:53:25,979 --> 00:53:27,614 ABOUT 15% OF ALL LUNG CANCER 1555 00:53:27,614 --> 00:53:29,583 CASES. 1556 00:53:29,583 --> 00:53:32,319 SO WHEN WE TAKE LUNG 1557 00:53:32,319 --> 00:53:32,886 ADENOCARCINOMAS, ONE OF THE 1558 00:53:32,886 --> 00:53:34,021 THINGS THAT HAS HAPPENED OVER 1559 00:53:34,021 --> 00:53:36,089 THE PAST TWO DECADES, AND THIS 1560 00:53:36,089 --> 00:53:37,958 REALLY IS IN PART BECAUSE OF THE 1561 00:53:37,958 --> 00:53:44,765 STUDIES THAT HAVE GONE ON TO 1562 00:53:44,765 --> 00:53:47,067 REALLY UNDERSTAND, TO SEQUENCE 1563 00:53:47,067 --> 00:53:48,602 THE CANCER GENOMES AND TO REALLY 1564 00:53:48,602 --> 00:53:51,271 UNDERSTAND THE MOLECULAR BASES 1565 00:53:51,271 --> 00:53:52,606 OF THESE TUMORS IS THAT NOW WE 1566 00:53:52,606 --> 00:53:55,209 KNOW THAT THERE ARE SPECIFIC 1567 00:53:55,209 --> 00:53:56,810 MOLECULAR ALTERATIONS, GENETIC 1568 00:53:56,810 --> 00:54:01,281 MUTATIONS THAT ARE PRESENT IN 1569 00:54:01,281 --> 00:54:02,816 MANY LUNG ADENOCARCINOMAS THAT 1570 00:54:02,816 --> 00:54:04,785 ARE PRESENT IN GENES WHICH 1571 00:54:04,785 --> 00:54:07,154 REALLY LEADS TO DRIVE 1572 00:54:07,154 --> 00:54:09,656 TUMORIGENESIS IN THOSE CONTEXTS. 1573 00:54:09,656 --> 00:54:11,859 AND SO ROY TOLD YOU ABOUT SOME 1574 00:54:11,859 --> 00:54:14,661 OF THOSE WHEN HE SPOKE ABOUT THE 1575 00:54:14,661 --> 00:54:16,063 EGF RECEPTOR MUTATIONS IN LUNG 1576 00:54:16,063 --> 00:54:17,498 CANCER, AND WE'LL TALK ABOUT 1577 00:54:17,498 --> 00:54:21,268 THOSE ALSO A LITTLE BIT MORE 1578 00:54:21,268 --> 00:54:22,703 EXTENSIVELY IN THIS 1579 00:54:22,703 --> 00:54:24,671 PRESENTATION, BUT HERE YOU CAN 1580 00:54:24,671 --> 00:54:26,039 SEE IF WE LOOK AT THIS CHART 1581 00:54:26,039 --> 00:54:28,775 HERE, YOU CAN SEE THAT THE EGF 1582 00:54:28,775 --> 00:54:31,612 RECEPTOR MUTATIONS IN THE 1583 00:54:31,612 --> 00:54:33,547 EPIDERMAL GROWTH FACTOR 1584 00:54:33,547 --> 00:54:34,314 RECEPTOR, I'LL TELL YOU A LITTLE 1585 00:54:34,314 --> 00:54:39,553 ABOUT THAT IN A LITTLE WHILE, 1586 00:54:39,553 --> 00:54:41,955 THOSE ARE QUITE COMMONLY 1587 00:54:41,955 --> 00:54:43,557 OBSERVED IN ADENOCARCINOMAS AS 1588 00:54:43,557 --> 00:54:45,859 ARE MUTATIONS IN THE KRAS 1589 00:54:45,859 --> 00:54:47,060 ONCOGENE, AND THEN THERE ARE A 1590 00:54:47,060 --> 00:54:49,530 NUMBER OF OTHER GENES WHERE 1591 00:54:49,530 --> 00:54:50,831 MUTATIONS ARE FOUND IN THESE 1592 00:54:50,831 --> 00:54:54,768 SORT OF SMALLER SLICES OF THIS 1593 00:54:54,768 --> 00:54:55,235 PIE CHART. 1594 00:54:55,235 --> 00:54:56,803 YOU CAN SEE THEM LISTED BELOW. 1595 00:54:56,803 --> 00:54:59,439 ONE OF THE REALLY IMPORTANT 1596 00:54:59,439 --> 00:55:00,974 THINGS TO THINK ABOUT IS THAT 1597 00:55:00,974 --> 00:55:05,112 WITH THIS KNOWLEDGE OF THESE 1598 00:55:05,112 --> 00:55:06,380 SPECIFIC ALTERATIONS AND THE 1599 00:55:06,380 --> 00:55:08,148 KNOWLEDGE THAT THESE MUTATIONS 1600 00:55:08,148 --> 00:55:12,519 THEN DRIVE LUNG CANCER 1601 00:55:12,519 --> 00:55:14,054 TUMORIGENESIS, IN PARALLEL, 1602 00:55:14,054 --> 00:55:15,322 THERAPIES WERE DEVELOPED THAT 1603 00:55:15,322 --> 00:55:18,825 COULD COUNTERACT THE ONCOGENIC 1604 00:55:18,825 --> 00:55:20,561 ACTIVITY OF THESE DIFFERENT 1605 00:55:20,561 --> 00:55:24,631 VARIANTS. 1606 00:55:24,631 --> 00:55:26,567 SO WE'VE SEEN SOME TREMENDOUS 1607 00:55:26,567 --> 00:55:28,302 ADVANCES OVER THE PAST COUPLE OF 1608 00:55:28,302 --> 00:55:29,603 DECADES BECAUSE AS A RESULT OF 1609 00:55:29,603 --> 00:55:32,773 THESE OBSERVATIONS, AND HERE YOU 1610 00:55:32,773 --> 00:55:37,110 CAN SEE THIS TIMELINE OF FDA 1611 00:55:37,110 --> 00:55:39,313 DRUG APPROVALS, OF DRUGS WITH 1612 00:55:39,313 --> 00:55:40,614 UNIQUE MECHANISMS OF ACTION THAT 1613 00:55:40,614 --> 00:55:44,318 HAVE HAPPENED OVER THE PAST FEW 1614 00:55:44,318 --> 00:55:44,618 YEARS. 1615 00:55:44,618 --> 00:55:45,719 I'LL SHOW YOU ACTUALLY SOME 1616 00:55:45,719 --> 00:55:47,888 OTHER TIMELINES AND OTHER GRAPHS 1617 00:55:47,888 --> 00:55:51,792 THAT REALLY CAN HIGHLIGHT HOW 1618 00:55:51,792 --> 00:55:53,760 THESE AGENTS TARGET DIFFERENT 1619 00:55:53,760 --> 00:55:55,095 MOLECULAR SUBSETS OF LUNG CANCER 1620 00:55:55,095 --> 00:55:58,999 BUT YOU CAN SEE HERE IN BLUE, 1621 00:55:58,999 --> 00:56:00,334 THESE ARE ALL TARGETED THERAPIES 1622 00:56:00,334 --> 00:56:02,002 AND AS WELL, WHAT HAS HAPPENED 1623 00:56:02,002 --> 00:56:03,537 DURING THESE PAST COUPLE OF 1624 00:56:03,537 --> 00:56:04,738 DECADES IS THIS HAS GONE HAND IN 1625 00:56:04,738 --> 00:56:06,673 HAND WITH THE DEVELOPMENT OF 1626 00:56:06,673 --> 00:56:08,742 IMMUNOTHERAPIES AND THOSE ARE 1627 00:56:08,742 --> 00:56:14,548 SHOWN HERE IN YELLOW HERE. 1628 00:56:14,548 --> 00:56:16,149 I THINK THIS IS HIGHLIGHT IN A 1629 00:56:16,149 --> 00:56:22,055 SLIGHTLY DIFFERENT WAY, BUT ALSO 1630 00:56:22,055 --> 00:56:23,156 MORE EXTENSIVELY FOR SOME OF THE 1631 00:56:23,156 --> 00:56:25,092 DIFFERENT MOLECULAR SUBSETS OF 1632 00:56:25,092 --> 00:56:28,362 LUNG ADENOCARCINOMAS THAT HARBOR 1633 00:56:28,362 --> 00:56:29,563 DIFFERENT GENETIC ALTERATIONS. 1634 00:56:29,563 --> 00:56:30,998 YOU CAN SEE HERE FOR EXAMPLE 1635 00:56:30,998 --> 00:56:32,866 TUMORS WITH EGFR MUTATIONS, 1636 00:56:32,866 --> 00:56:34,234 THESE ARE ALL OF THESE DIFFERENT 1637 00:56:34,234 --> 00:56:35,102 TARGETED THERAPIES AND APPROVALS 1638 00:56:35,102 --> 00:56:36,303 THAT HAVE BEEN DEVELOPED OVER 1639 00:56:36,303 --> 00:56:38,972 THE PAST FEW YEARS FOR TUMORS 1640 00:56:38,972 --> 00:56:41,074 THAT HARBOR EGF RECEPTOR 1641 00:56:41,074 --> 00:56:43,543 MUTATIONS, ALL THESE GREEN 1642 00:56:43,543 --> 00:56:43,744 BOXES. 1643 00:56:43,744 --> 00:56:46,713 THERE ALSO ARE TUMORS THAT HAVE 1644 00:56:46,713 --> 00:56:50,083 REARRANGEMENTS IN THE ANAPLASTIC 1645 00:56:50,083 --> 00:56:51,351 LYMPHOMA -- HERE IN ORANGE ARE 1646 00:56:51,351 --> 00:56:52,252 BOXES INDICATING AGENTS THAT 1647 00:56:52,252 --> 00:56:57,691 WERE APPROVED DURING THIS TIME 1648 00:56:57,691 --> 00:57:02,996 FRAME FOR -- LUNG CANCERS. 1649 00:57:02,996 --> 00:57:08,301 SO REALLY EXPLOSION OF THERAPIES 1650 00:57:08,301 --> 00:57:09,369 THAT HAVE BEEN DEVELOPED AS A 1651 00:57:09,369 --> 00:57:13,840 RESULT OF THESE FINDINGS AND 1652 00:57:13,840 --> 00:57:16,076 THESE MOLECULAR ANALYSES OF THE 1653 00:57:16,076 --> 00:57:16,309 TUMORS. 1654 00:57:16,309 --> 00:57:20,781 I REALLY LIKE TO SHOW THIS CHART 1655 00:57:20,781 --> 00:57:22,215 FROM THE LUNG CANCER RESEARCH 1656 00:57:22,215 --> 00:57:23,250 FOUNDATION WHICH SHOWS IF WE 1657 00:57:23,250 --> 00:57:24,785 LOOK AT LUNG CANCER, THESE FDA 1658 00:57:24,785 --> 00:57:26,453 DRUG APPROVALS OVER THE YEARS, 1659 00:57:26,453 --> 00:57:28,355 OVER THE DECADES, AND YOU CAN 1660 00:57:28,355 --> 00:57:31,191 SEE THAT THERE REALLY HAS BEEN A 1661 00:57:31,191 --> 00:57:34,261 REVOLUTION, I'D SAY, SINCE THE 1662 00:57:34,261 --> 00:57:36,863 EARLY 2000s WITH THE ADVENT OF 1663 00:57:36,863 --> 00:57:39,166 TARGETED THERAPIES, MANY OF THEM 1664 00:57:39,166 --> 00:57:41,134 APPROVED OVER THE PAST TWO 1665 00:57:41,134 --> 00:57:42,769 DECADES, AND YOU CAN SEE THOSE 1666 00:57:42,769 --> 00:57:44,471 ARE REPRESENTED BY THESE BLUE 1667 00:57:44,471 --> 00:57:47,307 AND WHITE PILLS HERE, AND THEN 1668 00:57:47,307 --> 00:57:51,912 IMMUNOTHERAPIES ALSO REPRESENTED 1669 00:57:51,912 --> 00:57:53,880 HERE BY THESE HELICES. 1670 00:57:53,880 --> 00:57:55,048 SO REALLY PARADIGM SHIFT IN THE 1671 00:57:55,048 --> 00:57:57,250 USE AND THE TREATMENT OF LUNG 1672 00:57:57,250 --> 00:58:01,488 CANCER. 1673 00:58:01,488 --> 00:58:03,190 SO THIS IS ALL WONDERFUL, WE'VE 1674 00:58:03,190 --> 00:58:04,424 TOLD YOU ABOUT ALL THESE NEW 1675 00:58:04,424 --> 00:58:05,092 THERAPIES, WE'VE TOLD YOU ABOUT 1676 00:58:05,092 --> 00:58:06,660 ALL OF THESE ADVANCES OF 1677 00:58:06,660 --> 00:58:09,629 DECREASES IN LUNG CANCER 1678 00:58:09,629 --> 00:58:10,063 MORTALITY. 1679 00:58:10,063 --> 00:58:11,798 SO HAND IN HAND WITH THAT GOOD 1680 00:58:11,798 --> 00:58:16,136 NEWS, HOWEVER, WE REALLY ALSO DO 1681 00:58:16,136 --> 00:58:17,771 HAVE TO POINT OUT THAT THERE IS 1682 00:58:17,771 --> 00:58:19,306 A MAJOR CHALLENGE IN THE FIELD 1683 00:58:19,306 --> 00:58:22,008 THAT REALLY IS HAMPERING THE 1684 00:58:22,008 --> 00:58:25,846 ABILITY TO CURE PATIENTS WITH 1685 00:58:25,846 --> 00:58:28,682 METASTATIC LUNG CANCER WITH 1686 00:58:28,682 --> 00:58:30,117 THESE TYPES OF THERAPEUTIC 1687 00:58:30,117 --> 00:58:30,450 APPROACHES. 1688 00:58:30,450 --> 00:58:32,452 AND THAT IS BECAUSE TUMORS CAN 1689 00:58:32,452 --> 00:58:34,421 BECOME RESISTANT TO THERAPY. 1690 00:58:34,421 --> 00:58:36,623 AND SO HERE IF WE HAVE A TUMOR, 1691 00:58:36,623 --> 00:58:39,760 THIS IS A TUMOR ILLUSTRATED HERE 1692 00:58:39,760 --> 00:58:40,861 PRE-TREATMENT, WE GIVE IT A 1693 00:58:40,861 --> 00:58:42,596 THERAPY, WHETHER IT BE AN 1694 00:58:42,596 --> 00:58:43,663 IMMUNOTHERAPY OR TARGETED 1695 00:58:43,663 --> 00:58:45,499 THERAPY, FOR EXAMPLE. 1696 00:58:45,499 --> 00:58:47,601 IF THE TUMOR DOESN'T SHRINK AT 1697 00:58:47,601 --> 00:58:49,603 ALL, THAT'S WHAT'S CALLED 1698 00:58:49,603 --> 00:58:52,439 PRIMARY RESISTANCE. 1699 00:58:52,439 --> 00:58:54,241 THE TUMOR CAN ALSO SHRINK AND 1700 00:58:54,241 --> 00:58:57,377 RESPOND INITIALLY BUT THEN GROW 1701 00:58:57,377 --> 00:58:59,212 OUT AGAIN. 1702 00:58:59,212 --> 00:59:02,048 BECAUSE IT DEVELOPS SECONDARY OR 1703 00:59:02,048 --> 00:59:05,852 ACQUIRED RESISTANCE. 1704 00:59:05,852 --> 00:59:07,287 AND HERE JUST TO ILLUSTRATE FOR 1705 00:59:07,287 --> 00:59:11,391 EXAMPLE THAT ACQUIRED RESISTANCE 1706 00:59:11,391 --> 00:59:12,692 IS COMMON BOTH TO TARGETED 1707 00:59:12,692 --> 00:59:15,462 THERAPIES AND TO I 1708 00:59:15,462 --> 00:59:15,829 IMMUNOTHERAPIES. 1709 00:59:15,829 --> 00:59:17,030 YOU CAN SEE HERE IN THE CONTEXT 1710 00:59:17,030 --> 00:59:20,100 OF KRAS G12C-DRIVEN LUNG TUMORS, 1711 00:59:20,100 --> 00:59:22,269 WE HAVE TUMORS THAT ARE 1712 00:59:22,269 --> 00:59:23,570 PRE-TREATMENT, YOU CAN SEE IN 1713 00:59:23,570 --> 00:59:25,639 THESE SCANS, YOU HAVE THE 1714 00:59:25,639 --> 00:59:26,640 TUMORS. 1715 00:59:26,640 --> 00:59:32,279 THESE TUMORS ARE TREATED WITH A 1716 00:59:32,279 --> 00:59:33,680 KRAS -- TARGETED THERAPY THAT 1717 00:59:33,680 --> 00:59:35,882 TARGETS KRAS DIRECTLY. 1718 00:59:35,882 --> 00:59:37,584 THE TUMORS SHRINK BUT THEN 1719 00:59:37,584 --> 00:59:41,955 EVENTUALLY THE TUMORS COME BACK. 1720 00:59:41,955 --> 00:59:43,857 EVEN HERE IN THE CONTEXT OF 1721 00:59:43,857 --> 00:59:45,625 IMMUNOTHERAPIES, YOU CAN SEE 1722 00:59:45,625 --> 00:59:46,827 THAT SORT OF THE NUMBER OF 1723 00:59:46,827 --> 00:59:52,532 PATIENTS AT RISK OF RELAPSE -- 1724 00:59:52,532 --> 00:59:54,601 OVER TIME, WHEN PATIENTS DEVELOP 1725 00:59:54,601 --> 00:59:56,403 PROGRESSIVE DISEASE, EVEN ON 1726 00:59:56,403 --> 00:59:56,870 IMMUNOTHERAPY. 1727 00:59:56,870 --> 00:59:58,705 SO ACQUIRED RESISTANCE IS A 1728 00:59:58,705 --> 01:00:02,209 MAJOR CHALLENGE. 1729 01:00:02,209 --> 01:00:03,276 SO WHAT I'D LIKE TO DO IS TALK 1730 01:00:03,276 --> 01:00:04,344 TO YOU A LITTLE BIT ABOUT SOME 1731 01:00:04,344 --> 01:00:07,314 OF THE WAYS IN WHICH WE'RE 1732 01:00:07,314 --> 01:00:08,849 STUDYING RESISTANCE, THINKING 1733 01:00:08,849 --> 01:00:09,983 ABOUT RESISTANCE, FIRST OF ALL 1734 01:00:09,983 --> 01:00:16,256 IN THE CONTEXT OF EGFR LUNG 1735 01:00:16,256 --> 01:00:17,424 CANCER, LABORATORY HAS SERVED AS 1736 01:00:17,424 --> 01:00:21,127 A PARADIGM FOR UNDERSTANDING 1737 01:00:21,127 --> 01:00:23,096 RESISTANCE TO TARGETED 1738 01:00:23,096 --> 01:00:23,864 THERAPIES. 1739 01:00:23,864 --> 01:00:26,466 SO I'LL ALSO TOUCH ON A LITTLE 1740 01:00:26,466 --> 01:00:27,968 BIT SOME OF THE WORK IN THE 1741 01:00:27,968 --> 01:00:32,505 COUCONTEXT OF IMMUNOTHERAPIES. 1742 01:00:32,505 --> 01:00:34,975 SO FIRST OF ALL WHEN WE THINK OF 1743 01:00:34,975 --> 01:00:36,509 EGFR RECEPTOR DRIVEN LUNG 1744 01:00:36,509 --> 01:00:42,048 CANCER, EGF RECEPTOR IS RECEPTOR 1745 01:00:42,048 --> 01:00:43,283 TYROSINE KINASE SO IT'S ON THE 1746 01:00:43,283 --> 01:00:45,986 CELL SERVICE, YOU CAN SEE HERE 1747 01:00:45,986 --> 01:00:50,557 THIS IS THE NUCLEUS, THIS BLUE 1748 01:00:50,557 --> 01:00:54,761 CIRCLE, AND E TBGF RECEPTOR NEEA 1749 01:00:54,761 --> 01:00:57,297 LIGAND THAT HAS TO BIND EGF 1750 01:00:57,297 --> 01:01:01,134 RECEPTOR TO BRING IT TOGETHER, 1751 01:01:01,134 --> 01:01:04,337 BRING DIFFERENT MONOMERS OF EGF 1752 01:01:04,337 --> 01:01:06,172 RECEPTOR TOGETHER AND LEAD TO 1753 01:01:06,172 --> 01:01:09,442 DIMERIZATION AND THEN ACTIVATION 1754 01:01:09,442 --> 01:01:10,644 OF EGF RECEPTOR. 1755 01:01:10,644 --> 01:01:12,345 SO YOU CAN SEE THIS LIGAND 1756 01:01:12,345 --> 01:01:14,114 REPRESENTED HERE BY THIS PINK 1757 01:01:14,114 --> 01:01:14,547 CIRCLE. 1758 01:01:14,547 --> 01:01:18,618 ONCE EGF RECEPTOR IS ACTIVE, IT 1759 01:01:18,618 --> 01:01:20,520 CAN TELL THE CELLS ESSENTIALLY 1760 01:01:20,520 --> 01:01:22,389 ONCE IT'S LIGAND BOUND TO DIVIDE 1761 01:01:22,389 --> 01:01:23,290 AND TO SURVIVE. 1762 01:01:23,290 --> 01:01:26,526 SO THAT'S WHAT HAPPENS IN NORMAL 1763 01:01:26,526 --> 01:01:27,594 HOMEOSTASIS, YOU REALLY HAVE TO 1764 01:01:27,594 --> 01:01:30,764 HAVE THOSE LIGANDS PRESENT TO 1765 01:01:30,764 --> 01:01:33,700 ACTIVATE THE EGF RECEPTOR. 1766 01:01:33,700 --> 01:01:36,569 WHEN A MUTATION IS PRESENT IN 1767 01:01:36,569 --> 01:01:39,172 LUNG CANCER, ONE OF THE THINGS 1768 01:01:39,172 --> 01:01:41,675 THAT CAN HAPPEN AND THE MUTATION 1769 01:01:41,675 --> 01:01:43,109 IS REPRESENTED BY THIS LIGHTNING 1770 01:01:43,109 --> 01:01:44,210 BOLT IS THAT THEN THE TUMOR 1771 01:01:44,210 --> 01:01:49,649 DOESN'T REALLY NEED -- THE EGF 1772 01:01:49,649 --> 01:01:50,650 RECEPTOR DOESN'T NEED THE LIGAND 1773 01:01:50,650 --> 01:01:52,719 TO GET ACTIVATED, IT GETS 1774 01:01:52,719 --> 01:01:55,956 ACTIVATED IN THE ABSENCE OF ANY 1775 01:01:55,956 --> 01:01:58,024 SPECIFIC SORT OF REAL EXOGENOUS 1776 01:01:58,024 --> 01:01:58,825 CONTROLS. 1777 01:01:58,825 --> 01:02:00,794 AND SO ONE WAY OF THINKING ABOUT 1778 01:02:00,794 --> 01:02:02,929 IT IS LIKE -- IT'S LIKE A LEAKY 1779 01:02:02,929 --> 01:02:03,363 FAUCET, RIGHT? 1780 01:02:03,363 --> 01:02:04,898 SO NORMALLY YOU CAN TURN THE 1781 01:02:04,898 --> 01:02:06,099 FAUCET ON, YOU CAN TURN THE 1782 01:02:06,099 --> 01:02:08,034 FAUCET OFF, CAN YOU CONTROL 1783 01:02:08,034 --> 01:02:09,903 THAT, BUT WHEN YOU HAVE THE EGFR 1784 01:02:09,903 --> 01:02:11,871 MUTATION OR THE MUTATION, IT'S 1785 01:02:11,871 --> 01:02:13,139 LIKE -- IT'S ALWAYS ON A LITTLE 1786 01:02:13,139 --> 01:02:17,844 BIT AND DRIPPING. 1787 01:02:17,844 --> 01:02:18,545 SO ONE OF THE THINGS THAT HAS 1788 01:02:18,545 --> 01:02:21,147 BEEN DEVELOPED OVER THE YEARS, 1789 01:02:21,147 --> 01:02:22,882 THESE TARGETED THERAPIES AGAINST 1790 01:02:22,882 --> 01:02:27,253 MUTATED EGF RECEPTOR HAVE BEEN 1791 01:02:27,253 --> 01:02:28,989 REALLY EFFECTIVE BECAUSE THEY 1792 01:02:28,989 --> 01:02:30,156 CAN ACTUALLY STOP THE LEAK. 1793 01:02:30,156 --> 01:02:32,025 SO YOU CAN GIVE THESE AGENTS, 1794 01:02:32,025 --> 01:02:34,127 THEY CAN STOP THAT LEAKY FAUCET, 1795 01:02:34,127 --> 01:02:35,962 THEY CAN ESSENTIALLY CLOSE THAT 1796 01:02:35,962 --> 01:02:37,797 FAUCET AGAIN AND STOP IT FROM 1797 01:02:37,797 --> 01:02:43,169 FUNCTIONING. 1798 01:02:43,169 --> 01:02:44,237 SO THAT'S HOW THEY WORK. 1799 01:02:44,237 --> 01:02:45,772 THEY WORK REALLY WELL, THEY WORK 1800 01:02:45,772 --> 01:02:46,773 VERY WELL AT THE BEGINNING, AND 1801 01:02:46,773 --> 01:02:51,678 THERE ARE NOW A NUMBER OF AGENTS 1802 01:02:51,678 --> 01:02:53,079 AND COMBINATIONS OF AGENTS THAT 1803 01:02:53,079 --> 01:02:55,815 ARE USED TARGETED THERAPIES THAT 1804 01:02:55,815 --> 01:02:58,752 ARE USED FOR THE TREATMENT OF 1805 01:02:58,752 --> 01:03:00,720 EGF RECEPTOR-DRIVEN LUNG CANCER. 1806 01:03:00,720 --> 01:03:02,956 SO HERE ON THE LEFT, YOU CAN SEE 1807 01:03:02,956 --> 01:03:04,324 A LIST OF SOME OF THESE 1808 01:03:04,324 --> 01:03:08,695 THERAPIES THAT ARE APPROVED FOR 1809 01:03:08,695 --> 01:03:11,931 THE TREATMENT OF ADVANCED EGFR 1810 01:03:11,931 --> 01:03:13,900 DN DRIVEN LUNG CANCER THAT NAIVE 1811 01:03:13,900 --> 01:03:17,337 TO TYROSINE KINASE INHIBITORS, 1812 01:03:17,337 --> 01:03:20,974 SOME OF THESE TYROSINE KINASE 1813 01:03:20,974 --> 01:03:22,175 INHIBITORS, OSIMERTINIB CAN ALSO 1814 01:03:22,175 --> 01:03:23,676 BE USED IN COMBINATION WITH 1815 01:03:23,676 --> 01:03:25,111 CHEMOTHERAPY OR ANOTHER THIRD 1816 01:03:25,111 --> 01:03:28,615 GENERATION TYROSINE KINASE 1817 01:03:28,615 --> 01:03:30,850 INHIBITOR, LAZERTINIB, CAN BE 1818 01:03:30,850 --> 01:03:33,286 USED WITH AN ANTIBODY TARGETING 1819 01:03:33,286 --> 01:03:38,825 EGF RECEPTOR AND THE MET 1820 01:03:38,825 --> 01:03:39,692 RECEPTOR IN COMBINATION. 1821 01:03:39,692 --> 01:03:41,027 SO THEY CAN BE USED TO TREAT 1822 01:03:41,027 --> 01:03:42,429 DISEASE IN THE METASTATIC 1823 01:03:42,429 --> 01:03:42,996 SETTING. 1824 01:03:42,996 --> 01:03:44,030 THERE'S ALSO OSIMERTINIB THAT 1825 01:03:44,030 --> 01:03:46,132 YOU HEARD FROM ROY THAT CAN BE 1826 01:03:46,132 --> 01:03:49,936 USED IN EARLIER STAGE DISEASE. 1827 01:03:49,936 --> 01:03:52,105 AND SO ONE OF THE THINGS THAT I 1828 01:03:52,105 --> 01:03:53,640 DID WANT TO TOUCH ON A LITTLE 1829 01:03:53,640 --> 01:03:57,343 BIT AND TALK ABOUT IN ONE OF THE 1830 01:03:57,343 --> 01:03:58,778 THINGS THAT REALLY HAS EMERGED 1831 01:03:58,778 --> 01:04:00,180 IN THE FIELD IN RECENT YEARS IS 1832 01:04:00,180 --> 01:04:02,015 OUR UNDERSTANDING THAT NOT ALL 1833 01:04:02,015 --> 01:04:04,651 EGF RECEPTOR MUTATIONS ARE 1834 01:04:04,651 --> 01:04:05,952 ALIKE, AND THEY CAN HAVE 1835 01:04:05,952 --> 01:04:07,487 DIFFERENT SENSITIVITIES TO THESE 1836 01:04:07,487 --> 01:04:12,158 TARGETED THERAPIES TO THESE 1837 01:04:12,158 --> 01:04:13,927 TYROSINE KINASE INTIB TORES SO 1838 01:04:13,927 --> 01:04:15,128 THAT'S A REALLY IMPORTANT 1839 01:04:15,128 --> 01:04:16,096 COMPONENT OF UNDERSTANDING HOW 1840 01:04:16,096 --> 01:04:17,564 BEST TO USE THESE AGENTS AND 1841 01:04:17,564 --> 01:04:20,867 WHETHER WE NEED TO THINK ABOUT 1842 01:04:20,867 --> 01:04:22,869 ALTERNATIVE STRIKE T STRATEGIES. 1843 01:04:22,869 --> 01:04:24,804 SO WE'VE TALKED ABOUT EGF 1844 01:04:24,804 --> 01:04:29,509 RECEPTOR MUTATIONS SORT OF AS -- 1845 01:04:29,509 --> 01:04:31,644 IN BULK AS ONE ENTITY BUT ONE OF 1846 01:04:31,644 --> 01:04:32,979 THE THINGS WE KNOW, YOU CAN LOOK 1847 01:04:32,979 --> 01:04:36,049 HERE AT THIS PIE CHART IN THE 1848 01:04:36,049 --> 01:04:41,788 CENTER, IS THAT E I THEY'RE ACTY 1849 01:04:41,788 --> 01:04:42,222 QUITE HETEROGENEOUS. 1850 01:04:42,222 --> 01:04:43,590 YOU HAVE A POINT MUTATION THAT 1851 01:04:43,590 --> 01:04:48,695 IS PRETTY COMMONLY OBSERVED, OR 1852 01:04:48,695 --> 01:04:50,964 SMALL IN FRAME DELETIONS IN EXON 1853 01:04:50,964 --> 01:04:55,235 19 AND BETWEEN THE L858R AND 1854 01:04:55,235 --> 01:04:56,636 EXON 19 DELETIONS ARE THE 1855 01:04:56,636 --> 01:04:57,904 COMMONLY OBSERVED MUTATIONS AND 1856 01:04:57,904 --> 01:04:59,139 THEN WE HAVE ANOTHER SUBSET OF 1857 01:04:59,139 --> 01:05:00,440 OTHER MUTATIONS THAT ARE ALSO 1858 01:05:00,440 --> 01:05:02,408 OBSERVED THAT ARE RARE. 1859 01:05:02,408 --> 01:05:03,843 BUT ONE OF THE THINGS THAT WE 1860 01:05:03,843 --> 01:05:05,578 ALSO KNOW IS THAT IF WE TAKE 1861 01:05:05,578 --> 01:05:07,080 THESE EXON 19 DELETIONS, THEY'RE 1862 01:05:07,080 --> 01:05:10,483 NOT ALL THE SAME. 1863 01:05:10,483 --> 01:05:11,484 THERE'S ONE THAT IS THE MOST 1864 01:05:11,484 --> 01:05:12,919 COMMONLY OBSERVED DELETION 1865 01:05:12,919 --> 01:05:14,154 MUTATION, BUT THEN THERE ARE A 1866 01:05:14,154 --> 01:05:18,024 LOT OF OTHER ONES AS WELL. 1867 01:05:18,024 --> 01:05:21,528 SO SOME OF THE THINGS THAT WE 1868 01:05:21,528 --> 01:05:22,729 AND OTHERS HAVE BEEN FINDING 1869 01:05:22,729 --> 01:05:23,830 OVER THE YEARS IS THAT ACTUALLY 1870 01:05:23,830 --> 01:05:27,167 NOT ALL MUTATIONS, EGFR 1871 01:05:27,167 --> 01:05:27,834 MUTATIONS ARE ALIKE. 1872 01:05:27,834 --> 01:05:29,335 SO I JUST WANTED TO POINT OUT 1873 01:05:29,335 --> 01:05:30,870 HERE ON THE LEFT, FOR EXAMPLE, 1874 01:05:30,870 --> 01:05:34,140 IF WE LOOK AT THE EGFR EXON 19 1875 01:05:34,140 --> 01:05:36,209 DELETIONS ON TREATMENT WITH 1876 01:05:36,209 --> 01:05:38,411 OSIMERTINIB, FOR EXAMPLE, ONE OF 1877 01:05:38,411 --> 01:05:40,146 THE THINGS WE CAN SEE IS THAT 1878 01:05:40,146 --> 01:05:42,882 OVERALL SURVIVAL FOR PATIENTS 1879 01:05:42,882 --> 01:05:47,120 TREATED WITH OSIMERTINIB WHOSE 1880 01:05:47,120 --> 01:05:48,221 TUMORS HARBOR THE DELETION IS 1881 01:05:48,221 --> 01:05:48,855 ABOUT 14 MONTHS. 1882 01:05:48,855 --> 01:05:50,557 BUT IF WE LOOK IN THAT SAME 1883 01:05:50,557 --> 01:05:52,425 CLINICAL TRIAL AND LOOK AT THE 1884 01:05:52,425 --> 01:05:55,161 SUBSET OF TUMORS WITH THE L858R 1885 01:05:55,161 --> 01:05:56,896 MUTATION, THE OVERALL SURVIVAL 1886 01:05:56,896 --> 01:05:58,431 IS ABOUT 33 MONTHS. 1887 01:05:58,431 --> 01:06:00,700 THIS IS SEEN WITH OSIMERTINIB 1888 01:06:00,700 --> 01:06:02,435 BUT ALSO WITH OTHER TYROSINE 1889 01:06:02,435 --> 01:06:03,102 KINASE INHIBITORS. 1890 01:06:03,102 --> 01:06:06,272 WE KNOW THE L858R TUMORS SEEM TO 1891 01:06:06,272 --> 01:06:09,242 BE A SUBSET THAT DOES A LITTLE 1892 01:06:09,242 --> 01:06:10,843 WORSE WITH TYROSINE KINASE 1893 01:06:10,843 --> 01:06:11,611 INHIBITOR MONOTHERAPY. 1894 01:06:11,611 --> 01:06:12,378 ONE OF THE THOUGHTS IS THAT 1895 01:06:12,378 --> 01:06:13,580 MAYBE THOSE ARE TUMORS THAT ONE 1896 01:06:13,580 --> 01:06:15,281 MIGHT WANT TO THINK ABOUT FROM 1897 01:06:15,281 --> 01:06:17,250 SOME OF THESE OTHER COMBINATION 1898 01:06:17,250 --> 01:06:21,888 THERAPIES OR THAT ARE POSSIBLE 1899 01:06:21,888 --> 01:06:24,123 IN THE FIRST LINE SETTING LIKE 1900 01:06:24,123 --> 01:06:25,225 OSIMERTINIB PLUS CHEMOTHERAPY. 1901 01:06:25,225 --> 01:06:26,859 ONE OF THE OTHER THINGS THAT 1902 01:06:26,859 --> 01:06:29,162 WE'VE BEEN WORKING ON AND OTHER 1903 01:06:29,162 --> 01:06:30,463 GROUPS HAVE ALSO BEEN WORKING ON 1904 01:06:30,463 --> 01:06:32,865 IS REALLY UNDERSTANDING MORE 1905 01:06:32,865 --> 01:06:34,267 ABOUT THE BIOLOGY AND THE 1906 01:06:34,267 --> 01:06:37,003 BIOCHEMISTRY OF THESE DIFFERENT 1907 01:06:37,003 --> 01:06:39,072 EGFR EXON 19 DELETION MUTATIONS 1908 01:06:39,072 --> 01:06:40,306 AND ONE OF THE THINGS THAT WE 1909 01:06:40,306 --> 01:06:41,908 FOUND SEVERAL YEARS AGO IS THAT 1910 01:06:41,908 --> 01:06:45,078 ACTUALLY FOR EXAMPLE THERE'S 1911 01:06:45,078 --> 01:06:47,914 THIS ONE EXON 19 DELETION 1912 01:06:47,914 --> 01:06:50,650 MUTATION THAT COMPARED TO THE 1913 01:06:50,650 --> 01:06:52,185 MORE COMMON ONES SEEMS TO HAVE 1914 01:06:52,185 --> 01:06:53,253 WORSE OUTCOMES UPON TREATMENT 1915 01:06:53,253 --> 01:06:55,321 WITH TYROSINE KINASE INHIBITORS, 1916 01:06:55,321 --> 01:06:56,756 THIS PURPLE LINE. 1917 01:06:56,756 --> 01:07:01,227 AND IN FACT, WE'VE DONE WORK 1918 01:07:01,227 --> 01:07:04,397 TOGETHER WITH MARK LEMON AND 1919 01:07:04,397 --> 01:07:06,266 SARAH GOLDBERG TO REALLY LOOK AT 1920 01:07:06,266 --> 01:07:08,735 THE BIOCHEMISTRY AND MOLECULAR 1921 01:07:08,735 --> 01:07:10,837 FEATURES OF THESE MUTANTS AND 1922 01:07:10,837 --> 01:07:12,372 FOUND A DIFFERENT AFFINITY FOR 1923 01:07:12,372 --> 01:07:16,509 ATP OF THE KINASE IN THIS 1924 01:07:16,509 --> 01:07:17,577 UNCOMMON EXON 19 DELETION 1925 01:07:17,577 --> 01:07:18,911 MUTATION COMPARED TO THE MORE 1926 01:07:18,911 --> 01:07:22,415 COMMON ONE. 1927 01:07:22,415 --> 01:07:24,284 SO REALLY BEGINNING TO 1928 01:07:24,284 --> 01:07:25,585 UNDERSTAND HOW THE MOLECULAR 1929 01:07:25,585 --> 01:07:26,886 FEATURES OF THESE INDIVIDUAL 1930 01:07:26,886 --> 01:07:28,521 MUTATIONS CAN ACTUALLY TELL US 1931 01:07:28,521 --> 01:07:30,923 SOMETHING ABOUT THE SENSITIVITY 1932 01:07:30,923 --> 01:07:32,892 TO THE TYROSINE KINASE 1933 01:07:32,892 --> 01:07:33,893 INHIBITORS AND I THINK THIS IS 1934 01:07:33,893 --> 01:07:34,961 REALLY WHERE WE'RE HEADING IN 1935 01:07:34,961 --> 01:07:36,496 THE FIELD OF PRECISION MEDICINE, 1936 01:07:36,496 --> 01:07:38,665 IS REALLY UNDERSTANDING THESE 1937 01:07:38,665 --> 01:07:40,300 FINE DETAILS BECAUSE NOW WE HAVE 1938 01:07:40,300 --> 01:07:45,104 SO MANY DRUGS AND SO MANY 1939 01:07:45,104 --> 01:07:46,306 POSSIBILITIES FOR TREATMENT WITH 1940 01:07:46,306 --> 01:07:48,074 DIFFERENT AGENTS. 1941 01:07:48,074 --> 01:07:49,275 SO WITH THAT, I'D LIKE TO MOVE 1942 01:07:49,275 --> 01:07:52,912 ALONG AND TELL YOU ABOUT SOME OF 1943 01:07:52,912 --> 01:07:55,148 THE CHALLENGES AND WHAT OUR 1944 01:07:55,148 --> 01:07:56,916 KNOWLEDGE IS ABOUT MECHANISMS OF 1945 01:07:56,916 --> 01:07:59,952 ACQUIRED RESISTANCE TO TARGETED 1946 01:07:59,952 --> 01:08:00,286 THERAPIES. 1947 01:08:00,286 --> 01:08:01,821 SO HERE YOU CAN SEE IN THESE 1948 01:08:01,821 --> 01:08:04,757 SCANS, THIS IS AN EXAMPLE OF 1949 01:08:04,757 --> 01:08:06,959 LUNGS WHERE YOU SEE THE TUMOR IS 1950 01:08:06,959 --> 01:08:08,394 PRESENT AT THE BEGINNING, BEFORE 1951 01:08:08,394 --> 01:08:09,896 TREATMENT WITH THE TYROSINE 1952 01:08:09,896 --> 01:08:10,997 KINASE INHIBITOR. 1953 01:08:10,997 --> 01:08:12,298 AFTER TREATMENT WITH THE 1954 01:08:12,298 --> 01:08:14,300 TYROSINE KINASE INHIBITOR, THE 1955 01:08:14,300 --> 01:08:16,135 TUMOR REALLY SHRINKS AWAY, BUT 1956 01:08:16,135 --> 01:08:18,004 THEN WHEN WE LOOK EVENTUALLY THE 1957 01:08:18,004 --> 01:08:20,373 TUMOR COMES BACK, AND THIS IS 1958 01:08:20,373 --> 01:08:21,808 REALLY THE EMERGENCE OF 1959 01:08:21,808 --> 01:08:23,676 RESISTANCE TO TYROSINE KINASE 1960 01:08:23,676 --> 01:08:24,510 INHIBITORS. 1961 01:08:24,510 --> 01:08:26,379 AND WITH SOME OF THE EARLY 1962 01:08:26,379 --> 01:08:27,780 GENERATION DRUGS, RESISTANCE 1963 01:08:27,780 --> 01:08:30,216 EMERGED ABOUT A YEAR AFTER 1964 01:08:30,216 --> 01:08:31,617 TREATMENT WITH SOME OF THESE 1965 01:08:31,617 --> 01:08:33,252 NEWER GENERATION DRUGS, LIKE 1966 01:08:33,252 --> 01:08:35,988 OSIMERTINIB, IT REALLY IS MOVED 1967 01:08:35,988 --> 01:08:37,890 TO MORE 1 1/2, 2 YEARS FOLLOWING 1968 01:08:37,890 --> 01:08:39,826 TREATMENT WITH THE AGENTS. 1969 01:08:39,826 --> 01:08:41,894 YET, RESISTANCE IS REALLY 1970 01:08:41,894 --> 01:08:44,630 INEVITABLE. 1971 01:08:44,630 --> 01:08:46,599 AND SO I THINK ONE OF THE THINGS 1972 01:08:46,599 --> 01:08:47,667 WE'VE LEARNED OVER THE YEARS 1973 01:08:47,667 --> 01:08:49,335 WITH THESE DIFFERENT EGFR 1974 01:08:49,335 --> 01:08:51,471 TYROSINE KINASE INHIBITORS AND I 1975 01:08:51,471 --> 01:08:58,144 SHOULD SAY THAT THESE SORT OF 1976 01:08:58,144 --> 01:08:59,912 CATEGORIES OF RESISTANCE 1977 01:08:59,912 --> 01:09:02,081 MECHANISMS CAN ALSO BE 1978 01:09:02,081 --> 01:09:03,282 EXTRAPOLATED TO DIFFERENT 1979 01:09:03,282 --> 01:09:03,716 TARGETED AGENTS. 1980 01:09:03,716 --> 01:09:05,685 SO I'M GOING TO TELL YOU ABOUT 1981 01:09:05,685 --> 01:09:07,987 WHAT WE KNOW IN THE CONTEXT OF 1982 01:09:07,987 --> 01:09:09,088 EGF RECEPTOR DRIVEN LUNG CANCER 1983 01:09:09,088 --> 01:09:10,490 BUT WE CAN EVEN LOOK AT THIS 1984 01:09:10,490 --> 01:09:13,659 MORE BROADLY AND THINK ABOUT IT 1985 01:09:13,659 --> 01:09:15,061 IN THAT CONTEXT. 1986 01:09:15,061 --> 01:09:19,432 SO FOR EXAMPLE, WE KNOW THAT ON 1987 01:09:19,432 --> 01:09:24,470 TARGET MUTATIONS IN EGF RECEPTOR 1988 01:09:24,470 --> 01:09:27,407 CAN OCCUR TO CONFER RESISTANCE. 1989 01:09:27,407 --> 01:09:30,576 SO -- AND THIS IS -- THERE ARE 1990 01:09:30,576 --> 01:09:33,746 VARIOUS DIFFERENT TYPES OF 1991 01:09:33,746 --> 01:09:37,350 MUTATIONS BUT I THINK ONE OF THE 1992 01:09:37,350 --> 01:09:40,186 MORE COMMON ONES WITH THE NEW 1993 01:09:40,186 --> 01:09:42,922 GENERATION DRUG OSIMERTINIB, 1994 01:09:42,922 --> 01:09:44,357 ACTUALLY ASSISTING A POSITION AT 1995 01:09:44,357 --> 01:09:47,727 WHICH EGF RECEPTOR BINDS 1996 01:09:47,727 --> 01:09:49,362 COVALENT -- OSIMERTINIB BINDS 1997 01:09:49,362 --> 01:09:50,763 COVALENTLY EGF RECEPTOR. 1998 01:09:50,763 --> 01:09:53,299 SO YOU CAN IMAGINE THAT IF YOU 1999 01:09:53,299 --> 01:09:55,134 MUTATE THAT SITE WHERE THE DRUG 2000 01:09:55,134 --> 01:09:57,870 BINDS THE PROTEIN, THEN THAT IT 2001 01:09:57,870 --> 01:09:59,272 CAN'T BIND ANYMORE. 2002 01:09:59,272 --> 01:10:00,706 AND SO -- AND SOME OF THESE 2003 01:10:00,706 --> 01:10:04,644 OTHER ALTERATIONS CAN, FOR 2004 01:10:04,644 --> 01:10:07,513 EXAMPLE, CREATE STERIC HINDRANCE 2005 01:10:07,513 --> 01:10:08,448 AND PREVENT REALLY THE DRUGS 2006 01:10:08,448 --> 01:10:08,981 FROM WORKING. 2007 01:10:08,981 --> 01:10:11,484 SO THESE ON-TARGET MUTATIONS ARE 2008 01:10:11,484 --> 01:10:13,786 ONE CATEGORY OF RESISTANCE 2009 01:10:13,786 --> 01:10:14,687 MECHANISMS. 2010 01:10:14,687 --> 01:10:18,057 WE ALSO CAN HAVE OFF-TARGET 2011 01:10:18,057 --> 01:10:19,258 MECHANISMS OF RESISTANCE. 2012 01:10:19,258 --> 01:10:22,428 AND THESE CAN BE CONSIDERED, FOR 2013 01:10:22,428 --> 01:10:24,764 EXAMPLE, BYPASS PATHWAY 2014 01:10:24,764 --> 01:10:26,132 ACTIVATION, SO WE CAN HAVE 2015 01:10:26,132 --> 01:10:29,435 ACTIVATION OF PATHWAYS THAT THEN 2016 01:10:29,435 --> 01:10:31,704 HAVE SIMILAR EFFECTS TO THE 2017 01:10:31,704 --> 01:10:33,840 EFFECTS OF MUTATED EGF RECEPTOR 2018 01:10:33,840 --> 01:10:35,208 IN THE LUNG CANCER CELLS. 2019 01:10:35,208 --> 01:10:38,711 SO YOU COULD IMAGINE ACTIVATION 2020 01:10:38,711 --> 01:10:41,013 OR HIGHER LEVELS IN ACTIVATION 2021 01:10:41,013 --> 01:10:43,382 OF ANOTHER RECEPTOR TYROSINE 2022 01:10:43,382 --> 01:10:46,018 KINASE THAT CAN ACTIVATE MANY OF 2023 01:10:46,018 --> 01:10:49,522 THE SIMILAR PATHWAYS, LIKE MET 2024 01:10:49,522 --> 01:10:51,824 OR HER-2, WHICH ARE ALSO 2025 01:10:51,824 --> 01:10:53,025 RECEPTOR TYROSINE KINASES. 2026 01:10:53,025 --> 01:10:54,660 SO THESE CAN GET AMPLIFIED, THEY 2027 01:10:54,660 --> 01:10:57,497 CAN GET ACTIVATED IN TUMORS THAT 2028 01:10:57,497 --> 01:10:59,599 ARE RESISTANT, OR WE CAN HAVE 2029 01:10:59,599 --> 01:11:01,968 ACTIVATION OF DOWNSTREAM 2030 01:11:01,968 --> 01:11:03,836 MOLECULES THAT ARE DOWNSTREAM OF 2031 01:11:03,836 --> 01:11:05,137 EGF RECEPTOR THAT ACTIVATE THOSE 2032 01:11:05,137 --> 01:11:06,873 SAME PATHWAYS THAT ARE ACTIVATED 2033 01:11:06,873 --> 01:11:08,641 BY EGFR. 2034 01:11:08,641 --> 01:11:14,146 AND SO THIS IS ANOTHER MECHANISM 2035 01:11:14,146 --> 01:11:15,748 OF ACQUIRED RESISTANCE, AND SO 2036 01:11:15,748 --> 01:11:17,717 IN THIS CASE, EVEN IF YOU'RE 2037 01:11:17,717 --> 01:11:19,552 BLOCKING THE ACTIVITY OF EGF 2038 01:11:19,552 --> 01:11:21,087 RECEPTOR WITH A TARGETED 2039 01:11:21,087 --> 01:11:22,054 THERAPY, THERE ARE OTHER 2040 01:11:22,054 --> 01:11:24,590 PATHWAYS THAT CAN GET AROUND IT. 2041 01:11:24,590 --> 01:11:27,093 ONE OF THE OTHER MECHANISMS OF 2042 01:11:27,093 --> 01:11:30,930 RESISTANCE THAT IS PERHAPS THE 2043 01:11:30,930 --> 01:11:31,797 MOST MYSTERIOUS THAT THERE'S A 2044 01:11:31,797 --> 01:11:34,000 LOT OF WORK THAT IS HAPPENING TO 2045 01:11:34,000 --> 01:11:35,735 REALLY UNDERSTAND THE BASIS FOR 2046 01:11:35,735 --> 01:11:37,470 IT IS THAT WE CAN SEE THAT SOME 2047 01:11:37,470 --> 01:11:40,873 OF THESE TUMORS CAN CHANGE THEIR 2048 01:11:40,873 --> 01:11:41,641 HISTOLOGIC FEATURES. 2049 01:11:41,641 --> 01:11:43,709 SO WE CAN START FROM THESE 2050 01:11:43,709 --> 01:11:46,112 ADENOCARCINOMAS THAT HAVE EGFR 2051 01:11:46,112 --> 01:11:46,779 MUTATIONS, FOR EXAMPLE, TREAT 2052 01:11:46,779 --> 01:11:49,615 THEM WITH A TYROSINE KINASE 2053 01:11:49,615 --> 01:11:50,716 INHIBITORS, AND THEN WHEN YOU 2054 01:11:50,716 --> 01:11:56,489 LOOK AT RESISTANCE, THE TUMORS 2055 01:11:56,489 --> 01:11:57,690 ARE DIFFERENT HISTOLOGICALLY. 2056 01:11:57,690 --> 01:11:59,325 SO FOR EXAMPLE, THEY CAN HAVE 2057 01:11:59,325 --> 01:12:01,427 ACQUIRED FEATURES OF SMALL CELL 2058 01:12:01,427 --> 01:12:03,362 LUNG CANCER, WHICH AS IF YOU 2059 01:12:03,362 --> 01:12:07,099 REMEMBER FROM ONE OF MY FIRST 2060 01:12:07,099 --> 01:12:08,267 SLIDES, ONE OF THE SUBSETS -- 2061 01:12:08,267 --> 01:12:09,569 ONE OF THE SMALLER SUBSETS OF 2062 01:12:09,569 --> 01:12:11,771 LUNG CANCER, SO TOTALLY 2063 01:12:11,771 --> 01:12:13,205 DIFFERENT TUMOR TYPES, OR CAN 2064 01:12:13,205 --> 01:12:15,241 ACQUIRE FEATURES OF SQUAMOUS 2065 01:12:15,241 --> 01:12:18,411 CELL LUNG CARCINOMAS, OR CAN 2066 01:12:18,411 --> 01:12:22,048 ALSO UNDERGO WHAT'S CALLED 2067 01:12:22,048 --> 01:12:23,449 EPITHELIAL TO MESENCHYMAL 2068 01:12:23,449 --> 01:12:26,185 TRANSITION AND LOOK SORT OF MORE 2069 01:12:26,185 --> 01:12:27,920 MESENCHYMAL, MORE MUSCLE-LIKE 2070 01:12:27,920 --> 01:12:35,595 CELLS IN A PROCESS CALLED 2071 01:12:35,595 --> 01:12:36,495 SARCOMATOID DIFFERENTIATION. 2072 01:12:36,495 --> 01:12:38,230 SO THE TUMOR CELLS ARE CHANGING 2073 01:12:38,230 --> 01:12:39,098 THEIR DEPENDENCE. 2074 01:12:39,098 --> 01:12:41,500 THEY DON'T DEPEND ON EGF 2075 01:12:41,500 --> 01:12:45,004 RECEPTOR ANYMORE. 2076 01:12:45,004 --> 01:12:47,607 OR REALLY HAVE SHIFTED THEIR 2077 01:12:47,607 --> 01:12:49,475 HISTOLOGY SO THERE ARE OTHER 2078 01:12:49,475 --> 01:12:53,846 WAYS ON WHICH THEY'RE GROWING 2079 01:12:53,846 --> 01:12:54,513 OUT. 2080 01:12:54,513 --> 01:12:56,482 I THINK THAT ONE OF THE THINGS 2081 01:12:56,482 --> 01:13:01,153 THAT WE ARE OBSERVING NOW IS 2082 01:13:01,153 --> 01:13:02,588 THAT WITH SOME OF THESE NEWER 2083 01:13:02,588 --> 01:13:04,657 GENERATION AGENTS AND 2084 01:13:04,657 --> 01:13:06,626 GENERATION -- NEW DRUGS LIKE 2085 01:13:06,626 --> 01:13:08,027 OSIMERTINIB THAT IS REALLY USED 2086 01:13:08,027 --> 01:13:09,595 A LOT IS THE FIRST LINE 2087 01:13:09,595 --> 01:13:12,431 TREATMENT FOR EGF RECEPTOR 2088 01:13:12,431 --> 01:13:13,633 DRIVEN LUNG CANCER IS NOT ONLY 2089 01:13:13,633 --> 01:13:16,369 DO WE SEE THESE MECHANISMS OF 2090 01:13:16,369 --> 01:13:17,703 RESISTANCE THAT I JUST TOLD YOU 2091 01:13:17,703 --> 01:13:18,571 ABOUT, BUT ONE OF THE THINGS 2092 01:13:18,571 --> 01:13:20,206 THAT HAS BEEN HAPPENING IS THAT 2093 01:13:20,206 --> 01:13:21,574 ESPECIALLY WHEN IT'S USED IN THE 2094 01:13:21,574 --> 01:13:23,709 FIRST LINE TREATMENT, WE STILL 2095 01:13:23,709 --> 01:13:25,344 DON'T KNOW WHAT THE MECHANISMS 2096 01:13:25,344 --> 01:13:26,979 OF RESISTANCE ARE IN MANY OF 2097 01:13:26,979 --> 01:13:30,483 THOSE TUMORS. 2098 01:13:30,483 --> 01:13:32,451 ALMOST 50% IN THIS DATASET, 2099 01:13:32,451 --> 01:13:32,885 ANALYZED HERE. 2100 01:13:32,885 --> 01:13:34,854 SO THIS REALLY REPRESENTS A 2101 01:13:34,854 --> 01:13:35,955 MAJOR CHALLENGE BECAUSE IT'S 2102 01:13:35,955 --> 01:13:40,559 TELLING US, WELL, ALTHOUGH WE 2103 01:13:40,559 --> 01:13:41,327 KNOW ABOUT SOME OF THE 2104 01:13:41,327 --> 01:13:42,595 MECHANISMS OF RESISTANCE, WITH 2105 01:13:42,595 --> 01:13:44,163 SOME OF THESE NEWER DRUGS, 2106 01:13:44,163 --> 01:13:45,364 THERE'S JUST SO MUCH THAT WE 2107 01:13:45,364 --> 01:13:47,233 DON'T UNDERSTAND AND THERE 2108 01:13:47,233 --> 01:13:48,534 AREN'T OBVIOUS GENETIC 2109 01:13:48,534 --> 01:13:51,070 ALTERATIONS THAT ARE TELLING US 2110 01:13:51,070 --> 01:13:52,605 WHAT THE MECHANISM OF RESISTANCE 2111 01:13:52,605 --> 01:13:55,775 IS. 2112 01:13:55,775 --> 01:14:00,146 AND SO WITH THAT, I DID WANT TO 2113 01:14:00,146 --> 01:14:01,247 TOUCH A LITTLE BIT ON SOME OF 2114 01:14:01,247 --> 01:14:04,083 THE CHALLENGES THAT THE FIELD 2115 01:14:04,083 --> 01:14:06,485 FACES TO REALLY TACKLE THE 2116 01:14:06,485 --> 01:14:09,755 PROBLEM OF DRUG RESISTANCE, AND 2117 01:14:09,755 --> 01:14:12,291 TO FIGURE OUT WAYS IN WHICH WE 2118 01:14:12,291 --> 01:14:14,460 CAN OVERCOME THIS RESISTANCE OR 2119 01:14:14,460 --> 01:14:16,662 PREVENT THIS RESISTANCE, REALLY 2120 01:14:16,662 --> 01:14:21,267 WE CAN GET CLOSER TO CURES IN 2121 01:14:21,267 --> 01:14:22,668 THESE ONCOGENE-DRIVEN LUNG 2122 01:14:22,668 --> 01:14:23,102 CANCERS. 2123 01:14:23,102 --> 01:14:27,373 I SHOW YOU THIS PAINTING HERE, 2124 01:14:27,373 --> 01:14:28,574 BECAUSE ONE OF THE THINGS THAT I 2125 01:14:28,574 --> 01:14:30,209 THINK ABOUT IS THAT WE'VE REALLY 2126 01:14:30,209 --> 01:14:31,544 MADE TREMENDOUS PROGRESS, WE'VE 2127 01:14:31,544 --> 01:14:33,512 LEARNED SO MUCH OVER THE YEARS, 2128 01:14:33,512 --> 01:14:36,716 AND WE REALLY -- THE FRUITS AT 2129 01:14:36,716 --> 01:14:37,983 THE BOTTOM OF THE TREE, BUT 2130 01:14:37,983 --> 01:14:39,085 THERE ARE LOTS OF FRUITS AT THE 2131 01:14:39,085 --> 01:14:40,486 TOP HERE AND WE HAVE TO REALLY 2132 01:14:40,486 --> 01:14:42,955 PICK THEM AND FIGURE THESE -- 2133 01:14:42,955 --> 01:14:45,191 DID GET TO THEM IF WE WANT TO 2134 01:14:45,191 --> 01:14:47,193 MAKE SORT OF MORE EXPONENTIAL 2135 01:14:47,193 --> 01:14:50,029 PROGRESS IN THE FIELD. 2136 01:14:50,029 --> 01:14:51,130 AND SO WHAT ARE SOME OF THE 2137 01:14:51,130 --> 01:14:52,331 THINGS THAT WE THINK ABOUT AND 2138 01:14:52,331 --> 01:14:53,866 WHAT ARE SOME OF THE CHALLENGES? 2139 01:14:53,866 --> 01:14:55,935 I THINK ONE OF THEM HERE IS THE 2140 01:14:55,935 --> 01:14:57,803 TARGETED AGENTS ARE CLEARLY NOT 2141 01:14:57,803 --> 01:14:58,237 SUFFICIENT. 2142 01:14:58,237 --> 01:15:01,073 WE NEED TO DISCOVER NEW UNTAPPED 2143 01:15:01,073 --> 01:15:03,375 VULNERABILITIES OF 2144 01:15:03,375 --> 01:15:06,979 ONCOGENE-DRIVEN LUNG CANCERS. 2145 01:15:06,979 --> 01:15:08,948 TACKLING RESISTANCE REQUIRES NEW 2146 01:15:08,948 --> 01:15:10,683 KNOWLEDGE OF THE LINKS BETWEEN 2147 01:15:10,683 --> 01:15:12,551 CANCER CELL PLASTICITY, THE 2148 01:15:12,551 --> 01:15:14,620 TUMOR MICROENVIRONMENT AND TUMOR 2149 01:15:14,620 --> 01:15:15,287 HETEROGENEITY. 2150 01:15:15,287 --> 01:15:17,456 WE JUST DON'T KNOW ENOUGH ABOUT 2151 01:15:17,456 --> 01:15:18,791 DRUG RESISTANCE YET, AND WE 2152 01:15:18,791 --> 01:15:20,092 REALLY NEED TO UNDERSTAND IT 2153 01:15:20,092 --> 01:15:23,362 BETTER. 2154 01:15:23,362 --> 01:15:24,463 AND THEN ONE OF THE THINGS THAT 2155 01:15:24,463 --> 01:15:27,099 IS STILL MYSTERIOUS IS WHEN WE 2156 01:15:27,099 --> 01:15:29,301 TREAT WITH A TARGETED AGENT, 2157 01:15:29,301 --> 01:15:33,439 WHAT MAKES SOME CANCER CELLS 2158 01:15:33,439 --> 01:15:34,640 SURVIVE THE TREATMENT WHILE THE 2159 01:15:34,640 --> 01:15:35,841 TARGETED THERAPIES CAN 2160 01:15:35,841 --> 01:15:36,942 ERADICATE, CAN GET RID OF THE 2161 01:15:36,942 --> 01:15:37,810 OTHER CELLS. 2162 01:15:37,810 --> 01:15:39,145 ANOTHER MYSTERY, AND I'LL TALK A 2163 01:15:39,145 --> 01:15:41,113 LITTLE BIT ABOUT THAT. 2164 01:15:41,113 --> 01:15:42,214 SO ONE OF THE THINGS THAT I 2165 01:15:42,214 --> 01:15:46,352 WANTED TO DO IS I JUST WANTED TO 2166 01:15:46,352 --> 01:15:47,353 HIGHLIGHT HOW WE ARE MAKING SOME 2167 01:15:47,353 --> 01:15:48,621 PROGRESS IN UNDERSTANDING SOME 2168 01:15:48,621 --> 01:15:49,955 OF THESE PREVIOUSLY UNKNOWN 2169 01:15:49,955 --> 01:15:51,390 MECHANISMS OF DRUG RESISTANCE, 2170 01:15:51,390 --> 01:15:53,893 AND THIS IS TO HIGHLIGHT A PAPER 2171 01:15:53,893 --> 01:15:55,528 THAT WE PUBLISHED A COUPLE OF 2172 01:15:55,528 --> 01:15:57,830 YEARS AGO, PART OF SOME OF THE 2173 01:15:57,830 --> 01:15:59,031 WORK THAT WE'RE DOING IN THE 2174 01:15:59,031 --> 01:16:01,534 CONTEXT OF OUR LUNG CANCER SPORE 2175 01:16:01,534 --> 01:16:03,636 AND REALLY NICE COLLABORATION 2176 01:16:03,636 --> 01:16:06,138 WITH THE HARVARD SPORE AND LUNG 2177 01:16:06,138 --> 01:16:10,409 CANCER AND PASIANA AND KADOSH IN 2178 01:16:10,409 --> 01:16:14,446 WHICH WE IDENTIFIED A ROLE FOR 2179 01:16:14,446 --> 01:16:19,819 THE SWISNF COMPLEX AND PROMOTING 2180 01:16:19,819 --> 01:16:22,588 TYROSINE KINASE INHIBITORS. 2181 01:16:22,588 --> 01:16:26,625 IT'S A CHROMATIN-REMODELING 2182 01:16:26,625 --> 01:16:28,027 COMPLEX, AND HERE INSTEAD OF 2183 01:16:28,027 --> 01:16:31,330 MUTATIONAL CHANGES THAT ARE 2184 01:16:31,330 --> 01:16:32,798 CONFERRING RESISTANCE, ONE OF 2185 01:16:32,798 --> 01:16:33,599 THE THINGS WE FOUND IS THAT 2186 01:16:33,599 --> 01:16:36,135 THERE ARE SOME TUMORS, SOME EGFR 2187 01:16:36,135 --> 01:16:37,670 MUTANT TUMORS THAT AT THE TIME 2188 01:16:37,670 --> 01:16:41,507 OF RESISTANCE REALLY RELY ON 2189 01:16:41,507 --> 01:16:44,109 THIS COMPLEX FUNCTIONING IN THE 2190 01:16:44,109 --> 01:16:45,211 CELLS SO THAT FOR EXAMPLE, IT 2191 01:16:45,211 --> 01:16:48,814 CAN ACTUALLY KEEP CHROMATIN OPEN 2192 01:16:48,814 --> 01:16:50,349 AT SITES THAT ARE IMPORTANT FOR 2193 01:16:50,349 --> 01:16:51,750 THE PROLIFERATION OF CELLS AND 2194 01:16:51,750 --> 01:16:53,752 FOR THE CELLS TO WITHSTAND 2195 01:16:53,752 --> 01:16:55,721 TREATMENT WITH A TARGETED AGENT. 2196 01:16:55,721 --> 01:16:57,256 HERE YOU CAN SEE AN EXAMPLE OF 2197 01:16:57,256 --> 01:17:01,961 SOME DATA HERE WHERE IF WE KNOCK 2198 01:17:01,961 --> 01:17:04,830 OUT SM ACA4 AND TREAT WITH 2199 01:17:04,830 --> 01:17:06,799 OSIMERTINIB, IT ACTUALLY 2200 01:17:06,799 --> 01:17:08,133 RESENSITIZES THESE TUMORS TO 2201 01:17:08,133 --> 01:17:11,403 TREATMENT AND HERE IN PATIENT 2202 01:17:11,403 --> 01:17:12,805 DERIVED XENOGRAPHED MODEL, WE 2203 01:17:12,805 --> 01:17:17,109 ACTUALLY USE A DRUG THAT TARGETS 2204 01:17:17,109 --> 01:17:19,511 THE COMPLEXES IN COMBINATION 2205 01:17:19,511 --> 01:17:21,080 WITH OSIMERTINIB, WE CAN KIND OF 2206 01:17:21,080 --> 01:17:22,948 SEE A PLATEAU IN TUMOR GROWTH. 2207 01:17:22,948 --> 01:17:25,784 SO THESE ARE SOME OF THE 2208 01:17:25,784 --> 01:17:26,585 MECHANISMS THAT WE'RE STARTING 2209 01:17:26,585 --> 01:17:29,121 TO UNCOVER AND REALLY THAT ARE 2210 01:17:29,121 --> 01:17:34,793 ALLOWING US TO UNDERSTAND NEW 2211 01:17:34,793 --> 01:17:36,328 APPROACHES TO -- NEW MECHANISMS 2212 01:17:36,328 --> 01:17:38,130 OF RESISTANCE BUT THEN NEW 2213 01:17:38,130 --> 01:17:40,499 POTENTIAL WAYS OF OVERCOMING 2214 01:17:40,499 --> 01:17:42,034 RESISTANCE, AND PERHAPS ALSO 2215 01:17:42,034 --> 01:17:44,870 PREVENTING RESISTANCE THAT COULD 2216 01:17:44,870 --> 01:17:47,606 BE REALLY IMPORTANT TO TAKE TO 2217 01:17:47,606 --> 01:17:49,608 THE CLINIC EVENTUALLY. 2218 01:17:49,608 --> 01:17:51,210 I THINK YOU KNOW, ONE OF THE 2219 01:17:51,210 --> 01:17:52,978 OTHER AREAS THAT I DID WANT TO 2220 01:17:52,978 --> 01:17:55,281 TOUCH ON BECAUSE I THINK IT IS A 2221 01:17:55,281 --> 01:17:55,948 MAJOR CHALLENGE AND SOMETHING 2222 01:17:55,948 --> 01:17:58,284 THAT WE'RE REALLY BEGINNING TO 2223 01:17:58,284 --> 01:18:02,187 LEARN SOMETHING ABOUT IS AS I 2224 01:18:02,187 --> 01:18:05,658 MENTIONED, IN A SUBSET OF TUMORS 2225 01:18:05,658 --> 01:18:06,992 THAT BECOME RESISTANT TO 2226 01:18:06,992 --> 01:18:07,660 TARGETED AGENTS, WE ACTUALLY 2227 01:18:07,660 --> 01:18:10,162 HAVE THIS SHIFT FROM THE TUMOR 2228 01:18:10,162 --> 01:18:12,131 LOOKING LIKE LUNG 2229 01:18:12,131 --> 01:18:13,565 ADENOCARCINOMA, ONE TUMOR TYPE, 2230 01:18:13,565 --> 01:18:15,100 ACTUALLY SHIFTING AND YOU CAN 2231 01:18:15,100 --> 01:18:17,169 SEE HERE'S AN EXAMPLE OF A LUNG 2232 01:18:17,169 --> 01:18:18,170 ADENOCARCINOMA, THIS IS WHAT IT 2233 01:18:18,170 --> 01:18:26,278 LOOKS LIKE, THEN AFTER TREATMENT 2234 01:18:26,278 --> 01:18:28,347 IT HAS COMPLETELY CHANGED AND 2235 01:18:28,347 --> 01:18:31,216 HAS FEATURES OF SMALL CELL LUNG 2236 01:18:31,216 --> 01:18:32,685 CANCER, SO A TOTALLY DIFFERENT 2237 01:18:32,685 --> 01:18:32,985 TUMOR TYPE. 2238 01:18:32,985 --> 01:18:34,386 THIS WAS FIRST DESCRIBED 2239 01:18:34,386 --> 01:18:40,526 ACTUALLY IN 20 2006, AND THEN 2240 01:18:40,526 --> 01:18:42,928 REALLY VALIDATED AND VERIFYING 2241 01:18:42,928 --> 01:18:45,331 LARGER DATASETS FROM SEVERAL 2242 01:18:45,331 --> 01:18:46,432 DIFFERENT GROUPS, AND WHAT WE 2243 01:18:46,432 --> 01:18:49,935 KNOW IN THESE TUMORS THAT IS 2244 01:18:49,935 --> 01:18:51,904 REALLY INTERESTING THAT THESE 2245 01:18:51,904 --> 01:18:53,572 TUMORS INITIALLY HAVE THE E DP. 2246 01:18:53,572 --> 01:18:57,076 F RECEPTOR MUTATION, THEY 2247 01:18:57,076 --> 01:18:59,044 EXPRESS ONCOGENIC EGFR WHICH IS 2248 01:18:59,044 --> 01:19:00,379 REALLY IMPORTANT FOR THE 2249 01:19:00,379 --> 01:19:01,680 SURVIVAL OF THESE CELLS, BUT 2250 01:19:01,680 --> 01:19:03,115 THEN MAP WHAPS WHEN THE 2251 01:19:03,115 --> 01:19:04,850 TUMORS -- WHEN THE SMALL CELL 2252 01:19:04,850 --> 01:19:06,719 LUNG CANCERS EMERGE, EXPRESSION 2253 01:19:06,719 --> 01:19:09,121 OF MUTATED EGF RECEPTOR IS LOST. 2254 01:19:09,121 --> 01:19:11,023 SO THE MUTATION IS STILL THERE, 2255 01:19:11,023 --> 01:19:13,859 BUT THE MUTANT IS NOT EXPRESSED, 2256 01:19:13,859 --> 01:19:15,027 AND ONE OF THE OTHER THINGS THAT 2257 01:19:15,027 --> 01:19:18,230 WE KNOW IS THAT THESE TUMORS ARE 2258 01:19:18,230 --> 01:19:19,765 CHARACTERIZED BY MUTATIONS IN 2259 01:19:19,765 --> 01:19:22,735 THE TUMOR SUPPRESSOR GENES P53 2260 01:19:22,735 --> 01:19:24,236 AND RETINOBLASTOMA, WHICH ARE 2261 01:19:24,236 --> 01:19:25,270 ALSO CHARACTERISTIC OF SMALL 2262 01:19:25,270 --> 01:19:29,308 CELL LUNG CANCERS. 2263 01:19:29,308 --> 01:19:30,709 WE KNOW THAT IF YOU LOOK AT 2264 01:19:30,709 --> 01:19:32,811 BASELINE, EGFR MUTANT TUMORS 2265 01:19:32,811 --> 01:19:36,749 THAT AT BASELINE HAVE P53 2266 01:19:36,749 --> 01:19:38,417 MUTATIONS AND RB1 MUTATIONS ARE 2267 01:19:38,417 --> 01:19:42,021 MORE LIKELY TO EMERGE AS SMALL 2268 01:19:42,021 --> 01:19:45,524 CELL LUNG CANCER AT THE TIME OF 2269 01:19:45,524 --> 01:19:50,329 RESISTANCE. 2270 01:19:50,329 --> 01:19:52,531 IN THIS CASE WE'RE IDENTIFYING 2271 01:19:52,531 --> 01:19:56,802 FEATURES UP FRONT THAT ARE 2272 01:19:56,802 --> 01:20:00,406 DISPOSED TO RESISTANCE EMERGING. 2273 01:20:00,406 --> 01:20:01,273 THINK ONE OF THE BIG QUESTIONS 2274 01:20:01,273 --> 01:20:02,274 IN THE FIELD IS WHAT ARE THE 2275 01:20:02,274 --> 01:20:03,709 CELLULAR AND MOLECULAR BASIS FOR 2276 01:20:03,709 --> 01:20:05,344 THIS TRANSFORMATION, AND I'D 2277 01:20:05,344 --> 01:20:06,345 JUST LIKE TO POINT OUT A COUPLE 2278 01:20:06,345 --> 01:20:07,980 OF THINGS RELATED TO THAT. 2279 01:20:07,980 --> 01:20:09,081 THERE ARE A LOT OF GROUPS 2280 01:20:09,081 --> 01:20:10,115 WORKING ON IT BUT ONE OF THE 2281 01:20:10,115 --> 01:20:11,717 THINGS THAT IS REALLY 2282 01:20:11,717 --> 01:20:13,585 FASCINATING IS THAT THE PROCESS 2283 01:20:13,585 --> 01:20:16,088 FOR THIS NEUROENDOCRINE 2284 01:20:16,088 --> 01:20:17,322 DIFFERENTIATION THAT WE SEE IN 2285 01:20:17,322 --> 01:20:20,726 LUNG CANCER THAT IS 2286 01:20:20,726 --> 01:20:22,227 TREATMENT-RESISTANT IS ANALOGOUS 2287 01:20:22,227 --> 01:20:27,966 OR HAS A PERIL LEL I A PARALLELT 2288 01:20:27,966 --> 01:20:33,906 OF PROSTATE CANCERS TREAT. 2289 01:20:33,906 --> 01:20:37,176 YOU CAN SEE IN THE TOP IN BLUE, 2290 01:20:37,176 --> 01:20:38,477 THIS SCHEMATIC FROM A FEW YEARS 2291 01:20:38,477 --> 01:20:39,945 AGO WHERE YOU HAVE LUNG CANCERS 2292 01:20:39,945 --> 01:20:43,115 WITH EGF RECEPTOR MUTATIONS. 2293 01:20:43,115 --> 01:20:44,316 EFFICIENTLY YOU CAN HAVE THE 2294 01:20:44,316 --> 01:20:45,651 EMERGENCE OF SMALL CELL LUNG 2295 01:20:45,651 --> 01:20:47,586 CANCER, YOU CAN ALSO HAVE 2296 01:20:47,586 --> 01:20:48,387 NEUROENDOCRINE DIFFERENTIATION 2297 01:20:48,387 --> 01:20:50,222 FOR PROSTATE CANCER SHOWN HERE 2298 01:20:50,222 --> 01:20:51,223 IN YELLOW. 2299 01:20:51,223 --> 01:20:53,525 AND SOME OF THE ALTERATIONS THAT 2300 01:20:53,525 --> 01:20:59,898 OCCUR, THE P53 MUTATIONS, RB 2301 01:20:59,898 --> 01:21:01,967 MUTATIONS, SOME OF THE OTHER 2302 01:21:01,967 --> 01:21:02,935 THINGS THAT CAN OCCUR THAT 2303 01:21:02,935 --> 01:21:04,570 HAPPEN IN THESE TUMORS THAT 2304 01:21:04,570 --> 01:21:06,138 UNDERGO THIS DIFFERENTIATION ARE 2305 01:21:06,138 --> 01:21:07,973 ANALOGOUS, SO WE HAVE THESE 2306 01:21:07,973 --> 01:21:09,174 PARALLELS BETWEEN DIFFERENT 2307 01:21:09,174 --> 01:21:10,709 CANCER TYPES TREATED WITH 2308 01:21:10,709 --> 01:21:11,810 TARGETED THERAPIES AND I THINK 2309 01:21:11,810 --> 01:21:16,048 WE CAN LEARN A LOT BY LEARNING 2310 01:21:16,048 --> 01:21:18,717 FROM BOTH OF THESE SYSTEMS. 2311 01:21:18,717 --> 01:21:24,823 I'D JUST LIKE ALSO TO POINT OUT 2312 01:21:24,823 --> 01:21:27,793 THAT SOME RECENT WORK THAT A 2313 01:21:27,793 --> 01:21:28,994 WHOLE LOT OF PROGRESS HAS BEEN 2314 01:21:28,994 --> 01:21:30,095 GOING INTO MODELING THE 2315 01:21:30,095 --> 01:21:34,666 REQUIREMENTS FOR THIS SMALL CELL 2316 01:21:34,666 --> 01:21:36,435 TRANSFER PLASTICITY IN VIVO FROM 2317 01:21:36,435 --> 01:21:43,775 HAROLD HA HAR MUST'S LAB FOR 2318 01:21:43,775 --> 01:21:47,179 EGFR -- IN WHICH YOU CAN -- IN 2319 01:21:47,179 --> 01:21:49,014 WHICH THEY'VE BEEN ABLE TO 2320 01:21:49,014 --> 01:21:50,682 ACTUALLY FOLLOW THE TUMOR CELLS 2321 01:21:50,682 --> 01:21:54,186 WHEN YOU FOR EXAMPLE GET RID OF 2322 01:21:54,186 --> 01:21:55,487 EGF RECEPTOR SO YOU DON'T HAVE 2323 01:21:55,487 --> 01:21:57,556 IT ANYMORE, AND THEN YOU LOOK AT 2324 01:21:57,556 --> 01:22:00,259 THE RESIDUAL DISEASE, SEE WHAT 2325 01:22:00,259 --> 01:22:04,596 HAPPENS AND IN THE PRESENCE, YOU 2326 01:22:04,596 --> 01:22:06,665 CAN ACTUALLY SEE THIS TRANSFORM 2327 01:22:06,665 --> 01:22:08,133 SMALL CELL LUNG CANCER EMERGE. 2328 01:22:08,133 --> 01:22:09,168 SO WE'RE BEGINNING TO LEARN 2329 01:22:09,168 --> 01:22:10,636 ABOUT THE REQUIREMENTS FOR THIS 2330 01:22:10,636 --> 01:22:12,571 TRANSFORMATION TO OCCUR THROUGH 2331 01:22:12,571 --> 01:22:15,107 MODELING. 2332 01:22:15,107 --> 01:22:16,875 I THINK WE'LL CONTINUE TO SEE 2333 01:22:16,875 --> 01:22:20,812 MANY ADVANCES IN OUR 2334 01:22:20,812 --> 01:22:22,114 UNDERSTANDING OF THIS TYPE OF 2335 01:22:22,114 --> 01:22:24,349 PLASTICITY IN THE COMING YEARS. 2336 01:22:24,349 --> 01:22:29,154 JUST TO HIGHLIGHT HOW -- THE 2337 01:22:29,154 --> 01:22:31,123 THINGS THAT WE'RE OBSERVING AND 2338 01:22:31,123 --> 01:22:35,194 LEARNING WITH EGF RECEPTOR 2339 01:22:35,194 --> 01:22:36,862 INHIBITORS ALSO HAVE SOME 2340 01:22:36,862 --> 01:22:37,696 PARALLELS AND SOME DIFFERENCES 2341 01:22:37,696 --> 01:22:39,464 IN THE CONTEXT OF KRAS 2342 01:22:39,464 --> 01:22:40,032 INHIBITORS. 2343 01:22:40,032 --> 01:22:40,899 SO AS I MENTIONED AT THE 2344 01:22:40,899 --> 01:22:42,768 BEGINNING OF MY TALK, KRAS IS 2345 01:22:42,768 --> 01:22:44,403 ANOTHER ONCOGENE THAT IS MUTATED 2346 01:22:44,403 --> 01:22:47,272 IN LUNG CANCER, AND THERE HAS 2347 01:22:47,272 --> 01:22:49,241 BEEN THE DEVELOPMENT, LARGELY 2348 01:22:49,241 --> 01:22:50,108 CONSIDERED UNDRUGGABLE UNTIL A 2349 01:22:50,108 --> 01:22:52,844 FEW YEARS AGO, WHEN THERE WERE 2350 01:22:52,844 --> 01:22:55,914 DRUGS THAT WERE DEVELOPED THAT 2351 01:22:55,914 --> 01:23:01,720 CAN TARGET ONCOGENIC KRAS, AND 2352 01:23:01,720 --> 01:23:03,422 WE NOW NOW FROM MANY GROUPS, I'M 2353 01:23:03,422 --> 01:23:07,326 SHOWING YOU SOME DATA FROM ONE 2354 01:23:07,326 --> 01:23:09,828 OF THE PAPERS SHOWING HOW 2355 01:23:09,828 --> 01:23:12,798 RESISTANCE EMERGES IN THE 2356 01:23:12,798 --> 01:23:15,867 CONTEXT OF TREATMENT WITH KRAS 2357 01:23:15,867 --> 01:23:17,202 INHIBITOR, SO OTHER TARGETED 2358 01:23:17,202 --> 01:23:19,037 AGENTS, AND WE CAN SEE HERE WE 2359 01:23:19,037 --> 01:23:21,807 CAN HAVE ACQUIRED KRAS 2360 01:23:21,807 --> 01:23:23,875 ALTERATIONS SO THESE ON-TARGET 2361 01:23:23,875 --> 01:23:25,644 MUTATIONS CAN ALSO HAPPEN HERE. 2362 01:23:25,644 --> 01:23:27,846 WE CAN ALSO SEE ACTIVATION OF 2363 01:23:27,846 --> 01:23:30,015 BYPASS SIGNALING PATHWAYS HERE 2364 01:23:30,015 --> 01:23:31,883 HIGHLIGHTED IN YELLOW, FOR 2365 01:23:31,883 --> 01:23:33,352 EXAMPLE, THAT HAPPEN IN THE 2366 01:23:33,352 --> 01:23:37,289 RESISTANT TUMORS. 2367 01:23:37,289 --> 01:23:39,124 AND ONE OF THE THINGS THAT CAN 2368 01:23:39,124 --> 01:23:40,993 ALSO HAPPEN AND HIGHLIGHTED IN 2369 01:23:40,993 --> 01:23:43,095 THESE TWO CASES HERE REALLY IN 2370 01:23:43,095 --> 01:23:45,731 PINK IS THAT WE HAVE HERE ALSO 2371 01:23:45,731 --> 01:23:48,133 AN EXAMPLE OF LINEAGE 2372 01:23:48,133 --> 01:23:49,935 PLASTICITY, WHERE LUNG 2373 01:23:49,935 --> 01:23:51,136 ADENOCARCINOMAS CAN CHANGE TO 2374 01:23:51,136 --> 01:23:53,639 ANOTHER HISTOLOGICAL SUBTYPE OF 2375 01:23:53,639 --> 01:23:55,607 SQUAMOUS CELL CARCINOMA. 2376 01:23:55,607 --> 01:23:56,708 AND THERE'S A LOT OF WORK IN THE 2377 01:23:56,708 --> 01:23:58,910 FIELD REALLY TRYING TO 2378 01:23:58,910 --> 01:24:00,979 UNDERSTAND WHY SOME TUMORS THAT 2379 01:24:00,979 --> 01:24:03,415 RESISTANCE WILL SHIFT FROM THESE 2380 01:24:03,415 --> 01:24:04,850 ADENOCARCINOMAS TO SQUAMOUS CELL 2381 01:24:04,850 --> 01:24:09,087 LUNG CARCINOMAS, AND JUST WANTED 2382 01:24:09,087 --> 01:24:10,322 TO SHOW YOU HERE THAT SOME WORK 2383 01:24:10,322 --> 01:24:14,259 HAS SHOWN THAT IF YOU ACTUALLY 2384 01:24:14,259 --> 01:24:15,894 TAKE A TUMOR AT BASELINE AND IT 2385 01:24:15,894 --> 01:24:18,764 HAS A SIGNATURE OF A SQUAMOUS 2386 01:24:18,764 --> 01:24:20,265 CELL CARCINOMA, THOSE CAN HAVE 2387 01:24:20,265 --> 01:24:22,801 WORSE OUTCOMES ON TREATMENT WITH 2388 01:24:22,801 --> 01:24:25,437 THESE KRAS INPIB HIB TORES 2389 01:24:25,437 --> 01:24:27,506 COMPARED TO TUMORS THAT DON'T 2390 01:24:27,506 --> 01:24:28,173 HAVE THIS SIGNATURE. 2391 01:24:28,173 --> 01:24:33,011 AND WORK HAS GONE INTO -- THIS 2392 01:24:33,011 --> 01:24:34,546 IS REALLY SHOWING THAT IN THE 2393 01:24:34,546 --> 01:24:35,847 CONTEXT SPECIFIC GENOMIC 2394 01:24:35,847 --> 01:24:38,950 CONTEXT, YOU ACTUALLY AT 2395 01:24:38,950 --> 01:24:40,385 RESISTANCE CAN SEE THIS CHANGE 2396 01:24:40,385 --> 01:24:42,120 FROM ADENOCARCINOMA TO SQUAMOUS 2397 01:24:42,120 --> 01:24:44,222 CELL CARCINOMA THAT YOU DON'T 2398 01:24:44,222 --> 01:24:45,991 SEE NECESSARILY IN OTHER GENOMIC 2399 01:24:45,991 --> 01:24:46,291 CONTEXTS. 2400 01:24:46,291 --> 01:24:47,826 SO WE'RE REALLY BEGINNING TO GET 2401 01:24:47,826 --> 01:24:51,997 A SENSE OF WHEN THESE TYPES OF 2402 01:24:51,997 --> 01:24:54,299 TRANSITIONS, WHEN THIS TYPE OF 2403 01:24:54,299 --> 01:25:01,973 PLASTICITY HAPPENS IN THE 2404 01:25:01,973 --> 01:25:04,943 CONTEXT OF KRAS G12C INHIBITORS, 2405 01:25:04,943 --> 01:25:05,811 TRANSFORMATION OCCURRING. 2406 01:25:05,811 --> 01:25:11,183 SO I'D JUST LIKE TO TAKE A FEW 2407 01:25:11,183 --> 01:25:12,050 MORE MINUTES IN THIS 2408 01:25:12,050 --> 01:25:12,818 PRESENTATION AND TELL YOU ABOUT 2409 01:25:12,818 --> 01:25:15,020 SOME OF THE WORK THAT WE'VE 2410 01:25:15,020 --> 01:25:16,221 BEEN -- WE AND OTHERS HAVE BEEN 2411 01:25:16,221 --> 01:25:20,058 DOING TO REALLY UNDERSTAND -- 2412 01:25:20,058 --> 01:25:21,259 I'VE TOLD YOU ABOUT RESISTANCE, 2413 01:25:21,259 --> 01:25:23,895 I'VE TOLD YOU ABOUT PRIMARY 2414 01:25:23,895 --> 01:25:24,996 RESISTANCE, I'VE TOLD YOU ABOUT 2415 01:25:24,996 --> 01:25:26,198 ACQUIRED RESISTANCE, BUT ALL OF 2416 01:25:26,198 --> 01:25:29,401 THIS IS SORT OF PREDICATED OR 2417 01:25:29,401 --> 01:25:30,602 RELIES ON THE FACT THAT WHEN WE 2418 01:25:30,602 --> 01:25:33,872 FIRST USE THE TARGETED 2419 01:25:33,872 --> 01:25:34,639 THERAPIES, THEY'RE NOT GETTING 2420 01:25:34,639 --> 01:25:36,108 RID OF ALL OF THE CELLS FROM THE 2421 01:25:36,108 --> 01:25:36,408 GET-GO. 2422 01:25:36,408 --> 01:25:37,642 AND THIS IS A BIG PROBLEM. 2423 01:25:37,642 --> 01:25:38,744 IT'S A BIG PROBLEM WITH ALL OF 2424 01:25:38,744 --> 01:25:42,314 THE TARGETED AGENTS BUT YOU CAN 2425 01:25:42,314 --> 01:25:43,682 SEE HERE IN THIS SLIDE IF WE 2426 01:25:43,682 --> 01:25:44,850 HAVE A PRE-TREATMENT TUMOR WITH 2427 01:25:44,850 --> 01:25:46,685 A CT SCAN POST TREATMENT SIX 2428 01:25:46,685 --> 01:25:50,889 MONTHS LAY TE YOU STI LATER, YOA 2429 01:25:50,889 --> 01:25:52,124 LITTLE BIT OF ACTUAL MORE LEFT 2430 01:25:52,124 --> 01:25:52,324 OVER. 2431 01:25:52,324 --> 01:25:58,063 IF WE LOOK AT THESE -- 2432 01:25:58,063 --> 01:26:00,031 OSIMERTINIB, YOU SEE MANY TUMORS 2433 01:26:00,031 --> 01:26:02,667 SHRINK BUT THERE'S REALLY A LOT 2434 01:26:02,667 --> 01:26:04,202 OF VARIABILITY IN HOW MUCH EACH 2435 01:26:04,202 --> 01:26:08,039 OF THESE TUMORS SHRINKS. 2436 01:26:08,039 --> 01:26:10,776 SO WE HAVE A LOT OF CELLS THAT 2437 01:26:10,776 --> 01:26:13,412 ARE LEFT OVER, AND SO SOME OF 2438 01:26:13,412 --> 01:26:16,681 THE WORK THAT IS HAPPENING IN 2439 01:26:16,681 --> 01:26:18,116 THE FIELD, I THINK SOME OF THE 2440 01:26:18,116 --> 01:26:21,420 VERY EXCITING WORK IS REALLY TO 2441 01:26:21,420 --> 01:26:23,388 UNDERSTAND WHAT THE MECHANISMS 2442 01:26:23,388 --> 01:26:27,793 OF THIS DRUG TOLERANCE ARE, AND 2443 01:26:27,793 --> 01:26:29,428 WE KNOW MANY OF THESE CELLS CAN 2444 01:26:29,428 --> 01:26:31,596 HAVE REDUCED RATES OF 2445 01:26:31,596 --> 01:26:33,131 PROLIFERATION, THESE PERSISTERS, 2446 01:26:33,131 --> 01:26:35,901 WE DRAW THEM DRUG TOLERANT 2447 01:26:35,901 --> 01:26:37,536 PERSISTERS IN THE FEEL, THEY CAN 2448 01:26:37,536 --> 01:26:39,304 HAVE DIFFERENCES IN METABOLIC 2449 01:26:39,304 --> 01:26:42,274 CHANGES, THEY CAN ACTIVATE, FOR 2450 01:26:42,274 --> 01:26:44,242 EXAMPLE, PROTECTIVE ANTIOXIDANT 2451 01:26:44,242 --> 01:26:44,676 MECHANISMS. 2452 01:26:44,676 --> 01:26:47,646 THEY CAN ALSO SHIFT, AND SHIFT 2453 01:26:47,646 --> 01:26:49,748 STATES, AND UNDERGO, FOR 2454 01:26:49,748 --> 01:26:51,516 EXAMPLE, EPITHELIAL TO 2455 01:26:51,516 --> 01:26:53,919 MESENCHYMAL TRANSITION, CHANGE 2456 01:26:53,919 --> 01:26:54,920 THESE -- THESE PROPERTIES OF THE 2457 01:26:54,920 --> 01:26:56,555 CELLS CAN CHANGE SO THAT THEY 2458 01:26:56,555 --> 01:26:59,758 DON'T REALLY CARE WHETHER A 2459 01:26:59,758 --> 01:27:01,059 TARGETED AGENT IS AROUND OR NOT. 2460 01:27:01,059 --> 01:27:02,594 AND THEN THE MICROENVIRONMENT 2461 01:27:02,594 --> 01:27:04,496 CAN, OF COURSE, INFLUENCE THE 2462 01:27:04,496 --> 01:27:06,598 SURVIVAL OF THESE DIFFERENT 2463 01:27:06,598 --> 01:27:06,898 CELLS. 2464 01:27:06,898 --> 01:27:08,033 SO THERE ARE LOTS OF DIFFERENT 2465 01:27:08,033 --> 01:27:09,034 PROCESSS THAT CAN HAPPEN, AND 2466 01:27:09,034 --> 01:27:10,535 WE'RE STARTING TO UNCOVER SOME 2467 01:27:10,535 --> 01:27:11,736 OF THAT. 2468 01:27:11,736 --> 01:27:18,176 I'D JUST LIKE TO POINT OUT SOME 2469 01:27:18,176 --> 01:27:20,178 DATA FROM OUR GROUP THAT WE 2470 01:27:20,178 --> 01:27:21,279 PUBLISHED LAST YEAR IN WHICH WE 2471 01:27:21,279 --> 01:27:23,782 SAW THAT IN PATIENT DERIVED 2472 01:27:23,782 --> 01:27:26,218 XENOGRAPHS, SO THESE ARE TUMORS 2473 01:27:26,218 --> 01:27:27,552 FROM -- PATIENT TUMORS IN WHICH 2474 01:27:27,552 --> 01:27:30,922 WE WERE ABLE TO MODEL THIS DRUG 2475 01:27:30,922 --> 01:27:31,790 TOLERANCE STATE, ONE OF THE 2476 01:27:31,790 --> 01:27:33,291 THINGS THAT WE SAW IS WE SAW 2477 01:27:33,291 --> 01:27:36,228 THAT YOU COULD HAVE ACTIVATION 2478 01:27:36,228 --> 01:27:41,900 OF EXPRESSION OF A HELIX PIONEER 2479 01:27:41,900 --> 01:27:45,470 TRANSCRIPTION FACTOR ASCL1 IN 2480 01:27:45,470 --> 01:27:46,204 THESE RESIDUAL CELLS. 2481 01:27:46,204 --> 01:27:48,373 YOU CAN SEE ON THE RIGHT, THESE 2482 01:27:48,373 --> 01:27:51,676 ARE EXAMPLES OF THE UNTREATED 2483 01:27:51,676 --> 01:27:53,211 TUMORS, WHERE YOU SEE EGF 2484 01:27:53,211 --> 01:27:56,047 RECEPTOR IS THERE AND YOU SEE 2485 01:27:56,047 --> 01:27:58,283 UN -- PHOSPHORYLATION OF EGF 2486 01:27:58,283 --> 01:28:01,520 REAP ACCEPTOR, WHEN YOU ACTUALLY 2487 01:28:01,520 --> 01:28:02,654 BLOCKAGETIVITY OF THE RECEPTOR, 2488 01:28:02,654 --> 01:28:04,356 IT'S SHUT OFF, BUT THEN YOU TURN 2489 01:28:04,356 --> 01:28:06,224 ON ASCL1 AND ACTUALLY ALL OF 2490 01:28:06,224 --> 01:28:08,159 THESE OTHER GENES THAT ARE 2491 01:28:08,159 --> 01:28:08,593 DOWNSTREAM TARGET. 2492 01:28:08,593 --> 01:28:10,195 SO YOU REALLY ARE TURNING ON 2493 01:28:10,195 --> 01:28:12,497 THIS PROGRAM, AND WHEN WE WENT 2494 01:28:12,497 --> 01:28:14,566 IN AND LOOKED MORE IN DETAIL AND 2495 01:28:14,566 --> 01:28:16,801 DID MORE FUNCTIONAL STUDIES, WE 2496 01:28:16,801 --> 01:28:18,904 SAW ASCL1 IN THESE TUMORS COULD 2497 01:28:18,904 --> 01:28:21,439 ACTUALLY TURN ON AN EPITHELIAL 2498 01:28:21,439 --> 01:28:23,975 TO TRANS ENG MALL TRANSITION 2499 01:28:23,975 --> 01:28:27,479 STATE THAT ALLOWS THE CELLS TO 2500 01:28:27,479 --> 01:28:27,812 SURVIVE. 2501 01:28:27,812 --> 01:28:29,014 THIS IS REALLY FASCINATING 2502 01:28:29,014 --> 01:28:31,650 BECAUSE IT TELLS US IF THIS ASCL 2503 01:28:31,650 --> 01:28:33,652 GENE GOES ON AND IS ON IN THESE 2504 01:28:33,652 --> 01:28:39,891 RESIDUAL CELLS, IT CAN THESE EMT 2505 01:28:39,891 --> 01:28:41,326 GENES, AND WHEN THEY'RE TREATED 2506 01:28:41,326 --> 01:28:43,228 WITH THE TYROSINE KINASE 2507 01:28:43,228 --> 01:28:44,195 INHIBITOR, THEY DON'T DIE, THEY 2508 01:28:44,195 --> 01:28:44,963 STAY ALIVE. 2509 01:28:44,963 --> 01:28:46,298 BUT IT ONLY HAPPENS IN CERTAIN 2510 01:28:46,298 --> 01:28:47,632 CELLS AND THERE ARE OTHER CELLS 2511 01:28:47,632 --> 01:28:49,601 WHERE EVEN IF YOU HAVE 2512 01:28:49,601 --> 01:28:51,136 ASCL1 THERE, THEY ARE JUST NOT 2513 01:28:51,136 --> 01:28:51,770 PERMISSIVE. 2514 01:28:51,770 --> 01:28:53,972 THAT DOESN'T HAPPEN, AND THEY 2515 01:28:53,972 --> 01:28:56,541 WILL STILL UNDERGO APOPTOSIS AND 2516 01:28:56,541 --> 01:28:58,944 DIE UPON TKI TREATMENT. 2517 01:28:58,944 --> 01:29:01,246 BUT THIS IS A NOVEL MECHANISM 2518 01:29:01,246 --> 01:29:02,881 THAT WE'RE WORKING TO UNDERSTAND 2519 01:29:02,881 --> 01:29:06,618 BETTER NOW. 2520 01:29:06,618 --> 01:29:08,787 IN THE LAST COUPLE OF MINUTES OF 2521 01:29:08,787 --> 01:29:11,122 THE PRESENTATION, I'D JUST LIKE 2522 01:29:11,122 --> 01:29:12,791 TO TELL YOU ABOUT SOME OF THE 2523 01:29:12,791 --> 01:29:16,494 WORK THAT WE'RE DOING TO 2524 01:29:16,494 --> 01:29:18,663 UNDERSTAND THE WORK WE'RE DOING 2525 01:29:18,663 --> 01:29:21,333 WITH IMMUNE CHECKPOINT 2526 01:29:21,333 --> 01:29:22,200 INHIBITORS, AND HERE AS YOU 2527 01:29:22,200 --> 01:29:24,836 HEARD FROM ROY, THE GREAT 2528 01:29:24,836 --> 01:29:25,704 ADVANCES. 2529 01:29:25,704 --> 01:29:27,572 WE SEE THAT MANY PATIENTS 2530 01:29:27,572 --> 01:29:30,208 SURVIVE FOR QUITE -- WE SEE A 2531 01:29:30,208 --> 01:29:32,744 NICE REALLY TAIL OF THE CURVE 2532 01:29:32,744 --> 01:29:34,045 IMPROVEMENTS IN SURVIVAL FOR 2533 01:29:34,045 --> 01:29:36,247 PATIENTS TREATED WITH IMMUNE 2534 01:29:36,247 --> 01:29:39,250 CHECKPOINT INHIBITORS, BUT ONE 2535 01:29:39,250 --> 01:29:41,987 OF THE THINGS THAT WE LEARNED 2536 01:29:41,987 --> 01:29:47,225 OVER THE YEARS AND WE'RE ABLE TO 2537 01:29:47,225 --> 01:29:48,660 LEVERAGE OUR BIOPSY PROGRAM THAT 2538 01:29:48,660 --> 01:29:52,731 ROY TOLD YOU ABOUT EARLIER, 2539 01:29:52,731 --> 01:29:54,366 SEVERAL YEARS AGO, WITH REALLY 2540 01:29:54,366 --> 01:29:55,367 WE KNEW THAT PATIENTS WERE 2541 01:29:55,367 --> 01:29:57,102 DEVELOPING ACQUIRED RESISTANCE 2542 01:29:57,102 --> 01:29:58,837 TO IMMUNE CHECKPOINT INHIBITORS 2543 01:29:58,837 --> 01:29:59,537 AS WELL. 2544 01:29:59,537 --> 01:30:03,274 SO SEVERAL YEARS AGO, WHAT WE 2545 01:30:03,274 --> 01:30:05,143 DID IS WE COLLECTED SPECIMENS 2546 01:30:05,143 --> 01:30:08,747 FROM PATIENTS WHO DEVELOPED 2547 01:30:08,747 --> 01:30:10,448 ACQUIRED RESISTANCE TO IMMUNE 2548 01:30:10,448 --> 01:30:12,517 CHECKPOINT INHIBITOR, WE WERE 2549 01:30:12,517 --> 01:30:14,486 ABLE TO COMPARE THEM TO THE 2550 01:30:14,486 --> 01:30:15,920 PRE-TREATMENT TUMOR SPECIMENS, 2551 01:30:15,920 --> 01:30:16,821 AND HERE YOU CAN SEE AN EXAMPLE 2552 01:30:16,821 --> 01:30:19,424 OF THIS IS ONE CASE WHERE 2553 01:30:19,424 --> 01:30:20,992 PATIENT WAS TREATED WITH A 2554 01:30:20,992 --> 01:30:23,028 COMBINATION OF IMMUNOTHERAPEUTIC 2555 01:30:23,028 --> 01:30:24,396 AGENTS, HAD AN AMAZING INITIAL 2556 01:30:24,396 --> 01:30:27,899 RESPONSE TO IMMUNOTHERAPY, BUT 2557 01:30:27,899 --> 01:30:30,135 EFFICIENTLY RESISTANCE DEVELOPED 2558 01:30:30,135 --> 01:30:30,769 THE IMMUNOTHERAPY. 2559 01:30:30,769 --> 01:30:32,303 AND WE WERE ABLE TO THEN GO 2560 01:30:32,303 --> 01:30:34,506 AHEAD AND WE DID WHOLE EXOME 2561 01:30:34,506 --> 01:30:36,274 SEQUENCING ON THESE TUMORS. 2562 01:30:36,274 --> 01:30:39,010 AND IN THIS CASE, WE FOUND 2563 01:30:39,010 --> 01:30:41,546 HOMOZYGOUS LOSS OF BETA 2 MICRO 2564 01:30:41,546 --> 01:30:43,114 GLOBULIN. 2565 01:30:43,114 --> 01:30:46,484 NOW, BETA 2 MICRO GLOBULIN IS A 2566 01:30:46,484 --> 01:30:53,058 FUNDAMENTAL COMPONENT OF THE HLA 2567 01:30:53,058 --> 01:30:53,992 ANTIGEN PRESENTATION MACHINERY. 2568 01:30:53,992 --> 01:30:57,696 SO WHAT HAPPENS IS THAT IN ORDER 2569 01:30:57,696 --> 01:31:01,599 FOR OUR CELLS TO BE RECOGNIZED 2570 01:31:01,599 --> 01:31:05,136 BY THE IMMUNE SYSTEM, THEY NEED 2571 01:31:05,136 --> 01:31:07,138 TO PRESENT ANTIGENS ON THE CELL 2572 01:31:07,138 --> 01:31:07,472 SURFACE. 2573 01:31:07,472 --> 01:31:11,509 WHEN THEY DO THAT, T CELLS WILL 2574 01:31:11,509 --> 01:31:13,945 THEN RECOGNIZE THOSE CELLS, 2575 01:31:13,945 --> 01:31:14,612 THOSE ANTIGENS. 2576 01:31:14,612 --> 01:31:18,416 SO THAT'S REALLY IMPORTANT FOR A 2577 01:31:18,416 --> 01:31:21,820 T-CELL TO REACT TO A TUMOR CELL. 2578 01:31:21,820 --> 01:31:28,093 AND SO WHEN YOU LOSE BETA 2 -- 2579 01:31:28,093 --> 01:31:29,427 WHAT HAPPENS IS THAT HLA COMPLEX 2580 01:31:29,427 --> 01:31:31,162 CANNOT BE FORMED, SO THOSE 2581 01:31:31,162 --> 01:31:33,264 CANCER CELLS THEN CANNOT PRESENT 2582 01:31:33,264 --> 01:31:33,732 ANTIGEN. 2583 01:31:33,732 --> 01:31:35,467 SO THEY BECOME INVISIBLE TO THE 2584 01:31:35,467 --> 01:31:36,334 IMMUNE SYSTEM. 2585 01:31:36,334 --> 01:31:37,569 INVISIBLE TO THE T CELLS, WHICH 2586 01:31:37,569 --> 01:31:40,839 IS A REALLY GOOD WAY OF EVADING 2587 01:31:40,839 --> 01:31:42,173 THE IMMUNE SYSTEM. 2588 01:31:42,173 --> 01:31:45,677 AND SO THERE'S A SUBSET OF 2589 01:31:45,677 --> 01:31:47,445 TUMORS THAT DEVELOP ACQUIRED 2590 01:31:47,445 --> 01:31:49,180 RESISTANCE TO THESE IMMUNE 2591 01:31:49,180 --> 01:31:52,183 CHECKPOINT INHIBITORS BY 2592 01:31:52,183 --> 01:31:53,384 ACTUALLY BECOMING INVISIBLE TO 2593 01:31:53,384 --> 01:31:54,486 THE IMMUNE SYSTEM. 2594 01:31:54,486 --> 01:31:55,887 AND OTHER GROUPS HAVE GONE ON TO 2595 01:31:55,887 --> 01:31:58,423 DO MORE WORK AND THEY SEE A 2596 01:31:58,423 --> 01:32:00,525 SUBSET OF TUMORS, A SMALL SUBSET 2597 01:32:00,525 --> 01:32:02,627 OF TUMORS THAT HAVE MUTATIONS, 2598 01:32:02,627 --> 01:32:04,829 FOR EXAMPLE, IN BETA 2 MICRO 2599 01:32:04,829 --> 01:32:07,265 GLOBULIN, HERE IS AN EXAMPLE 2600 01:32:07,265 --> 01:32:10,101 FROM A STUDY THAT WAS PUBLISHED 2601 01:32:10,101 --> 01:32:11,336 LAST YEAR, BUT ONE OF THE THINGS 2602 01:32:11,336 --> 01:32:12,904 THAT WE'RE REALLY LEARNING, AND 2603 01:32:12,904 --> 01:32:15,840 I JUST WANT TO HIGHLIGHT THIS, 2604 01:32:15,840 --> 01:32:17,308 IS THAT WE CAN LEARN THIS FROM 2605 01:32:17,308 --> 01:32:18,276 THE GENETICS, FROM LOOKING AT 2606 01:32:18,276 --> 01:32:20,011 THE TUMORS, WE SEE A SMALL 2607 01:32:20,011 --> 01:32:23,648 SUBSET THAT HAVE THESE 2608 01:32:23,648 --> 01:32:24,215 ALTERATIONS. 2609 01:32:24,215 --> 01:32:26,151 BUT ONE OF THE THINGS THAT'S 2610 01:32:26,151 --> 01:32:27,786 REALLY IMPORTANT IS THESE 2611 01:32:27,786 --> 01:32:28,953 PATHWAYS, ANTIGEN PRESENTATION, 2612 01:32:28,953 --> 01:32:30,054 CAN ALSO BE REGULATED IN 2613 01:32:30,054 --> 01:32:30,688 DIFFERENT WAYS. 2614 01:32:30,688 --> 01:32:31,890 IT DOESN'T HAVE TO BE GENETIC. 2615 01:32:31,890 --> 01:32:36,227 IT CAN ALSO BE, FOR EXAMPLE, 2616 01:32:36,227 --> 01:32:38,496 SIGNALING THAT CAN LEAD TO -- 2617 01:32:38,496 --> 01:32:39,931 CAN SHUT IT OFF OR TURN IT DOWN, 2618 01:32:39,931 --> 01:32:42,901 AND YOU CAN SEE HERE IF YOU 2619 01:32:42,901 --> 01:32:46,738 ACTUALLY LOOK AT THE LEVELS OF 2620 01:32:46,738 --> 01:32:48,540 THE PROTEINS, OF HLA PROTEIN, 2621 01:32:48,540 --> 01:32:50,141 YOU CAN SEE IN THE TUMORS 2622 01:32:50,141 --> 01:32:52,443 RESISTANT TO IMMUNE CHECKPOINT 2623 01:32:52,443 --> 01:32:53,978 INHIBITORS, PLU CHEMOTHERAPY THE 2624 01:32:53,978 --> 01:32:55,980 LEVELS ARE LOWER THAN IN TUMORS 2625 01:32:55,980 --> 01:32:57,182 ONLY TREATED WITH CHEMOTHERAPY 2626 01:32:57,182 --> 01:32:58,049 OR TARGETED THERAPY. 2627 01:32:58,049 --> 01:32:59,284 SO WE MAKE THE ARGUMENT HERE 2628 01:32:59,284 --> 01:33:01,186 THAT WE REALLY NEED TO LOOK MORE 2629 01:33:01,186 --> 01:33:02,821 BROADLY, GO BEYOND LOOKING AT 2630 01:33:02,821 --> 01:33:05,023 MUTATIONS BUT LOOK ACTUALLY AT 2631 01:33:05,023 --> 01:33:06,991 THE PROTEIN LEVEL AND I THINK 2632 01:33:06,991 --> 01:33:08,660 WE'LL PROBABLY SEE A LARGER 2633 01:33:08,660 --> 01:33:12,163 FACTION OF TUMORS WITH 2634 01:33:12,163 --> 01:33:13,498 RESISTANCE THAT HAVE DEFECTS IN 2635 01:33:13,498 --> 01:33:14,199 THIS PATHWAY. 2636 01:33:14,199 --> 01:33:15,934 A LOT OF WORK IS GOING ON TO 2637 01:33:15,934 --> 01:33:17,502 UNDERSTAND OTHER MECHANISMS OF 2638 01:33:17,502 --> 01:33:17,836 RESISTANCE. 2639 01:33:17,836 --> 01:33:22,473 SO I'D LIKE TO CLOSE REALLY 2640 01:33:22,473 --> 01:33:24,008 WITH -- CLOSE WITH TALKING ABOUT 2641 01:33:24,008 --> 01:33:25,877 HOW WE'VE REALLY, I THINK, GONE 2642 01:33:25,877 --> 01:33:27,545 A LONG WAY IN THE PAST COUPLE OF 2643 01:33:27,545 --> 01:33:29,180 DECADES, REALLY UNDERSTANDING 2644 01:33:29,180 --> 01:33:33,685 THE IMPORTANCE OF PARTNERING OUR 2645 01:33:33,685 --> 01:33:36,588 HISTOLOGICAL DIAGNOSIS, 2646 01:33:36,588 --> 01:33:37,455 IMMUNOHISTOCHEMICAL DIAGNOSIS OF 2647 01:33:37,455 --> 01:33:39,190 TUMORS WITH MOLECULAR PROFILING 2648 01:33:39,190 --> 01:33:40,291 WITH UNDERSTANDING OF THE 2649 01:33:40,291 --> 01:33:42,427 BIOLOGY OF THE TUMORS, WITH THE 2650 01:33:42,427 --> 01:33:44,729 HOPES THAT WE CAN REALLY TREAT 2651 01:33:44,729 --> 01:33:46,798 TUMORS IN A MORE TAILORED 2652 01:33:46,798 --> 01:33:49,467 FASHION, BUT THEN DISEASE 2653 01:33:49,467 --> 01:33:51,202 PROGRESSION, IF WE CAN DO REPEAT 2654 01:33:51,202 --> 01:33:52,303 BIOPSIES, WE CAN STUDY THE 2655 01:33:52,303 --> 01:33:54,772 MECHANISMS OF RESISTANCE AND 2656 01:33:54,772 --> 01:33:56,074 INCORPORATE THERAPEUTIC STUDIES, 2657 01:33:56,074 --> 01:33:57,375 FUNCTIONAL STUDIES, TO REALLY 2658 01:33:57,375 --> 01:33:59,077 CONTINUE TO IMPROVE THE 2659 01:33:59,077 --> 01:34:00,178 TREATMENT OF LUNG CANCER FOR 2660 01:34:00,178 --> 01:34:01,045 PATIENTS. 2661 01:34:01,045 --> 01:34:03,681 I'D LIKE TO SHOW HERE PICTURES 2662 01:34:03,681 --> 01:34:07,318 OF MEMBERS OF MY LAB, AND THE 2663 01:34:07,318 --> 01:34:09,287 TEAM, AND THE MANY COLLABORATORS 2664 01:34:09,287 --> 01:34:10,722 AND PEOPLE WE WORK WITH. 2665 01:34:10,722 --> 01:34:14,559 AND THANK YOU VERY MUCH. 2666 01:34:14,559 --> 01:34:16,127 >> WELL, KATARINA, THANK YOU 2667 01:34:16,127 --> 01:34:18,429 VERY MUCH FOR THAT INCREDIBLE 2668 01:34:18,429 --> 01:34:21,699 PRESENTATION AND ALSO THANK YOU 2669 01:34:21,699 --> 01:34:23,201 TO ROY FOR HIS SPECTACULAR 2670 01:34:23,201 --> 01:34:24,035 PRESENTATION AS WELL. 2671 01:34:24,035 --> 01:34:31,376 THIS HAS JUST BEEN ABSOLUTELY 2672 01:34:31,376 --> 01:34:32,677 INCREDIBLE, HEARING THE TWO OF 2673 01:34:32,677 --> 01:34:37,515 YOUR PRESENTATIONS. 2674 01:34:37,515 --> 01:34:39,083 JUST SEEING THE BREATHTAKING 2675 01:34:39,083 --> 01:34:40,051 PROGRESS THAT'S BEEN MADE IN THE 2676 01:34:40,051 --> 01:34:41,486 LAST TWO OR THREE DECADES IN 2677 01:34:41,486 --> 01:34:42,020 THIS FIELD. 2678 01:34:42,020 --> 01:34:43,688 IT'S REALLY AMAZING. 2679 01:34:43,688 --> 01:34:47,358 SO JUST TO START THINGS OFF, ONE 2680 01:34:47,358 --> 01:34:49,260 OF THE MEMBERS OF OUR AUDIENCE 2681 01:34:49,260 --> 01:34:51,930 WAS STRUCK BY THE FACT THAT MANY 2682 01:34:51,930 --> 01:34:53,798 OF THE THINGS THAT YOU'RE 2683 01:34:53,798 --> 01:34:55,900 TALKING ABOUT WITH REGARD TO 2684 01:34:55,900 --> 01:34:57,535 LUNG CANCER PROBABLY APPLY TO 2685 01:34:57,535 --> 01:34:59,137 MANY OTHER KINDS OF CANCERS. 2686 01:34:59,137 --> 01:35:00,204 >> I'M HERE TOO. 2687 01:35:00,204 --> 01:35:01,839 DO YOU SEE ME? 2688 01:35:01,839 --> 01:35:03,274 >> PARDON ME? 2689 01:35:03,274 --> 01:35:04,008 >> THIS IS ROY. 2690 01:35:04,008 --> 01:35:05,610 I JUST WANTED TO MAKE SURE -- I 2691 01:35:05,610 --> 01:35:06,778 WAS ON A DIFFERENT COMPUTER -- 2692 01:35:06,778 --> 01:35:07,312 THAT YOU SEE ME. 2693 01:35:07,312 --> 01:35:09,147 >> YES, YES, WE DO SEE YOU. 2694 01:35:09,147 --> 01:35:11,115 YES, INDEED. 2695 01:35:11,115 --> 01:35:13,618 SO ANYWAY, THE QUESTIONER WAS 2696 01:35:13,618 --> 01:35:15,286 POINTING OUT THAT MANY OF THE 2697 01:35:15,286 --> 01:35:19,590 THINGS THAT YOU'VE SO NICELY 2698 01:35:19,590 --> 01:35:20,692 DEMONSTRATED IN LUNG CANCER 2699 01:35:20,692 --> 01:35:21,893 PROBABLY HAPPENED IN OTHER FORMS 2700 01:35:21,893 --> 01:35:25,196 OF CANCER AS WELL. 2701 01:35:25,196 --> 01:35:29,600 ARE THERE TUMORS FOR EXAMPLE IN 2702 01:35:29,600 --> 01:35:34,272 OTHER ANATOMIC SITES THAT HAVE 2703 01:35:34,272 --> 01:35:38,042 EGFR MUTATIONS AND COULD THE 2704 01:35:38,042 --> 01:35:41,212 EGFR INHIBITORY DRUGS BE USED IN 2705 01:35:41,212 --> 01:35:45,950 THOSE FORMS OF CANCER? 2706 01:35:45,950 --> 01:35:49,687 >> SO I THINK JUST TO -- THERE 2707 01:35:49,687 --> 01:35:50,888 ARE -- SO ONE OF THE THINGS, 2708 01:35:50,888 --> 01:35:54,492 THESE TYPES OF MUTATIONS I WAS 2709 01:35:54,492 --> 01:35:55,927 TELLING YOU ABOUT ARE MOSTLY 2710 01:35:55,927 --> 01:35:58,062 LUNG CANCER ASSOCIATED MUTATIONS 2711 01:35:58,062 --> 01:36:02,834 IN EFF RECEPTORS, VERY 2712 01:36:02,834 --> 01:36:04,002 INTERESTING BUT THEY'RE REALLY 2713 01:36:04,002 --> 01:36:05,069 EXCLUSIVELY FOUND IN LUNG 2714 01:36:05,069 --> 01:36:05,303 CANCERS. 2715 01:36:05,303 --> 01:36:08,373 THERE ARE OTHER TYPES OF 2716 01:36:08,373 --> 01:36:09,941 MUTATIONS IN EGF RECEPTOR FOUND 2717 01:36:09,941 --> 01:36:11,275 IN OTHER TUMOR TYPES. 2718 01:36:11,275 --> 01:36:13,344 YOU CAN HAVE MUTATIONS, FOR 2719 01:36:13,344 --> 01:36:15,013 EXAMPLE, IN GLIOMAS, THERE ARE 2720 01:36:15,013 --> 01:36:18,182 THESE EGFR B3 MUTATIONS, THERE 2721 01:36:18,182 --> 01:36:22,353 ALSO CAN BE SOME CHANGES IN THE 2722 01:36:22,353 --> 01:36:24,355 LEVELS OF EGF RECEPTOR THAT CAN 2723 01:36:24,355 --> 01:36:28,426 BE FOUND IN DIFFERENT TUMORS, 2724 01:36:28,426 --> 01:36:29,827 AND ALSO THERE ARE DIFFERENT 2725 01:36:29,827 --> 01:36:30,795 THERAPEUTIC STRATEGIES TO TREAT 2726 01:36:30,795 --> 01:36:30,995 THEM. 2727 01:36:30,995 --> 01:36:34,032 SO THERE ARE COLON CANCERS, FOR 2728 01:36:34,032 --> 01:36:35,099 EXAMPLE, THAT CAN BE TREATED 2729 01:36:35,099 --> 01:36:37,502 WITH EGF RECEPTOR ANTIBODIES AND 2730 01:36:37,502 --> 01:36:39,270 ACTUALLY YOU CAN HAVE RESISTANCE 2731 01:36:39,270 --> 01:36:41,906 TO THOSE EGFR ANTIBODIES DEVELOP 2732 01:36:41,906 --> 01:36:44,809 AND THE RESISTANCE, THOUGH, IS 2733 01:36:44,809 --> 01:36:48,513 MORE LINKED THAN TO THE 2734 01:36:48,513 --> 01:36:49,947 ANTIBODIES THAT WORK AGAINST E 2735 01:36:49,947 --> 01:36:51,149 GMENT F RECEPTORS. 2736 01:36:51,149 --> 01:36:52,583 SO FOR EXAMPLE, YOU'D HAVE MORE 2737 01:36:52,583 --> 01:36:54,185 THE MUTATIONS THAT ARE IN THE 2738 01:36:54,185 --> 01:36:55,686 EXTRACELLULAR DOMAIN OF EGF 2739 01:36:55,686 --> 01:36:56,888 RECEPTOR THAT WOULD CONFER 2740 01:36:56,888 --> 01:36:58,056 RESISTANCE TO THE ANTIBODIES. 2741 01:36:58,056 --> 01:36:59,891 WE DIDN'T TALK TOO MUCH ABOUT 2742 01:36:59,891 --> 01:37:02,960 ANTIBODIES TODAY AGAINST EGF 2743 01:37:02,960 --> 01:37:05,296 RECEPTOR, BUT SO THERE ARE 2744 01:37:05,296 --> 01:37:07,932 PARALLELS, I THINK, WITH REGARD 2745 01:37:07,932 --> 01:37:11,002 TO EGF RECEPTOR PLAYING A ROLE 2746 01:37:11,002 --> 01:37:14,105 IN OTHER CANCER TYPES AS WELL. 2747 01:37:14,105 --> 01:37:16,307 SOME OF THESE TYROSINE KINASE 2748 01:37:16,307 --> 01:37:17,375 INHIBITORS DON'T NECESSARILY 2749 01:37:17,375 --> 01:37:19,177 WORK AS WELL IN THESE OTHER 2750 01:37:19,177 --> 01:37:19,610 CANCER TYPES. 2751 01:37:19,610 --> 01:37:21,612 THEY SEEM TO WORK PARTICULARLY 2752 01:37:21,612 --> 01:37:25,083 WELL ON THESE LUNG CANCER 2753 01:37:25,083 --> 01:37:28,886 ASSOCIATED MUTATIONS. 2754 01:37:28,886 --> 01:37:30,655 >> SO IT WOULD BE OVERSIMPLIFIED 2755 01:37:30,655 --> 01:37:32,256 THEN TO SAY THAT WELL, WE COULD 2756 01:37:32,256 --> 01:37:36,461 JUST REORGANIZE OUR TAXONOMY OF 2757 01:37:36,461 --> 01:37:37,895 CANCER BY SAYING, WELL, THESE 2758 01:37:37,895 --> 01:37:41,599 ARE JUST ALL EGFR TUMORS AND 2759 01:37:41,599 --> 01:37:43,434 THEN WE HAVE THESE OTHER TUMORS 2760 01:37:43,434 --> 01:37:46,370 THAT ARE WHATEVER, KRAS TUMORS 2761 01:37:46,370 --> 01:37:47,805 OR WHAT HAVE YOU. 2762 01:37:47,805 --> 01:37:51,242 THEY DIFFER ACTUALLY IN THEIR 2763 01:37:51,242 --> 01:37:52,443 CHARACTERISTICS, NOT ONLY BY THE 2764 01:37:52,443 --> 01:37:55,947 KINASE INVOLVED, BUT BY THE 2765 01:37:55,947 --> 01:37:57,648 ANATOMIC ORIGIN OF THE TUMOR AS 2766 01:37:57,648 --> 01:37:59,117 WELL. 2767 01:37:59,117 --> 01:38:00,418 >> YES, ABSOLUTELY. 2768 01:38:00,418 --> 01:38:03,821 I THINK IT DEFINITELY -- I THINK 2769 01:38:03,821 --> 01:38:04,589 ACTUALLY IF ANYTHING, WE'RE KIND 2770 01:38:04,589 --> 01:38:05,556 OF GOING IN THE OTHER DIRECTION 2771 01:38:05,556 --> 01:38:07,458 OF REALLY SAYING WE'RE REALLY 2772 01:38:07,458 --> 01:38:10,194 UNDERSTANDING MORE ABOUT THE 2773 01:38:10,194 --> 01:38:13,097 DETAILS ABOUT HOW YOU HAVE THESE 2774 01:38:13,097 --> 01:38:15,500 DIFFERENT MUTATIONS OR DIFFERENT 2775 01:38:15,500 --> 01:38:16,934 INVOLVEMENT OF THE PATHWAYS AND 2776 01:38:16,934 --> 01:38:18,436 DIFFERENT TUMORS AND HOW THEY 2777 01:38:18,436 --> 01:38:19,704 CONTRIBUTE DIFFERENTLY IN 2778 01:38:19,704 --> 01:38:20,805 DIFFERENT ANATOMIC SITES. 2779 01:38:20,805 --> 01:38:22,006 AND THAT'S IMPORTANT TO KEEP IN 2780 01:38:22,006 --> 01:38:24,208 MIND AND THINK ABOUT. 2781 01:38:24,208 --> 01:38:24,742 >> OKAY. 2782 01:38:24,742 --> 01:38:25,443 ALL RIGHT. 2783 01:38:25,443 --> 01:38:30,248 WELL, NOW WE HAVE ANOTHER 2784 01:38:30,248 --> 01:38:34,418 QUESTION, JUST GOING BACK TO DR. 2785 01:38:34,418 --> 01:38:37,622 ARE THERE ANY CASES OF INCREASED 2786 01:38:37,622 --> 01:38:38,823 INTRACRANIAL PRESSURE IN 2787 01:38:38,823 --> 01:38:40,925 PATIENTS WITH BRAIN METASTASES 2788 01:38:40,925 --> 01:38:43,161 TREATED WITH IMMUNE CHECKPOINT 2789 01:38:43,161 --> 01:38:44,395 INHIBITORS? 2790 01:38:44,395 --> 01:38:47,765 >> THAT'S A GOOD QUESTION. 2791 01:38:47,765 --> 01:38:49,700 CERTAINLY INCREASED INTRACRANIAL 2792 01:38:49,700 --> 01:38:51,435 PRESSURE WOULD BE A SIGN OR A 2793 01:38:51,435 --> 01:38:53,738 SYMPTOM OF BRAIN METASTASES. 2794 01:38:53,738 --> 01:38:56,407 I GUESS THEIR THINKING IS 2795 01:38:56,407 --> 01:38:58,709 THEY'RE AN IMMUNE REACTION AND 2796 01:38:58,709 --> 01:39:01,345 SWELLING. 2797 01:39:01,345 --> 01:39:02,647 THAT, I THINK HAS BEEN REPORTED 2798 01:39:02,647 --> 01:39:03,514 BUT VERY RARELY. 2799 01:39:03,514 --> 01:39:07,185 I THINK WHAT WE'VE FOUND IS THAT 2800 01:39:07,185 --> 01:39:08,920 THESE DRUGS APPEAR TO GET ACROSS 2801 01:39:08,920 --> 01:39:10,688 THE BLOOD BRAIN BARRIER, THE 2802 01:39:10,688 --> 01:39:13,257 IMMUNE CHECKPOINT INHIBITORS, 2803 01:39:13,257 --> 01:39:15,560 AND THE IMMUNE EFFECT OCCURS AND 2804 01:39:15,560 --> 01:39:17,862 IT OCCURS IN AN EFFICACIOUS WAY 2805 01:39:17,862 --> 01:39:23,701 WITHOUT CAUSING SYMPTOMATIC OR 2806 01:39:23,701 --> 01:39:26,537 PROCESSES IN THE BRAIN THAT 2807 01:39:26,537 --> 01:39:27,838 REQUIRE INTERVENTION. 2808 01:39:27,838 --> 01:39:32,009 SO WE'RE VERY MUCH EVEN WITH 2809 01:39:32,009 --> 01:39:33,978 BIGGER LESIONS NOW TREATING 2810 01:39:33,978 --> 01:39:36,113 PATIENTS WITH IMMUNOTHERAPY IN 2811 01:39:36,113 --> 01:39:37,748 LUNG CANCER RIGHT NOW, THE MOST 2812 01:39:37,748 --> 01:39:39,850 COMMONLY USED THERAPY IS 2813 01:39:39,850 --> 01:39:42,186 CHEMOTHERAPY WITH PEMBROLIZUMAB 2814 01:39:42,186 --> 01:39:43,588 FOR PATIENTS WITH METASTATIC 2815 01:39:43,588 --> 01:39:44,822 DISEASE. 2816 01:39:44,822 --> 01:39:48,159 ANY -- WE DO IT FOR ALL 2817 01:39:48,159 --> 01:39:49,260 PD-L1 STATUS, EVEN THE ZEROS 2818 01:39:49,260 --> 01:39:51,295 BECAUSE IT'S THE BELIEF THAT 2819 01:39:51,295 --> 01:39:53,664 THERE WAS ACTIVITY, ZERO DOESN'T 2820 01:39:53,664 --> 01:39:54,865 ALWAYS MEAN YOU'RE ZERO, AND WE 2821 01:39:54,865 --> 01:39:57,068 ARE USING IT, YOU KNOW, WITH THE 2822 01:39:57,068 --> 01:39:58,536 BRAIN, BUT YOU WATCH CAREFULLY 2823 01:39:58,536 --> 01:40:00,805 AND YOU LOOK FOR CLINICAL SIGNS 2824 01:40:00,805 --> 01:40:03,874 AND YOU FOLLOW MRIs QUITE 2825 01:40:03,874 --> 01:40:04,175 FREQUENTLY. 2826 01:40:04,175 --> 01:40:05,042 >> OKAY. 2827 01:40:05,042 --> 01:40:07,445 WELL, THANK YOU VERY MUCH. 2828 01:40:07,445 --> 01:40:10,381 SO ANOTHER MEMBER OF THE 2829 01:40:10,381 --> 01:40:13,351 AUDIENCE IS ASKING THE QUESTION, 2830 01:40:13,351 --> 01:40:16,887 THE TUMOR MICROENVIRONMENT IS 2831 01:40:16,887 --> 01:40:21,692 VERY INTERESTING AND CANCER 2832 01:40:21,692 --> 01:40:22,493 METAMORPHOSIS IS VERY 2833 01:40:22,493 --> 01:40:23,127 INTERESTING AS WELL. 2834 01:40:23,127 --> 01:40:24,929 DOES IT CHANGE WITHOUT TREATMENT 2835 01:40:24,929 --> 01:40:26,564 AS WELL? 2836 01:40:26,564 --> 01:40:28,232 HAVE SPECIFIC DIETS DESCRIBED TO 2837 01:40:28,232 --> 01:40:29,967 BE CLINICALLY MEANINGFUL OTHER 2838 01:40:29,967 --> 01:40:38,676 THAN THE TYPICAL TEU AMER TURMER 2839 01:40:38,676 --> 01:40:40,911 CRUCIFEROUS VEGETABLES, THAT 2840 01:40:40,911 --> 01:40:42,013 LUNG CANCER PATIENTS SHOULD BE 2841 01:40:42,013 --> 01:40:44,315 ON TO POTENTIATE THEIR RESPONSE? 2842 01:40:44,315 --> 01:40:46,517 >> YOU WANT TO START, KATY, 2843 01:40:46,517 --> 01:40:47,485 ABOUT THE MICROENVIRONMENT? 2844 01:40:47,485 --> 01:40:49,720 >> I CAN COMMENT ON THE 2845 01:40:49,720 --> 01:40:50,121 MICROENVIRONMENT. 2846 01:40:50,121 --> 01:40:54,692 SO THE TUMOR MICROENVIRONMENT 2847 01:40:54,692 --> 01:40:58,963 CHANGES AS TUMORS PROGRESS. 2848 01:40:58,963 --> 01:41:00,498 SO YOU CAN HAVE CHANGES IN THE 2849 01:41:00,498 --> 01:41:01,465 MICROENVIRONMENT AS THE TUMOR 2850 01:41:01,465 --> 01:41:08,539 GETS LARGER, GETS MORE ADVANCED, 2851 01:41:08,539 --> 01:41:09,940 AND ALSO WHEN YOU HAVE 2852 01:41:09,940 --> 01:41:11,042 METASTASIS FOR EXAMPLE, I THINK 2853 01:41:11,042 --> 01:41:12,310 THAT'S ONE OF THE SITUATIONS IN 2854 01:41:12,310 --> 01:41:13,944 WHICH THE TUMOR MICROENVIRONMENT 2855 01:41:13,944 --> 01:41:15,980 CHANGES A LOT, BECAUSE SUDDENLY 2856 01:41:15,980 --> 01:41:20,318 A LUNG TUMOR IS NOW GROWING IN 2857 01:41:20,318 --> 01:41:21,819 THE CONTEXT OF THE LIVER OR THE 2858 01:41:21,819 --> 01:41:22,687 CONTEXT OF THE BRAIN. 2859 01:41:22,687 --> 01:41:26,190 I THINK ONE OF THE THINGS THAT 2860 01:41:26,190 --> 01:41:29,860 WE SEE FROM DIFFERENT THERAPIES, 2861 01:41:29,860 --> 01:41:32,296 YOU CAN SEE A LOT OF CHANGES IN 2862 01:41:32,296 --> 01:41:35,333 THE TUMOR MICROENVIRONMENT AND 2863 01:41:35,333 --> 01:41:36,300 ALSO THE ARCHITECTURE OF THE 2864 01:41:36,300 --> 01:41:37,134 TUMOR CHANGES. 2865 01:41:37,134 --> 01:41:40,538 SO YES, DEFINITELY THE TUMOR 2866 01:41:40,538 --> 01:41:43,207 MICROENVIRONMENT CHAIRNTION OVER 2867 01:41:43,207 --> 01:41:44,842 TIME, AND IT CHANGES EVEN WITH 2868 01:41:44,842 --> 01:41:46,510 DIFFERENT THERAPIES, NOT JUST 2869 01:41:46,510 --> 01:41:47,945 WITH IMMUNOTHERAPIES, RIGHT? 2870 01:41:47,945 --> 01:41:49,513 THE TUMOR MICROENVIRONMENT IS 2871 01:41:49,513 --> 01:41:51,282 COMPOSED OF BLOOD VESSEL CELLS, 2872 01:41:51,282 --> 01:41:54,552 IT'S COMPOSED OF SMOOTH -- 2873 01:41:54,552 --> 01:41:55,853 DIFFERENT FIBROBLASTS, DIFFERENT 2874 01:41:55,853 --> 01:41:57,455 CELLS THAT HOLD EVERYTHING 2875 01:41:57,455 --> 01:41:57,988 TOGETHER. 2876 01:41:57,988 --> 01:41:59,423 SO YES, THERE ARE LOTS OF 2877 01:41:59,423 --> 01:42:04,829 CHANGES THAT HAPPEN. 2878 01:42:04,829 --> 01:42:06,097 >> SORRY, DANIEL. 2879 01:42:06,097 --> 01:42:08,132 >> NO, I WAS JUST GOING TO SAY 2880 01:42:08,132 --> 01:42:10,534 THAT IT SOUNDS LIKE THEN AS THE 2881 01:42:10,534 --> 01:42:12,536 TUMOR METASTASIZE, IT BECOMES 2882 01:42:12,536 --> 01:42:14,205 JUST MORE AND MORE DIFFICULT TO 2883 01:42:14,205 --> 01:42:15,840 USE A TARGETED THERAPY BECAUSE 2884 01:42:15,840 --> 01:42:18,242 OF THE FACT THAT THE TUMOR IS 2885 01:42:18,242 --> 01:42:21,812 RESIDING IN MULTIPLE DIFFERENT 2886 01:42:21,812 --> 01:42:22,713 MILIEUS. 2887 01:42:22,713 --> 01:42:24,014 >> AND I THINK ONE OF THE THINGS 2888 01:42:24,014 --> 01:42:28,686 THAT WE'RE TRYING TO UNDERSTAND 2889 01:42:28,686 --> 01:42:29,887 AT THE EXPERIMENTAL LEVEL NOW AT 2890 01:42:29,887 --> 01:42:32,490 LEAST IS HOW DIFFERENT MICRO 2891 01:42:32,490 --> 01:42:33,357 ENVIRONMENTS CONTRIBUTE TO THE 2892 01:42:33,357 --> 01:42:34,558 RESPONSE TO DIFFERENT TARGETED 2893 01:42:34,558 --> 01:42:35,493 THERAPIES, FOR EXAMPLE. 2894 01:42:35,493 --> 01:42:36,260 THERE MIGHT BE SOME MICRO 2895 01:42:36,260 --> 01:42:37,061 ENVIRONMENTS THAT ARE BETTER 2896 01:42:37,061 --> 01:42:40,097 THAN OTHERS. 2897 01:42:40,097 --> 01:42:41,265 SO WE JUST HAVE TO UNDERSTAND 2898 01:42:41,265 --> 01:42:41,632 THAT. 2899 01:42:41,632 --> 01:42:42,900 I THINK THERE'S STILL A LOT OF 2900 01:42:42,900 --> 01:42:45,302 WORK TO DO IN THAT ARENA. 2901 01:42:45,302 --> 01:42:46,837 >> I WAS GOING TO SAY, THAT'S 2902 01:42:46,837 --> 01:42:49,073 THE OLD SEED AND SOIL HYPOTHESIS 2903 01:42:49,073 --> 01:42:52,042 FROM YEARS AGO, AND TUMORS DO 2904 01:42:52,042 --> 01:42:53,444 BEHAVE DIFFERENTLY IN DIFFERENT 2905 01:42:53,444 --> 01:42:53,878 AREAS. 2906 01:42:53,878 --> 01:42:56,046 I THINK THE FACT THAT THE 2907 01:42:56,046 --> 01:42:56,814 MICROENVIRONMENT CAN CHANGE AND 2908 01:42:56,814 --> 01:42:58,449 WE HAVE TO THINK WHEN WE DO 2909 01:42:58,449 --> 01:42:59,850 COMBINATION THERAPIES WHAT IS 2910 01:42:59,850 --> 01:43:01,685 THE OTHER THERAPY DOING TO THE 2911 01:43:01,685 --> 01:43:02,186 MICROENVIRONMENT, THAT'S 2912 01:43:02,186 --> 01:43:03,320 IMPORTANT TO CONSIDER. 2913 01:43:03,320 --> 01:43:05,523 AND ACTUALLY WE JUST HAD A TALK 2914 01:43:05,523 --> 01:43:06,757 TODAY WHERE METABOLISM CAN HAVE 2915 01:43:06,757 --> 01:43:09,927 AN EFFECT ON THE 2916 01:43:09,927 --> 01:43:11,028 MICROENVIRONMENT. 2917 01:43:11,028 --> 01:43:13,431 I GUESS NUTRITION COULD AFFECT 2918 01:43:13,431 --> 01:43:14,465 METABOLISM, SO YES, I WOULD SAY 2919 01:43:14,465 --> 01:43:15,666 THIS IS DEFINITELY GOING TO BE 2920 01:43:15,666 --> 01:43:17,101 AN AREA IF WE THINK TO THE 2921 01:43:17,101 --> 01:43:19,236 FUTURE AND INNOVATION THAT COULD 2922 01:43:19,236 --> 01:43:21,972 BE IMPORTANT. 2923 01:43:21,972 --> 01:43:25,042 RIGHT NOW IN -- THERE ARE THINGS 2924 01:43:25,042 --> 01:43:27,445 I WOULD RECOMMEND LIKE TURMERIC 2925 01:43:27,445 --> 01:43:29,146 OR OTHER SUPPLEMENTS, BUT 2926 01:43:29,146 --> 01:43:30,781 SCIENTIFIC STUDY AND I'M SURE 2927 01:43:30,781 --> 01:43:32,650 THERE IS A BASIS TO HOW 2928 01:43:32,650 --> 01:43:35,820 AFFECTING THE METABOLISM AND 2929 01:43:35,820 --> 01:43:36,954 THAT ENVIRONMENT CAN HAVE AN 2930 01:43:36,954 --> 01:43:40,057 EFFECT ON THE MICROENVIRONMENT. 2931 01:43:40,057 --> 01:43:41,659 >> OKAY. 2932 01:43:41,659 --> 01:43:43,060 ANOTHER MEMBER OF THE AUDIENCE 2933 01:43:43,060 --> 01:43:47,097 IS ASKING WHY DON'T ALL SMOKERS 2934 01:43:47,097 --> 01:43:47,965 GET CANCER? 2935 01:43:47,965 --> 01:43:50,835 WHY ARE SOME PROTECTED? 2936 01:43:50,835 --> 01:43:52,236 >> THAT'S A GREAT QUESTION. 2937 01:43:52,236 --> 01:43:56,941 FIRST OF ALL, ONE THING I DIDN'T 2938 01:43:56,941 --> 01:43:57,908 MENTION BUT I'LL TELL YOU ABOUT 2939 01:43:57,908 --> 01:44:01,479 IS WITH IMMUNOTHERAPY WHICH 2940 01:44:01,479 --> 01:44:02,546 ACTUALLY I BELIEVE CAN CURE SOME 2941 01:44:02,546 --> 01:44:04,081 PATIENTS IT REALLY ONLY WORKS IN 2942 01:44:04,081 --> 01:44:04,548 SMOKERS. 2943 01:44:04,548 --> 01:44:06,550 SO SOMETIMES I'LL GIVE A LECTURE 2944 01:44:06,550 --> 01:44:09,420 AND PEOPLE LIKE SHOULD I HAVE 2945 01:44:09,420 --> 01:44:11,055 SMOKED OR SHOULD I START 2946 01:44:11,055 --> 01:44:16,627 SMOKING, THAT'S SORT OF IRONIC. 2947 01:44:16,627 --> 01:44:19,196 BUT BASICALLY WHY SOME SMOKERS 2948 01:44:19,196 --> 01:44:20,631 DON'T HAVE LUNG CANCER, IT'S ALL 2949 01:44:20,631 --> 01:44:20,965 GENETICS. 2950 01:44:20,965 --> 01:44:24,335 I HAD A GRANDMOTHER WHO LIVED TO 2951 01:44:24,335 --> 01:44:25,736 99, SHE SMOKED LIKE A CHIMNEY. 2952 01:44:25,736 --> 01:44:27,137 SHE HAD A LOT OF THINGS BUT SHE 2953 01:44:27,137 --> 01:44:28,506 NEVER HAD LUNG CANCER. 2954 01:44:28,506 --> 01:44:28,939 WE DON'T KNOW. 2955 01:44:28,939 --> 01:44:30,374 BUT STILL IF YOU SMOKE, YOUR 2956 01:44:30,374 --> 01:44:33,010 CHANCE OF GETTING LUNG CANCER IS 2957 01:44:33,010 --> 01:44:33,944 ENORMOUSLY HIGHER. 2958 01:44:33,944 --> 01:44:34,979 BY THE WAY, ONE THING I WANT TO 2959 01:44:34,979 --> 01:44:39,083 MAKE A CASE FOR, THIS CAME OUT 2960 01:44:39,083 --> 01:44:40,885 OF NIH AND NCI SPONSORED 2961 01:44:40,885 --> 01:44:41,352 RESEARCH IS SCREENING. 2962 01:44:41,352 --> 01:44:42,753 SO PEOPLE WHO SMOKE OR ARE 2963 01:44:42,753 --> 01:44:45,055 FORMER SMOKERS WITHIN 15 YEARS 2964 01:44:45,055 --> 01:44:46,557 SHOULD GET SCREENED. 2965 01:44:46,557 --> 01:44:50,594 ACTUALLY IT'S 20 YEARS NOW. 2966 01:44:50,594 --> 01:44:52,763 IT'S 20 PACK YEARS OF SMOKING. 2967 01:44:52,763 --> 01:44:54,198 BUT PEOPLE WHO SMOKE, SCREENING 2968 01:44:54,198 --> 01:44:55,366 SAVES LIVES AND WE NEED TO DO 2969 01:44:55,366 --> 01:44:58,636 MORE SCREENING FOR THAT. 2970 01:44:58,636 --> 01:45:03,307 I WORKED WITH THE LATE KEY HAHN, 2971 01:45:03,307 --> 01:45:04,608 WE MUST WORK ON SMOKING 2972 01:45:04,608 --> 01:45:05,943 CESSATION BUT THOSE PATIENTS WHO 2973 01:45:05,943 --> 01:45:08,178 STOP, WE NEED TO SCREEN THEM AND 2974 01:45:08,178 --> 01:45:08,479 FOLLOW THEM. 2975 01:45:08,479 --> 01:45:12,016 SO SOME PEOPLE, UR KNOW, SOME 2976 01:45:12,016 --> 01:45:13,317 PEOPLE DON'T HAVE GOOD DIET AND 2977 01:45:13,317 --> 01:45:14,418 THEY DON'T GET HEART DISEASE. 2978 01:45:14,418 --> 01:45:16,253 YOU GET LUCKY. 2979 01:45:16,253 --> 01:45:17,454 BUT SMOKING -- BY THE WAY, I'VE 2980 01:45:17,454 --> 01:45:20,190 BEEN VERY INVOLVED WITH AACR AND 2981 01:45:20,190 --> 01:45:21,358 OTHER ORGANIZATIONS ON THE 2982 01:45:21,358 --> 01:45:23,427 SMOKING TASK FORCES AND WE WORK 2983 01:45:23,427 --> 01:45:27,364 VERY CLOSELY WITH NCI. 2984 01:45:27,364 --> 01:45:31,802 TOBACCO STILL IS TOO HIGH. 2985 01:45:31,802 --> 01:45:33,470 WE'VE GOT IT DOWN, 13, 14% OF 2986 01:45:33,470 --> 01:45:35,739 THE POPULATION, CERTAIN PART OF 2987 01:45:35,739 --> 01:45:37,508 THE COUNTRY, CERTAIN SOASH YOAL 2988 01:45:37,508 --> 01:45:39,643 ECONOMIC GROUPS, SO SMOKING IS 2989 01:45:39,643 --> 01:45:43,080 DEFINITELY SOMETHING TO NOT DO. 2990 01:45:43,080 --> 01:45:44,682 >> AND YOU MENTIONED SCREENING, 2991 01:45:44,682 --> 01:45:46,283 SO OF COURSE ONE OF THE WAYS OF 2992 01:45:46,283 --> 01:45:50,454 SCREENING WOULD BE BY IMAGING 2993 01:45:50,454 --> 01:45:51,989 BUT WOULD THERE BE ANY UTILITY 2994 01:45:51,989 --> 01:45:57,628 FOR SCREENING BY LOOKING FOR 2995 01:45:57,628 --> 01:45:58,829 CELL-FREE DNA IN THE BLOOD? 2996 01:45:58,829 --> 01:46:01,332 >> KATY AND I WERE JUST 2997 01:46:01,332 --> 01:46:02,433 DISCUSSING THAT AT A MEETING 2998 01:46:02,433 --> 01:46:03,167 RECENTLY. 2999 01:46:03,167 --> 01:46:04,702 DO YOU WANT TO GO FIRST, KATIE? 3000 01:46:04,702 --> 01:46:06,670 >> I THINK THAT'S AN EMERGING 3001 01:46:06,670 --> 01:46:07,204 TECHNOLOGY, RIGHT? 3002 01:46:07,204 --> 01:46:11,475 AND I THINK PEOPLE ARE WORKING 3003 01:46:11,475 --> 01:46:12,977 ON USING CELL-FREE DNA FOR 3004 01:46:12,977 --> 01:46:13,310 SCREENING. 3005 01:46:13,310 --> 01:46:18,549 I THINK IF WE COULD, THAT WOULD 3006 01:46:18,549 --> 01:46:19,850 BE A REALLY IMPORTANT ADVANCE 3007 01:46:19,850 --> 01:46:22,586 AND PERHAPS A WAY OF GETTING 3008 01:46:22,586 --> 01:46:23,554 ACCESS TO MORE PEOPLE. 3009 01:46:23,554 --> 01:46:25,856 I MEAN, I THINK EVENTUALLY IT 3010 01:46:25,856 --> 01:46:28,158 WOULD BE IDEAL IF WE COULD USE 3011 01:46:28,158 --> 01:46:32,630 CELL-FREE DNA OR BLOOD-BASED 3012 01:46:32,630 --> 01:46:33,797 BIOPSY TECHNOLOGIES. 3013 01:46:33,797 --> 01:46:34,798 IT SOUNDS LIKE A BIOPSY BUT IT'S 3014 01:46:34,798 --> 01:46:35,866 ACTUALLY JUST DOING A BLOOD TEST 3015 01:46:35,866 --> 01:46:37,067 TO SCREEN FOR LUNG CANCER AND 3016 01:46:37,067 --> 01:46:38,569 OTHER CANCERS AS WELL 3017 01:46:38,569 --> 01:46:42,539 EVENTUALLY. 3018 01:46:42,539 --> 01:46:44,174 I DON'T THINK WE'RE QUITE THERE 3019 01:46:44,174 --> 01:46:45,876 YET, A LOT OF WORK TO DO BUT 3020 01:46:45,876 --> 01:46:46,477 HOPEFULLY THAT'S THE DIRECTION 3021 01:46:46,477 --> 01:46:47,144 THE FIELD IS GOING IN. 3022 01:46:47,144 --> 01:46:48,512 >> THERE ARE TWO TYPES OF WAYS 3023 01:46:48,512 --> 01:46:50,247 OF DOING THIS. 3024 01:46:50,247 --> 01:46:52,082 YOU HAVE A PATIENT WHO THAT'S' 3025 01:46:52,082 --> 01:46:57,421 'S HAD ATUMOR RESECTED, SHOULD T 3026 01:46:57,421 --> 01:46:58,856 ADJUVANT THERAPY OR NOT? 3027 01:46:58,856 --> 01:47:01,592 IN THE ADORA TRIAL, THERE WE CAN 3028 01:47:01,592 --> 01:47:03,961 DO A TUMOR INFORMED ASSAY, IT'S 3029 01:47:03,961 --> 01:47:05,062 MORE SENSITIVE BECAUSE YOU'RE 3030 01:47:05,062 --> 01:47:07,364 LOOKING AT MORE MUTATIONS, 3031 01:47:07,364 --> 01:47:09,066 DIFFERENT ASSAYS, METHYLATION 3032 01:47:09,066 --> 01:47:09,700 FRAGMENTATION. 3033 01:47:09,700 --> 01:47:13,103 THE ASSAYS ARE CONTINUING TO GET 3034 01:47:13,103 --> 01:47:14,171 BETTER AND BETTER. 3035 01:47:14,171 --> 01:47:15,139 CERTAINLY IF SOMETHING IS 3036 01:47:15,139 --> 01:47:16,473 POSITIVE IN SOMEONE WITH KNOWN 3037 01:47:16,473 --> 01:47:19,309 CANCER, I THINK THAT IS 3038 01:47:19,309 --> 01:47:21,045 CONCERNING, AND THAT'S SOMETHING 3039 01:47:21,045 --> 01:47:21,712 WE CAN FOLLOW. 3040 01:47:21,712 --> 01:47:22,880 THEN THERE'S THE SCREENING, THE 3041 01:47:22,880 --> 01:47:23,981 PEOPLE WHO DON'T HAVE CANCER 3042 01:47:23,981 --> 01:47:24,314 YET. 3043 01:47:24,314 --> 01:47:25,416 ONE OF THE REASONS WHY LUNG 3044 01:47:25,416 --> 01:47:27,451 CANCER SCREENING IS NOT AS 3045 01:47:27,451 --> 01:47:28,986 POPULAR AND THAT IS THE UPTAKE 3046 01:47:28,986 --> 01:47:31,622 HAS BEEN LOWER, IS IT'S NOT AS 3047 01:47:31,622 --> 01:47:33,123 EASY TO DO AS SCREENING FOR 3048 01:47:33,123 --> 01:47:35,292 BREAST CANCER OR COLON CANCER. 3049 01:47:35,292 --> 01:47:36,927 WITH COLON CANCER, YOU DO THE 3050 01:47:36,927 --> 01:47:38,028 PROCEDURE, YOU GO AND YOU 3051 01:47:38,028 --> 01:47:39,430 USUALLY DO THE PROCEDURE AND 3052 01:47:39,430 --> 01:47:39,963 YOU'RE DONE. 3053 01:47:39,963 --> 01:47:41,832 WITH BREAST CANCER, IT'S A LOT 3054 01:47:41,832 --> 01:47:43,267 EASIER TO DO THE BIOPSY. 3055 01:47:43,267 --> 01:47:44,001 SO NOT ALWAYS. 3056 01:47:44,001 --> 01:47:46,336 BUT IN LUNG CANCER, IF YOU SEE 3057 01:47:46,336 --> 01:47:46,970 SOMETHING THAT YOU DON'T KNOW, 3058 01:47:46,970 --> 01:47:49,239 YOU HAVE TO DO AN OPEN 3059 01:47:49,239 --> 01:47:50,441 PROCEDURE. 3060 01:47:50,441 --> 01:47:51,008 VIDEO-ASSISTED PROCEDURE. 3061 01:47:51,008 --> 01:47:51,975 IT'S A BIGGER DEAL. 3062 01:47:51,975 --> 01:47:53,711 THERE ARE TESTS NOW, YOU CAN 3063 01:47:53,711 --> 01:47:56,313 LOOK AT CELL-FREE DNA, MAYBE MAY 3064 01:47:56,313 --> 01:47:57,648 NOT BE POSITIVE. 3065 01:47:57,648 --> 01:47:59,149 THERE ARE ALSO COMPANIES OUT 3066 01:47:59,149 --> 01:48:00,017 THERE NOW THAT HAVE THESE 3067 01:48:00,017 --> 01:48:04,188 CLASSIFIERS THAT CAN LOOK AT 3068 01:48:04,188 --> 01:48:04,822 DIFFERENT PROTEOMIC CLASSIFIER 3069 01:48:04,822 --> 01:48:07,424 OR SOME SORT OF GENOMIC TEST TO 3070 01:48:07,424 --> 01:48:08,859 HELP DETERMINE YES OR NO IF THE 3071 01:48:08,859 --> 01:48:10,094 RISK IS HIGH. 3072 01:48:10,094 --> 01:48:12,229 ALL THESE THINGS NEED TO BE 3073 01:48:12,229 --> 01:48:12,463 STUDIED. 3074 01:48:12,463 --> 01:48:13,564 THE ONLY WAY THEY'RE GOING TO BE 3075 01:48:13,564 --> 01:48:16,066 STUDIED IS THROUGH, I WOULD SAY, 3076 01:48:16,066 --> 01:48:16,433 COLLABORATIONS. 3077 01:48:16,433 --> 01:48:17,901 I'D LIKE TO SEE THIS DONE 3078 01:48:17,901 --> 01:48:19,636 PERHAPS THROUGH THE SPORES, MOVE 3079 01:48:19,636 --> 01:48:20,838 TO EARLIER DISEASE, WE CAN 3080 01:48:20,838 --> 01:48:22,172 COLLECT THESE SAMPLES AND PULL 3081 01:48:22,172 --> 01:48:22,840 THEM TOGETHER. 3082 01:48:22,840 --> 01:48:24,408 IT'S SOMETHING THAT I'M VERY 3083 01:48:24,408 --> 01:48:25,342 DRIVEN TO DO IN THE NEXT PHASE 3084 01:48:25,342 --> 01:48:28,078 OF MY CAREER. 3085 01:48:28,078 --> 01:48:30,547 HAVING DONE THIS NOW FOR OVER 30 3086 01:48:30,547 --> 01:48:33,517 YEARS, I CAN TELL YOU, WE'LL DO 3087 01:48:33,517 --> 01:48:34,718 MUCH BETTER BY FINDING THESE 3088 01:48:34,718 --> 01:48:36,987 LUNG CANCERS EARLIER, SCREENING, 3089 01:48:36,987 --> 01:48:38,388 EITHER PREVENTING OR TREATING 3090 01:48:38,388 --> 01:48:39,790 THEM EARLY, EVEN WITH EVERYTHING 3091 01:48:39,790 --> 01:48:41,658 I'VE SHOWED WITH THE ADVANCES IN 3092 01:48:41,658 --> 01:48:42,092 METASTATIC DISEASE. 3093 01:48:42,092 --> 01:48:47,231 >> I THINK ANOTHER USE OF 3094 01:48:47,231 --> 01:48:48,699 CELL-FREE DNA IS ALSO EVEN IN 3095 01:48:48,699 --> 01:48:51,902 THE METASTATIC SETTING WHERE YOU 3096 01:48:51,902 --> 01:48:52,870 CAN IDENTIFY PATIENTS WHOSE 3097 01:48:52,870 --> 01:48:56,940 TUMOR IS NOT RESPONDING TO 3098 01:48:56,940 --> 01:48:58,342 TREATMENT, AND THEN CAN FOR 3099 01:48:58,342 --> 01:48:59,943 EXAMPLE ADD OTHER AGENTS OR 3100 01:48:59,943 --> 01:49:03,046 OTHER DRUGS. 3101 01:49:03,046 --> 01:49:04,181 SO YOU COULD START, FOR EXAMPLE, 3102 01:49:04,181 --> 01:49:06,083 IN THE CASE OF A PATIENT WITH E 3103 01:49:06,083 --> 01:49:10,888 IM. FR DRIVEN LUNG CANCER, START 3104 01:49:10,888 --> 01:49:11,955 WITH -- OSIMERTINIB BUT IF YOU 3105 01:49:11,955 --> 01:49:14,391 SEE THE CELL-FREE DNA IS STILL 3106 01:49:14,391 --> 01:49:15,759 THERE, THE MUTATION IS STILL 3107 01:49:15,759 --> 01:49:16,994 THERE IN THE BLOOD AFTER A 3108 01:49:16,994 --> 01:49:17,728 CERTAIN PERIOD OF TIME, THEN 3109 01:49:17,728 --> 01:49:21,665 MAYBE THAT IS THE SUBSET OF 3110 01:49:21,665 --> 01:49:23,400 PATIENTS FOR WHOM YOU'D LIKE TO 3111 01:49:23,400 --> 01:49:24,935 ADD ADDITIONAL THERAPY TO SEE 3112 01:49:24,935 --> 01:49:25,269 RESPONSES. 3113 01:49:25,269 --> 01:49:29,106 SO PEOPLE ARE EVALUATING THESE 3114 01:49:29,106 --> 01:49:30,808 TYPES OF CONCEPTS IN CLINICAL 3115 01:49:30,808 --> 01:49:31,708 TRIALS NOW, AND I THINK THEY'LL 3116 01:49:31,708 --> 01:49:36,847 BE VERY HELPFUL. 3117 01:49:36,847 --> 01:49:37,614 BECAUSE OF COURSE THERE'S 3118 01:49:37,614 --> 01:49:38,582 TOXICITY WITH ADDED TREATMENT SO 3119 01:49:38,582 --> 01:49:42,386 YOU ONLY WANT TO GIVE IF 3120 01:49:42,386 --> 01:49:44,621 NECESSARY. 3121 01:49:44,621 --> 01:49:46,223 >> ANOTHER MEMBER OF THE 3122 01:49:46,223 --> 01:49:49,493 AUDIENCE IS COMMENTING ON RADON. 3123 01:49:49,493 --> 01:49:52,996 AND COMMENTING THAT NO ONE TALKS 3124 01:49:52,996 --> 01:49:54,198 ABOUT RADON ANYMORE. 3125 01:49:54,198 --> 01:49:55,799 USED TO BE A BIG ISSUE. 3126 01:49:55,799 --> 01:49:59,469 WONDER WHY. 3127 01:49:59,469 --> 01:50:01,738 >> IT'S AN ISSUE FOR US HERE IN 3128 01:50:01,738 --> 01:50:02,039 CONNECTICUT. 3129 01:50:02,039 --> 01:50:06,643 YOU HAVE A BASEMENT, RADON IS A 3130 01:50:06,643 --> 01:50:10,647 CAUSATIVE FACTOR OF LUNG CANCER. 3131 01:50:10,647 --> 01:50:11,415 AS IS ASBESTOS. 3132 01:50:11,415 --> 01:50:14,451 I HAD BOTH IN MY BASEMENT. 3133 01:50:14,451 --> 01:50:19,389 YOU HAVE THESE RADON DETECTORS 3134 01:50:19,389 --> 01:50:21,124 AND THEIR ABATEMENT SYSTEMS. 3135 01:50:21,124 --> 01:50:22,860 LUNG CANCER -- SMOKING IS BY FAR 3136 01:50:22,860 --> 01:50:24,595 THE NUMBER ONE CAUSE WI BUT YOUE 3137 01:50:24,595 --> 01:50:26,363 GOT RADON, ASBESTOS, THEN OF 3138 01:50:26,363 --> 01:50:27,331 COURSE YOU'VE GOT POLLUTION. 3139 01:50:27,331 --> 01:50:28,966 THINGS IN THE AIR. 3140 01:50:28,966 --> 01:50:29,967 SOMETHING WE'VE HEARD A LOT 3141 01:50:29,967 --> 01:50:32,369 ABOUT FROM CHARLIE SWANTON AND 3142 01:50:32,369 --> 01:50:34,104 THE WORK HE'S REALLY LEADING OUT 3143 01:50:34,104 --> 01:50:34,404 OF ENGLAND. 3144 01:50:34,404 --> 01:50:36,707 SO NO, I THINK ONE DOES NEED TO 3145 01:50:36,707 --> 01:50:38,642 KEEP AN EYE OUT FORAY DONE, AND 3146 01:50:38,642 --> 01:50:39,643 CERTAINLY IF YOU LIVE IN AN AREA 3147 01:50:39,643 --> 01:50:40,844 WHERE IT'S PREVALENT, I WOULD 3148 01:50:40,844 --> 01:50:43,881 HOPE IT'S PART OF AN INSPECTION 3149 01:50:43,881 --> 01:50:44,648 FOR A HOME. 3150 01:50:44,648 --> 01:50:46,083 WHAT DO YOU THINK ABOUT, KATIE, 3151 01:50:46,083 --> 01:50:46,383 FORAY DONE? 3152 01:50:46,383 --> 01:50:49,586 >> I THINK IT'S BEEN DIFFICULT 3153 01:50:49,586 --> 01:50:53,957 TO STUDY, ESPECIALLY TO MODEL 3154 01:50:53,957 --> 01:50:55,692 THAT AND REALLY BE ABLE TO STUDY 3155 01:50:55,692 --> 01:50:57,427 THE EFFECTS OF RADON ON LUNG 3156 01:50:57,427 --> 01:50:57,661 CANCER. 3157 01:50:57,661 --> 01:50:58,862 I KNOW THERE ARE GROUPS THAT ARE 3158 01:50:58,862 --> 01:51:03,133 WORKING ON THIS. 3159 01:51:03,133 --> 01:51:04,334 SO SOMETHING THAT PEOPLE SHOULD 3160 01:51:04,334 --> 01:51:06,069 CERTAINLY BE AWARE OF AND MAKE 3161 01:51:06,069 --> 01:51:12,743 SURE THEY CHECK IN THEIR HOUSES. 3162 01:51:12,743 --> 01:51:15,045 >> OKAY, ANOTHER OF THE MEMBER 3163 01:51:15,045 --> 01:51:16,947 OF OUR AUDIENCE COMMENTS, GREAT 3164 01:51:16,947 --> 01:51:17,948 WORK, THANK YOU. 3165 01:51:17,948 --> 01:51:19,816 IS TUMOR HISTOLOGICAL 3166 01:51:19,816 --> 01:51:21,251 TRANSFORMATION TRIGGERED BY 3167 01:51:21,251 --> 01:51:23,620 TREATMENT WITH TYROSINE KINASE 3168 01:51:23,620 --> 01:51:25,822 INHIBITORS OR KRAS INHIBITORS, 3169 01:51:25,822 --> 01:51:27,958 OR IT MAY HAPPEN INDEPENDENTLY 3170 01:51:27,958 --> 01:51:32,930 OF THESE THERAPIES. 3171 01:51:32,930 --> 01:51:34,765 >> I THINK THAT'S A GREAT 3172 01:51:34,765 --> 01:51:35,198 QUESTION. 3173 01:51:35,198 --> 01:51:37,067 IT CAN ALSO HAPPEN INDEPENDENTLY 3174 01:51:37,067 --> 01:51:43,273 OF THE THERAPIES. 3175 01:51:43,273 --> 01:51:44,274 OCCASIONALLY YOU WILL SEE TUMORS 3176 01:51:44,274 --> 01:51:46,109 THAT HAVE A MIX OF HISTOLOGY. 3177 01:51:46,109 --> 01:51:48,378 SO ADENOCARCINOMA AND SQUAMOUS 3178 01:51:48,378 --> 01:51:50,347 CELL CARCINOMA OR ADENOCARCINOMA 3179 01:51:50,347 --> 01:51:52,316 AND SMALL CELL LUNG CANCER 3180 01:51:52,316 --> 01:51:53,183 INDEPENDENT OF THERAPIES. 3181 01:51:53,183 --> 01:51:57,020 WE'RE JUST SI SEEING THIS 3182 01:51:57,020 --> 01:51:58,021 TRANSFORMATION AND DETECTING 3183 01:51:58,021 --> 01:52:00,057 THAT IS ASSOCIATED WITH 3184 01:52:00,057 --> 01:52:01,591 TREATMENT, SORT OF MORE COMMONLY 3185 01:52:01,591 --> 01:52:09,333 NOW WITH THESE AGENTS. 3186 01:52:09,333 --> 01:52:10,567 >> I WOULD AGREE. 3187 01:52:10,567 --> 01:52:12,302 IT'S IMPORTANT TO KNOW BECAUSE 3188 01:52:12,302 --> 01:52:13,270 THE THERAPIES ARE VERY 3189 01:52:13,270 --> 01:52:13,537 DIFFERENT. 3190 01:52:13,537 --> 01:52:15,138 >> AND WOULD IT BE FAIR TO SAY 3191 01:52:15,138 --> 01:52:21,144 THAT ACTUALLY THE SUPRE SORT OF 3192 01:52:21,144 --> 01:52:22,112 ANCESTRAL CELL TYPE THAT GIVES 3193 01:52:22,112 --> 01:52:23,547 RISE TO THESE DIFFERENT LUNG 3194 01:52:23,547 --> 01:52:29,519 CANCERS IS THE SAME GOING TO 3195 01:52:29,519 --> 01:52:31,488 SMALL CELL TUMORS VERSUS 3196 01:52:31,488 --> 01:52:32,923 ADENOCARCINOMA VERSUS SQUAMOUS 3197 01:52:32,923 --> 01:52:34,324 CELL CARCINOMAS? 3198 01:52:34,324 --> 01:52:39,663 THEY SEEM TO BE AT LEAST CAPABLE 3199 01:52:39,663 --> 01:52:45,369 OF METAMORPHOSING FROM ONE TO 3200 01:52:45,369 --> 01:52:45,635 THE OTHER. 3201 01:52:45,635 --> 01:52:47,204 >> THE WAY WE THINK ABOUT IT, WE 3202 01:52:47,204 --> 01:52:48,171 THINK ABOUT DIFFERENT CELLS 3203 01:52:48,171 --> 01:52:50,107 GIVING RISE TO, SAY, SMALL CELL 3204 01:52:50,107 --> 01:52:52,642 LUNG CANCER AND DIFFERENT CELLS, 3205 01:52:52,642 --> 01:52:54,845 MORE PERIPHERAL ALVEOLAR CELLS 3206 01:52:54,845 --> 01:52:57,014 GIVING RISE TO LUNG 3207 01:52:57,014 --> 01:52:57,781 ADENOCARCINOMAS, FOR EXAMPLE, 3208 01:52:57,781 --> 01:52:59,182 BUT I THINK WE'RE LEARNING THAT 3209 01:52:59,182 --> 01:53:02,052 THERE ARE CELLS THAT HAVE A LOT 3210 01:53:02,052 --> 01:53:03,887 MORE -- ARE A LOT MORE PLASTIC. 3211 01:53:03,887 --> 01:53:07,824 THERE'S A LOT MORE OF AN ABILITY 3212 01:53:07,824 --> 01:53:12,396 TO SHIFT SORTD OF IN SORT OF ID 3213 01:53:12,396 --> 01:53:15,565 CELL STATE THAN I THINK WE 3214 01:53:15,565 --> 01:53:17,134 ORIGINALLY MIGHT HAVE THOUGHT. 3215 01:53:17,134 --> 01:53:18,602 >> AND THIS WOULD PRESUMABLY BE 3216 01:53:18,602 --> 01:53:20,904 AT LEAST IN PART DUE TO 3217 01:53:20,904 --> 01:53:24,741 EPIGENETIC CHANGES RATHER THAN 3218 01:53:24,741 --> 01:53:25,742 MUTATIONAL CHANGES? 3219 01:53:25,742 --> 01:53:27,277 >> YEAH, I THINK THERE'S A 3220 01:53:27,277 --> 01:53:28,478 COMBINATION OF THINGS THAT ARE 3221 01:53:28,478 --> 01:53:30,881 HAPPENING, SO THERE'S SOME 3222 01:53:30,881 --> 01:53:32,949 MUTATIONAL CHANGES THAT I THINK 3223 01:53:32,949 --> 01:53:38,622 SET THE STAGE FOR THEN THIS TYPE 3224 01:53:38,622 --> 01:53:40,190 OF HIS HIT OR MISS TOE LOGICAL 3225 01:53:40,190 --> 01:53:41,258 TRANSFORMATION TO BE ABLE TO 3226 01:53:41,258 --> 01:53:42,993 HAPPEN, IN PART THROUGH 3227 01:53:42,993 --> 01:53:43,760 EPIGENETIC CHANGES AS WELL. 3228 01:53:43,760 --> 01:53:45,495 SO I THINK IT'S PROBABLY A 3229 01:53:45,495 --> 01:53:49,332 COMBINATION OF FACTORS THAT 3230 01:53:49,332 --> 01:53:50,000 REALLY LINE UP. 3231 01:53:50,000 --> 01:53:51,401 AND YOU PROBABLY HAVE CELLS THAT 3232 01:53:51,401 --> 01:53:52,502 ARE POISED IN A CERTAIN 3233 01:53:52,502 --> 01:53:55,105 SITUATION, RIGHT, TO GO INTO ONE 3234 01:53:55,105 --> 01:53:56,606 DIRECTION OR GO IN A DIFFERENT 3235 01:53:56,606 --> 01:54:01,144 DIRECTION. 3236 01:54:01,144 --> 01:54:03,313 >> ANOTHER OF OUR MEMBERS OF THE 3237 01:54:03,313 --> 01:54:06,149 GROUP HERE IS ASKING, IS THERE A 3238 01:54:06,149 --> 01:54:08,418 ROLE FOR ENDO STATIN INHIBITORS 3239 01:54:08,418 --> 01:54:11,154 OF BLOOD SUPPLY IN LUNG CANCER? 3240 01:54:11,154 --> 01:54:15,225 THE SORT OF THING THAT JUDAH 3241 01:54:15,225 --> 01:54:16,393 FOLKMAN DISCOVERED YEARS AGO. 3242 01:54:16,393 --> 01:54:18,028 >> I'LL LET RAY ANSWER THAT 3243 01:54:18,028 --> 01:54:18,295 QUESTION. 3244 01:54:18,295 --> 01:54:20,263 HE'S WORKED A LOT WITH THESE. 3245 01:54:20,263 --> 01:54:23,934 >> I ACTUALLY DID NCI FUNDED 3246 01:54:23,934 --> 01:54:25,902 STUDIES OF ENDOSTATIN AND WORKED 3247 01:54:25,902 --> 01:54:26,470 WITH JUDAH. 3248 01:54:26,470 --> 01:54:29,639 YOU KNOW, ANGIOGENESIS IS 3249 01:54:29,639 --> 01:54:32,142 CLEARLY INVOLVED IN TUMOR 3250 01:54:32,142 --> 01:54:34,978 METASTASIS AND DRUGS THAT TARGET 3251 01:54:34,978 --> 01:54:37,614 ANGIOGENESIS ARE IMPORTANT, AND 3252 01:54:37,614 --> 01:54:40,217 THEY'RE USED IN A NUMBER OF 3253 01:54:40,217 --> 01:54:45,255 TUMOR TYPES, SMALL MOLECULES 3254 01:54:45,255 --> 01:54:46,556 THAT TARGET VEGF. 3255 01:54:46,556 --> 01:54:49,726 THE TYPE OF AMAZING RESPONSE 3256 01:54:49,726 --> 01:54:51,361 WHERE IT'S DESCRIBED IN MICE 3257 01:54:51,361 --> 01:54:53,463 WITH ENDOSTATIN WAS NEVER REALLY 3258 01:54:53,463 --> 01:54:54,865 SEEN IN PATIENTS. 3259 01:54:54,865 --> 01:54:57,033 SO THE IDEA THAT YOU COULD USE 3260 01:54:57,033 --> 01:54:59,536 AN AGENT THAT WAS WITHOUT 3261 01:54:59,536 --> 01:55:00,737 CHEMOTHERAPY THAT COULD TARGET 3262 01:55:00,737 --> 01:55:02,906 TUMOR BLOOD VESSELS AND MU TORES 3263 01:55:02,906 --> 01:55:04,407 WOULD SHRINK AND METASTASES 3264 01:55:04,407 --> 01:55:06,643 WOULD SHRINK WOULD NEVER BE 3265 01:55:06,643 --> 01:55:06,977 SEEN. 3266 01:55:06,977 --> 01:55:08,145 BUT I WILL TELL YOU THAT 3267 01:55:08,145 --> 01:55:09,446 CERTAINLY IN LUNG CANCER, I'LL 3268 01:55:09,446 --> 01:55:11,748 JUST FOCUS ON THAT, VEGF 3269 01:55:11,748 --> 01:55:13,049 INHIBITION HAS ACTUALLY BECOME 3270 01:55:13,049 --> 01:55:14,584 UP WITH OF THE MOST HOT TOPICS, 3271 01:55:14,584 --> 01:55:16,219 I'M ACTUALLY WRITING AN 3272 01:55:16,219 --> 01:55:18,188 EDITORIAL ON IT RIGHT NOW, NEWS 3273 01:55:18,188 --> 01:55:20,590 AND VIEWS, BECAUSE THEY'RE RIGHT 3274 01:55:20,590 --> 01:55:22,425 NOW SPECIFIC AGENTS THAT TARGET 3275 01:55:22,425 --> 01:55:24,628 PD-1 AND VEGF THAT ACTUALLY 3276 01:55:24,628 --> 01:55:26,463 STUDIES ALBEIT IN CHINA BEING 3277 01:55:26,463 --> 01:55:29,199 REPEATED IN THE U.S. HAVE SHOWN 3278 01:55:29,199 --> 01:55:30,534 SUPERIOR PROGRESSION-FREE 3279 01:55:30,534 --> 01:55:34,471 SURVIVAL IN METASTATIC LUNG 3280 01:55:34,471 --> 01:55:39,276 CANCER OVER IMMUNOTHERAPY ALONE. 3281 01:55:39,276 --> 01:55:40,277 WHY IS THAT WORKING? 3282 01:55:40,277 --> 01:55:42,546 IT IS KNOWN THAT VEGF DOES HAVE 3283 01:55:42,546 --> 01:55:44,748 SOME EFFECT ON IMMUNE 3284 01:55:44,748 --> 01:55:45,682 PRESENTATION, SO THAT COULD BE 3285 01:55:45,682 --> 01:55:46,383 ONE OF THE THINGS. 3286 01:55:46,383 --> 01:55:47,817 I DON'T KNOW IF SHE'S ON THE 3287 01:55:47,817 --> 01:55:49,920 LINE BUT MY OLD MENTOR AND 3288 01:55:49,920 --> 01:55:52,822 FRIEND BEV TYSHIRE WHO I WORKED 3289 01:55:52,822 --> 01:55:54,791 WITH AT DANA FARBER YEARS AGO 3290 01:55:54,791 --> 01:55:57,627 SHOWED THAT YOU HAVE AN EFFECT 3291 01:55:57,627 --> 01:55:59,829 ON TUMOR BLOOD VESSELS AND YOU 3292 01:55:59,829 --> 01:56:01,131 ACTUALLY EYE WRONGLY INCREASE 3293 01:56:01,131 --> 01:56:03,400 FLOAL, SO IT COULD BE A WAY TO 3294 01:56:03,400 --> 01:56:04,734 INCREASE T-CELL INFILTRATION 3295 01:56:04,734 --> 01:56:05,402 INTO TUMORS. 3296 01:56:05,402 --> 01:56:06,803 A NUMBER OF APPROACHES WE'RE 3297 01:56:06,803 --> 01:56:10,207 LOOKING AT HERE IN OUR LAB WITH 3298 01:56:10,207 --> 01:56:11,408 LEIPING CHEN AND OTHERS TO DO SO 3299 01:56:11,408 --> 01:56:12,142 AS WELL. 3300 01:56:12,142 --> 01:56:14,010 SO YES, I THINK THERE'S PROMISE, 3301 01:56:14,010 --> 01:56:15,445 CERTAINLY IN MACULAR 3302 01:56:15,445 --> 01:56:17,180 DEGENERATION, WE USE VEGF 3303 01:56:17,180 --> 01:56:17,847 INHIBITORS. 3304 01:56:17,847 --> 01:56:19,482 SO VEGF IS THERE BUT I REMEMBER 3305 01:56:19,482 --> 01:56:21,685 WHEN I WAS A FELLOW AT DANA 3306 01:56:21,685 --> 01:56:23,853 FARBER AND JUDAH CAME AND TALKED 3307 01:56:23,853 --> 01:56:25,021 AND MADE GRAND ROUNDS, WE ALL 3308 01:56:25,021 --> 01:56:26,456 RAN UP, WE ALL WANTED TO WORK 3309 01:56:26,456 --> 01:56:27,857 WITH HIS LAB AND WORK WITH HIM 3310 01:56:27,857 --> 01:56:29,326 AND THE CONCEPT IS RIGHT, IT'S 3311 01:56:29,326 --> 01:56:30,193 JUST DIFFERENT AGENTS THAT WILL 3312 01:56:30,193 --> 01:56:34,831 GO FORWARD. 3313 01:56:34,831 --> 01:56:35,432 >> ALL RIGHT. 3314 01:56:35,432 --> 01:56:36,900 I THINK AT THIS POINT, ALL GOOD 3315 01:56:36,900 --> 01:56:38,068 THINGS HAVE TO COME TO AN END 3316 01:56:38,068 --> 01:56:40,370 AND THIS IS YET ANOTHER REALLY 3317 01:56:40,370 --> 01:56:41,338 SPECTACULAR GREAT THING THAT 3318 01:56:41,338 --> 01:56:42,973 WE'RE GOING TO HAVE TO CALL TO A 3319 01:56:42,973 --> 01:56:43,740 CLOSE. 3320 01:56:43,740 --> 01:56:45,475 THIS WAS REALLY, REALLY 3321 01:56:45,475 --> 01:56:45,809 WONDERFUL. 3322 01:56:45,809 --> 01:56:50,614 THANK YOU BOTH SO MUCH FOR THE 3323 01:56:50,614 --> 01:56:52,382 SPECTACULAR PRESENTATIONS. 3324 01:56:52,382 --> 01:56:55,885 WE'RE NOW TWO MINUTES AWAY FROM 3325 01:56:55,885 --> 01:56:56,519 OUR DEADLINE. 3326 01:56:56,519 --> 01:57:00,123 I GUESS I COULD THROW IN THAT 3327 01:57:00,123 --> 01:57:02,626 OBLIGATE QUESTION FOR ANY OF 3328 01:57:02,626 --> 01:57:03,860 THESE PRESENTATIONS, WHAT'S THE 3329 01:57:03,860 --> 01:57:07,197 ROLE OF THE MICROBIOME IN YOUR 3330 01:57:07,197 --> 01:57:10,267 WORK? 3331 01:57:10,267 --> 01:57:10,700 [LAUGHTER] 3332 01:57:10,700 --> 01:57:13,003 WE'LL WAIT FOR THE NEXT 3333 01:57:13,003 --> 01:57:13,570 PRESENTATION. 3334 01:57:13,570 --> 01:57:17,707 WE'LL INVITE YOU BACK FOR THAT, 3335 01:57:17,707 --> 01:57:18,708 I GUESS. 3336 01:57:18,708 --> 01:57:19,476 >> THAT WOULD BE GREAT. 3337 01:57:19,476 --> 01:57:20,777 THERE ARE A LOT OF PEOPLE 3338 01:57:20,777 --> 01:57:22,646 WORKING ON THE MICROBIOME IN 3339 01:57:22,646 --> 01:57:23,480 LUNG CANCER. 3340 01:57:23,480 --> 01:57:25,148 BUT WE HAVEN'T DONE WORK 3341 01:57:25,148 --> 01:57:28,652 DIRECTLY IN THAT AREA. 3342 01:57:28,652 --> 01:57:32,022 >> WELL, DR. KASTNER, YOU'RE A 3343 01:57:32,022 --> 01:57:33,023 WONDERFUL MODERATOR FOR A 3344 01:57:33,023 --> 01:57:35,659 PRINCETON GUY. 3345 01:57:35,659 --> 01:57:44,834 >> YES, WELL, THANK YOU! 3346 01:57:44,834 --> 01:57:47,237 YOU HAVE A GOOD AFTERNOON, AND 3347 01:57:47,237 --> 01:57:48,538 AGAIN, THANK YOU FOR EVERYTHING 3348 01:57:48,538 --> 01:57:49,205 THAT YOU'VE DONE. 3349 01:57:49,205 --> 01:57:50,940 AND ALL OF THE WORK THAT YOU'RE 3350 01:57:50,940 --> 01:57:53,410 DOING AND CONTINUING TO DO. 3351 01:57:53,410 --> 01:57:55,245 >> THANK YOU VERY MUCH. 3352 01:57:55,245 --> 01:57:56,880 >> WE APPRECIATE ALL THE SUPPORT 3353 01:57:56,880 --> 01:57:58,415 OF THE NCI AND NIH AND THE SPORE 3354 01:57:58,415 --> 01:57:59,783 GROUP BECAUSE IT'S BEEN A BIG 3355 01:57:59,783 --> 01:58:07,157 PART OF OUR WORK.