>> GOOD AFTERNOON EVERYONE, AND WELCOME TO TODAY'S SPECIAL GRAND ROUNDS. THE 10TH ANNUAL JOHN LAWS DECKER MEMORIAL LECTURE WHICH IS GIVEN AS PART OF OUR CONTEMPORARY MEDICINE GREAT TEACHERS SERIES. SO LET ME TELL YOU A LITTLE BIT ABOUT DR. DECKER, AND THEN WE'LL HAVE A BRIEF PRESENTATION BY OUR CHAIR OF OUR COMMITTEE THAT'S GOING TO SELECT THE NEXT WINNER AND THEN I'LL INTRODUCE OUR SPEAKER. THIS ANNUAL PRESENTATION HONORS THE LEGACY OF JOHN DECKER WHO SERVED AS THE CLINICAL CENTER DIRECTOR FROM 1983 TO 1990. AND IT'S AMAZING SOME OF THE ADVANCES THAT OCCURRED DURING THAT TIME, INCLUDING THE DEVELOPMENT OF THE PET PROGRAM HERE AT THE NIH, THE USE OF MRI AS WELL AS THE INTRODUCTION OF THE CLINICAL CENTER'S ARTS PROGRAM, WHICH WAS A MAJOR INTEREST THAT JOHN DECKER STARTED. I'M ALSO PARTICULARLY PLEASED TO WELCOME DR. DECKER'S SON, DAVID DECKER HERE, I THINK HE'S HERE OR HE MIGHT BE A FEW MINUTES LATE. HERE HE IS. THERE. WELCOME AND WE'RE DELIGHTED THAT YOU COULD BE HERE. DR. DECKER'S WIFE LUCILLE SADLY PASSED AWAY IN 2011. SHE HAD BEEN A FAITHFUL ATTENDEE AT THESE LECTURES. WE MISS HER. EVEN AFTER RETIRING, JOHN DECKER REMAINED VERY ACTIVE AT THE CLINICAL CENTER IN AWE MAYORIVES STATES AND AT THAT TIME HE WROTE HIS BOOKS PROTO MECHANICKICS A GUIDE TO PREPARING A CLINICAL RESEARCH STUDY WHICH IS A LIVING DOCUMENT THAT HELPED PREPARE US FOR WHAT WE'RE DOING TODAY. EACH FALL IS CLINICAL FELLOWS CHOOSE THE INDIVIDUAL TO RECEIVE THE DISTINGUISHED CLINICAL TEACHER AWARD, WHAT I CONSIDER ONE OF THE MOST IMPORTANT AWARDS HERE AT THE NIH. AND THAT INDIVIDUAL'S ALSO TAPPED TO DELIVER THIS LECTURE. JOHN DECKER WAS AN INSPIRING LEADER AND MENTOR, AND SO IN MANY RESPECTS, THIS IS AN ABSOLUTELY FITTING AND APPROPRIATE LECTURE TO REMEMBER JOHN DECKER. BEFORE INTRODUCING THE SPEAKER, THEN, LET ME INTRODUCE DR. ABBAS ALLIE WHO TEACHES THE COACH'S AWARD SELECTION COMMITTEE AND HE WILL TALK TO YOU FOR A MOMENT ABOUT THE NEXT SLIDE. >> THANK YOU. THANK YOU TO OUR 2012 DISTINGUISHED CLINICAL TEACHER AWARD WINNER DR. FOJO. THANK YOU FOR DR. DECKER FOR THE ONGOING SUPPORT FOR THIS LECTURE SERIES. AT THIS TIME I WOULD LIKE TO FORMALLY ANNOUNCE THE OPENING OF NOMINATIONS FOR THE 2013 DISTINGUISHED CLINICAL TEACHER AWARD WHICH RECOGNIZES EXCELLENCE IN CLINICAL TEACHING AND MENTORSHIP HERE AT THE NIH. NOMINATIONS WILL BE ACCEPTED FROM THE FOLLOWING SOURCES. ALL CURRENT NIH CLINICAL FELLOWS, NIH RESEARCH FELLOWS WHO HAVE A DIRECT RESPONSIBILITY AT THE NIH AND CLINICAL FELLOWS WHO COMPLETED THEIR CLINICAL ROLES WITHIN THE LAST SIX MONTHS. SUBMISSIONS OF NOMINATIONS MAY BE ACCESSED BY THE WEBSITE AT THE ADDRESS SHOWN ABOVE BY CLICKING ON THE LINK. APPLICATIONS WILL BE ACCEPTED UNTIL AUGUST OF THIS YEAR AND THE WINNER WILL BE ANNOUNCED AT THE CLINICAL CENTER GRAND ROUNDS TEACHER LECTURE IN SEPTEMBER. THANK YOU. >> DON'T FORGET TO SUBMIT YOUR SUBMISSIONS. OKAY. SO NOW IT'S MY DISTINCT PLEASURE TO INTRODUCE TODAY'S SPEAKER, DR. ANTONIO, OR AS WE KNOW HIM, TITO FOJO. WHO WAS BORN IN HAVANA CUBA AND MOVED TO THE STATES WITH HIS FAMILY IN 1960 AND BECAME A U.S. CITIZEN IN 1970. DR. FOJO RECEIVED HIS MD AND PH.D. IN BIOCHEMISTRY FROM THE UNIVERSITY OF MIAMI AND THEN HE COMPLETED AN INTERNSHIP AND RESIDENCY AT INTERNAL MEDICINE AT THE WASHINGTON UNIVERSITY BARNS HOSPITAL IN ST. LOUIS AND REMAINED THERE FOR ADDITIONAL YEARS' CHIEF RESIDENCE. HE CAME TO THE NCI IN 1982 AS A CLINICAL ASSOCIATE IN THE MEDICINE BRANCH NOW CALLED THE MEDICAL ONCOLOGY BRANCH. AFTER THREE YEARS WITH IRA PASSON AND MICHAEL GODSON HE ASSUMED THE POSITION OF SENIOR INVESTIGATOR IN THE MEDICINE BRANCH AND SERVE AS ACTING CHIEF OF THERAPEUTIC SECTION. HE'S ALSO THE PROGRAM DIRECTOR OF THE MEDICAL ONCOLOGY FELLOWSHIP IN THE NCI. HIS RESEARCH INTERESTS FOCUS ON BOTH HIS LABORATORY AND CLINICAL INTERESTS RELATED TO DRUG RESISTANCE. UNDERSTANDING IT AND OVERCOMING IT, AND ON THE MECHANISMS OF ACTIONS AND RESISTANCES OF THE MICROTUBULE AGENTS. THOSE HAVE BEEN HIS CLINICAL EFFORTS AND ALWAYS HAD A TRANSLATIONAL. HE'S THE SENIOR EDITOR IN CANCER RESEARCH AND THE ASSOCIATE EDITOR OF CLINICAL CANCER RESEARCH, MOLECULAR CANCER THERAPEUTICS, JOURNAL OF EXPERIMENTAL THERAPEUTICS AND ONCOLOGY AS WELL AS THE ONCOLOGISTS. AND TODAY'S IN RECOGNITION OF THIS AWARD, HE'S GOING TO PRESENT THE LECTURE, NOVEL MAYOR DIMES -- PARADIGMS IN CANCER THAT WILL LEAD TO BETTER THERAPEUTICS. WELCOME. [APPLAUSE] >> THANK YOU. THANK YOU FOR THE KIND INTRODUCTION AND THANK YOU ALL FOR COMING. I SEE A LOT OF FACES ... SO LET'S GET STARTED. I HAVE NO DISCLOSURES. I THINK THIS IS THE SLIDE WE CAN PROBABLY EXECUTIVE HERE, WHAT -- PROBABLY SKIP HERE. I HAVE ONE OBJECTIVE AND THAT'S TO HOPEFULLY CHANGE YOUR THINKING ABOUT HOW WE EVALUATE CANCER. IF I SUCCEED IN THAT THEN I THINK BOTH OF US WILL BE ALL THE BETTER FOR IT. DR. DECKER APPARENTLY DIDN'T WANT TO RETIRE IN 1990 AND HE CONTINUED TO WORK. AND THIS IS THE BOOK THAT WAS REFERRED TO. I HADN'T LOOKED AT IT BEFORE BUT I LOOKED AT IT IN PREPARATION FOR THIS LECTURE. IT'S REMARKABLE ALL THAT'S IN THERE. THINGS TODAY WE TAKE FOR GRANTED. THOSE OF US WHO PROBABLY COMPLAINED BACK IN THE 80'S WHEN WE HAD THOSE 60 PAGE PROTOCOLS, I MEAN AT SOME LEVEL WE HAVE TO BLAME DECKER FOR THAT BUT ALSO WE HAVE TO BE GRATEFUL FOR THAT. HE DID A REMARKABLE JOB. WHEN YOU READ THAT YOU JUST SAY GEEZ HE KNEW ALL OF THIS YEARS AGO. THAT'S PRETTY REMARKABLE. ONE OF THE THINGS, I DON'T EXPECT YOU TO SEE THIS UP HERE, THE GOALS HOWEVER IS HIGH QUALITY OF THE SUBJECT RESEARCH TO ANSWER THE SCIENTIFICALLY IMPORTANT QUESTION. I WOULD SAY IT DOESN'T QUITE SAY IT IN THERE BUT THE OTHER THING IS THAT HE THOUGHT IT WAS PROBABLY ETHICAL THAT WE GENERATE AND OBSTRUCT THE CLINICAL TRIAL AS WE SHOULD. AND WE THINK THAT TODAY WE NEED TO PUBLISH THE TRIALS. I'M GOING TO CONVINCE YOU THAT WE ARE PUBLISHING THEM LIKE WE ARE NOT HARVESTING ALL THE DATA ALL THE KNOWLEDGE THAT WE SHOULD. LET ME BEGIN WITH THE SAGA IN THE 1960'S AND 1970'S WHICH WAS AN EXCITING TIME AS CANCERS AS A WHOLE EXIST SPECIALLY HERE IN THE CLINICAL CENTER. EFFECTING HUMOR SHRINKAGE RIGHT HERE IN BUILDING 20, DEVITAE GIVES A COMBINATION OF FOUR DRUGS TO A PATIENT FOR THE FIRST TIME. AND PATIENTS ARE HAVING PRETTY REMARKABLE RESPONSES. IT WASN'T LONG BEFORE MANY OF THESE PATIENTS WERE RELAXING AND MANY THERAPIES WERE BEING TRIED. IT'S AT THIS POINT THIS GENTLEMAN ENTERS INTO THE DISCUSSION. HIS NAMES IS CHARLES MOTORIAL. HE THOUGHT MAYBE A DRUG WAS DOING WELL AND AS ANOTHER SOMEONE MIGHT THING IT WASN'T AS WELL AND HE THOUGHT WE NEEDED A COMMON LANGUAGE. NOW MOERTEL DIDN'T THINK THE BEST WAY YOU HAD TRIAL AT A MEETING WAS MAYBE HAVE A START TRACK EVENT AND HAVE SOMEBODY IN THE SPOT AND HIS IDEA OF FUN WAS TO GATHER 16 ONCOLOGISTS WITHIN 12 SPHERES AND THE SPHERES HAVE BEEN CONSTRUCTED TO INDICATE TUMORS. HE HAD THEM MAKE 1,920 MEASUREMENTS. THE LEGEND HAS IT THAT ACTUALLY THIS HAPPENED OVER DINNER AND THAT ALTHOUGH THEY SAY THAT THEY USED VARIOUS THINGS, WHAT THEY USED WAS THE COVER ON THE TABLE TO SIMULATE THE SOFT TISSUE. BASICALLY HE HAD 12 SOLID SPHERES THEY RANGE IN SIZE FROM 1.8 TO 14.5 CENTIMETERS IN DIAMETER. THEY HAD A THIN LAYER THAT MEASURED .5 INCHES. THERE'S AN AMERICAN THING ABOUT CENTIMETERS. THAT WAS SUPPOSED TO IMITATE SKIN AND ANOTHER COVER THAT WAS 1.5 INCHES IN THICKNESS WAS SUPPOSED TO IMITATE THE ABDOMINAL WALL. THINGS HAVE CHANGED. SO THE 16 PEOPLE THAT WERE THERE WERE TOLD TO BRING WITH THEM WHATEVER THEY NEEDED SO THAT THEY COULD EACH 16 PHYSICIANS TO MEASURE THE DIME YOU IF YOU ARE OF EACH SPHERE USING THE TECHNIQUE OF A RULER OR CALIBER HE EMPLOYED IN CLINICAL PRACTICE. ALL THE WOMEN IN THE AUDIENCE WILL KNOW THESE WERE [INDISCERNIBLE] AT THAT TIME. WHAT THEY DIDN'T KNOW WAS THAT MOERTEL HAD TAKEN THE TROUBLE OF MAKING FOUR OF THE SPHERES TO BE TWO EQUAL PAYERS. IN THAT WAY THERE WAS WEAR A COMPARE FREAK DISABILITY OF THE ABILITY TO MEASURE THESE THINGS. WHAT HE FOUND WAS THAT BETWEEN TWO DIFFERENT INVESTIGATORS WERE ASKED TO MEASURE THESE SPHERES, 50% -- I'M SORRY, 6.8% OF THE TIME THEY THOUGHT THAT THESE SPHERES COULD DIFFER BY AS MUCH AS 50%. REMARKABLY NEARLY 25% OF THE TIME THEY THOUGHT THAT THE SPHERES DIFFERED BY 25%. EVEN THE SAME INVESTIGATOR 7.8% OF THE TIME THOUGHT THAT THE SPHERES THAT WERE IDENTICAL WERE DIFFERENT, AND 18% OF THE TIME THOUGHT THAT THEY WERE 25% DIFFERENCE. IT WAS BASED ON THAT THAT MOERTEL SAID THAT WELL IF SOMEBODY TELLS ME IT WAS 25% I REALLY CAN'T TRUST THEM BECAUSE THERE'S AN 18-24% CHANCE IT MIGHT BE AN ERROR. ONLY ABOUT A 7-8% CHANCE IT WILL BE AN ERROR IF THE DIFFERENCE IS 50%. SO BASICALLY HE SAID WE CAN TRUST THE 50% DIFFERENCE. AND IT WAS BASED ON THAT. IN THE BEGINNING IT WAS CHOSEN FOR OPERATIONAL REASONS NOT FOR EFFICACY THAT WE EVOLVED IN THE ASSESSMENT OF EFFICACY. WHEN WE TALK ABOUT 50% REDUCTION REALIZE THERE WAS NO BASIS IN ANY SCIENCE, IT'S JUST WHAT COULD BE MEASURED ACCURATELY THAT WE CAN ALL THINK THAT. O V E R TIME. THAT EVOLVED AND THE WORLD HEALTH ORGANIZATION ADAPTED THIS VALUE OF 15% FOR TUMORS. SUBSEQUENTLY IN 2000 RESIST CAME TO BEING IT STANDS FOR RESPONSE EVALUATION CRITERIA IN SOLID TUMORS. BASICALLY EXCEPT THEY SAY WE'RE NOT GOING TO MEASURE TWO DIMENSIONS AS WE HAVE FOR ALL THESE YEARS WE'RE ONLY GOING TO MEASURE ONE DIMENSION. THEY'RE SIMILAR BUT NOT IDENTICAL AND I WON'T REALLY GO INTO DETAIL INTO HOW THEY'RE SIMILAR. JUST NOW THAT THIS ALLOWS YOU TO PROGRESS FOR A LITTLE BIT LONGER BEFORE THEY AND/OR AS PROGRESSION IN THE TREATMENT. IT'S BEEN YEARS SINCE THEY HAD THESE OBSERVATIONS. WE SHOULD BE THINKING OF DIFFERENT WAYS OF ASSESSING EFFICACY. I THINK PROBABLY BUT THAT'S ANOTHER TALK. LET ME JUST TELL YOU WHAT WE HAVE DONE. SO THIS BEGAN FOR ME WITH A DISCUSSION I HAD WITH MY WIFE, AND IT HAD TO DO WITH IMROWB A DRUG THAT WAS -- WE THOUGHT THIS WOULD REVERSE A CHRONIC DISEASE. THOSE WHO TREAT HYPERTENSION, DIABETES AND OTHER CHRONIC DISEASES WERE RECOGNIZED THAT SOMETIMES WHAT ONCOLOGISTS THINK IS CRAWNESSITY IS WHAT YOU THINK IS CHRONIC DISEASE. THIS WAS GOING TO MAKE KID KEY NARNS -- IT WAS INTERESTING THAT 74% OF THE PATIENT HAD SOME SORT OF SHRINKAGE IN THEIR TUMOR. THIS IS CALLED A -- FIRST TIME I SAW ONE I SAID WHO IS THIS DR. WATERFALL WHO GOT A PLOT NAMED AFTER HIM. IT'S JUST LIKE THEY LOOK LIKE A WATERFALL. EACH INDIVIDUAL PATIENT HAS BEEN PLOTTED. WHAT YOU'RE SEEING IS THE BEST RESULT THAT THEY HAVE. THE MAXIMUM SHRINKAGE OR THE WORST RESULT THAT THEY HAD BEFORE THEY CAME OFF STUDY, THE MAXIMUM INCREASE IN THOSE THAT HAD NO SHRINKAGE. AND YOU COULD SEE HERE THE MAJORITY OF PATIENTS HAD SOME SORT OF SHRINKAGE OF TUMOR. SO TO ME WHEN I LOOKED AT THIS, I SAID MAYBE THIS CRAWNESSITY WHO HAD ANYTHING TO DO WITH THE SLOWING OF THE TUMOR. MAYBE THAT EXPLAINS THIS CROWNESSITY, WE'RE NOT SLOWING TUMORS AT ALL WE'RE SHRINKING THEM. I KNEW WHO HAD THE ANSWER TO THAT. HE'S IN THE AUDIENCE TODAY, WILL FRED STAIN. HE'S EMERITUS PROFESSOR. THAT'S HIS WIFE. I WENT TO WILL FRED AND POSTED THE PROBLEM MUCH IN THE SAME WAY HE'S SMILING HERE AND HE SAID YOU CAN SOLVE THIS PROBLEM. LET'S GET SOME DATA. ACTUALLY WILLFRED HAD NO EXPERIENCE IN CLINICAL MATTERS. HE HAS A PH.D. AND HE HAD PUBLISHED MANY PAPERS AND REALLY CHANNELS, CARRIERS AND PUMPS IS SOMETHING HE KNOWS A LOT ABOUT. IT'S REMARKABLE HOW HIS INSIGHT HAS BEEN EVER SO HELPFUL. SO THIS IS WHAT EMERGED FROM THESE CONVERSATIONS. A CLINICIAN IN THE CLINIC WILL BE TREATING A PATIENT WITH A CHEMOTHERAPY DRUG. WHAT THEY MEASURE IS SHOWN HERE BY THE BLUE LINE. MAYBE IF THINGS WERE GOING WELL, THERE'S SOME SHRINKAGE IN THE TUMOR AND THEN SUBSEQUENTLY UNFORTUNATELY AS IS THE CASE IN MOST PATIENTS WHO HAVE METASTATIC CANCER, THE TUMOR REGROWS. I WANT YOU ALL FROM HERE ON IN TO BE THINKING ABOUT THIS IN A DIFFERENT WAY. EVERY TIME YOU SEE A TUMOR AND YOU SEE A MEASUREMENT, YOU SHOULD THINK THERE'S TWO SIMULTANEOUS PROCESSES GOING ON HERE. THERE'S A FRACTION OF THE TUMOR IN THIS PATIENT WITH METASTATIC CANCER THAT IS SENSIBLE TO THE CHEMOTHERAPY AND IS GOING TO DISAPPEAR OR REGRESS. THAT WE DON'T HAVE TO WORRY ABOUT. WHAT WE HAVE TO WORRY ABOUT IS THE OTHER FRACTION OF THE TUMOR THAT IS THERE. I'M LOOKING AT A CT SCAN IN THIS DAY AND AGE SHOWN HERE BY THE GREEN LINE AND IT'S GROWING BECAUSE IT'S NOT SENSITIVE TO THE THERAPY THAT I'VE ADMINISTERING. IT'S THAT FRACTION THAT I NEED TO WORRY ABOUT. I KID ALL THE TIME WHAT WE DO HERE AT THE NIH IS FIGURE OUT DIFFERENT THINGS SUCH AS THE FACT THAT GROWING TUMORS KILL PATIENTS. IN FACT THAT'S WHAT THIS IS ALL ABOUT. IN FACT WHAT YOU'LL SEE THE FASTER THEY GROW THE QUICKER THEY KILL A PATIENT. SO AT ANY POINT IN TIME, THIS MEASUREMENT THEN IS COMPOSED OF SOMETHING THAT IS PROGRESSING AND SOME TUMOR THAT'S GROWING. THIS ALL CAN BE DEFINED BY THIS EQUATION WHICH IS SIMPLE AND DON'T GET TURNED OUT BECAUSE OF THE INFLATION HERE ON THE BOARD HERE ON THE SLIDE. BASICALLY THE QUANTITATIVE TUMOR AT TIME T IS AN EXPONENTIALAL OF THE CONSTANT TIMES THE TIME IT TRANSPIRED [INDISCERNIBLE] MINUS ONE IS SIMPLY INSERTED SO WE CAN BEGIN A VALUE OF ONE AND WORK FROM THERE. WE COULD JUST AS EASILY BEGIN AT ZERO BUT THIS ALLOWS US TO LOOK AT THE DECAY FROM THE ORIGINAL VALUE. SO WHAT WE DID WAS WE SAID WE NEED DATA, WE HAD SOME DATA AND WE SAID WE NEED MORE DATA. AND WE'RE GOING TO TALK TO JIMMY WHO WORKED FOR STEVE ROSENBERG AND ANY NUMBER OF THINGS. AT THAT TIME THEY DID A TRIAL WHAT WE KNOW TO BE MY FAVORITE DRUG WHICH IS -- HE DIDN'T KNOW IT AS HE WAS BEGINNING A LONG TRAIL FOR THIS DRUG. AWE VASTEN WHO DOESN'T KNOW IS THE BIGGEST DRUG IN THE WORLD NOW OWNED BY ROCHE. BASICALLY IT IS AN ANTI-BODY THAT BINDS CIRCULATING VEG F THE VASCULAR AND ENDOTHELIAL GROWTH FACTOR. VEG F ENGAGES TWO RECEPTORS, ACTUALLY MORE THAN TWO BUT FOR PURPOSES OF THIS DISCUSSION TWO RECEPTORS THAT IT COMBINES TO WHICH ACTIVATE THE CELLS, INCLUDING NORMAL CELLS AS WELL AS MALIGNANT CELLS IN WHAT MIGHT BE THOUGHT OF AS A BENEFICIAL WAY. JIM HAD SHOWN THAT IF HE LOOKED AT PATIENTS IN THIS STUDY WHO RECEIVED A PLACEBO, AND WHO GOT THE HIGHER DOSE OF IN TERMS OF WHEN THEIR TUMORS PROGRESSED. THERE WAS A DELAY IN THE TIME TO PROGRESSION AND I STILL REMEMBER THE DAY DOWN IN RADIOLOGY WE WERE THERE. WE DIDN'T HAVE THE PACK SYSTEM, WE WERE ALL THERE MEASURING TUMORS ON THE SCREEN AND JIM CAME DOWN AND SAID SOMETHING HAPPENED TO ME THAT'S INCREDIBLE. WE GOT A CALL FROM THE COMPANY AND THEY'RE STOPPING THE TRIAL BECAUSE IT'S POSSIBLE THERE'S ACTUALLY A POSSIBLE RUPT IN THIS TRIAL. SO WE GOT JIM'S DATA, HANDED IT OVER TO WILLFRED AND WILLFRED THEN PUT THAT DATA TO THE EQUATION THAT I SHOWED YOU IN THE PREVIOUS SLIDE. IN THE MAJORITY OF CASES, JAMES VERY CAREFULLY MEASURED TUMORS THAT DID PERFECTLY WELL TO CURVES IN A SINGLE PLOT AND THESE CURVES CONFORM TO THIS EQUATION. YOU CAN SEE HOW WELL THE TUMOR MEASUREMENTS FORMED TO THE CURVE. OCCASIONALLY THERE WAS A PATIENT IN WHOM THE DATA WAS SCATTERED AND THIS IS LARGELY PATIENTS THAT ONE HAD IN THE SIZE OF THEIR TUMORS. WE THEN LOOKED AT THIS, WE WERE ABLE TO CALCULATE FROM THIS, FROM THE FORMULA A REGRESSION RE CONSTANT OR DECAY OR GENE OR GROWTH CONSTANT. I'LL DROP THE WORD CONSTANT. INDEED THEY ARE CONSTANT BUT WE'RE LOOKING AT A GROWTH RATE AND REGRESSION RATE. WHAT I'LL COME TO TELL YOU HOVER AND OVER AGAIN IS THAT THE GROWTH RATE IS AN IMPORTANT ONE WHICH COMES BACK TO WHAT I TOLD YOU IN THE ORIGINAL PICTURE BUT WHAT REALLY MATTERS IS HOW RAPIDLY THE TUMOR THAT IS RESISTENT IS GROWING. WE CHANGED DATA, WE WERE ABLE TO CALCULATE A GROWTH RATE AND A REGRESSION RATE. AND FORGET THE LOW DOSE HERE. THE PATIENT WITH THE PLACEBO AND THE PATIENTS WITH THE HIGH DOSE. THIS IS THE RATE OF GROWTH, THIS IS A LOGARITHMIC SCALE SO THIS IS SILVER -- THE RATE OF GROWTH ARE THOSE WHO GOTTEN HIGH DOSE. IN HALF OF THEM WAS BASICALLY LOWER THAN THE MAJORITY OF PATIENTS WHO HAD GOTTEN THE PLACEBO. SO WHAT IT WAS DOING WAS LARGELY SLOWING THE GROWTH OF THE TUMORS. IF YOU LOOK AT THE DECAY CONSTANT, IT WAS SOMEWHAT FASTER AND NOT STATISTICALLY DIFFERENT WHEN YOU COMPARED THE PLACEBO TO THE HIGH DOSE. WHEN WE LOOKED AT THE CORRELATION BETWEEN THE RATE OF GROWTH SHOWN HERE AGAIN IN THE LOGARITHMIC SCALE AND HOW LONG THE PATIENT SURVIVED, WE SAW THAT BOTH WITH ALL, IN ALL THREE COHORTS THAT THE FASTER THE TUMOR WAS GROWING, WHICH IS HERE, LARGER RATE OF GROWTH FOR A SMALLER NEGATIVE NUMBER, THEN PATIENTS DID LESS. AND THE LONGER THEY LIVED. WE ALL KNEW THAT BUT NOW WE COULD MEASURE THAT AND MEASURE IT QUITE ACCURATELY. BUT THEN OF COURSE ALSO WHAT GOT OUR INTERESTS THE FACT THAT WHEREAS JAMES HAPPENED THE STUDY STOPPED WHEN THERE WAS EVIDENCE OF PROGRESSION HAD BEEN DELAYED WHEN THE DATA WAS FINALLY ANALYZED, THERE WAS SOME DISAPPOINTMENT BECAUSE THE OVERALL SURVIVAL WAS NOT THAT DIFFERENT. ALTHOUGH THEY HAD A GREAT ADVANTAGE IN TERMS OF DELAYING PROGRESSION, THE PLACEBO PATIENTS HAD 453 DAYS AND PATIENTS WITH THE HIGH DOSE ONLY 490. THIS WAS THE DAYS WHEN WE STILL DIDN'T HAVE A LOT OF OPTIONS IN RENAL CELL CARCINOMA. AND THESE PATIENTS BASICALLY WENT HOME TO DIE AS DID THESE PATIENTS. NONE OF THE THERAPIES THAT WERE AVAILABLE WERE EITHER OFFERED TO PATIENTS WITH REAL CANCER OR IF THEY WERE, THEY WERE INEFFECTIVE. SO WE ACTUALLY HAD AN EXPERIMENT HERE THAT WAS DONE THEN AND COULD NEVER AGAIN BE REDONE. WHEN WE LOOKED AT IT WE COULD MODEL WHAT HAPPENED TO THE PATIENTS WHO HAS BEEN ON THE PLACEBO LINE AND WE COULD CLEARLY SEE HOW MUCH TUMOR THAT MUST HAVE TIED AT THE TIME THAT THEY DIED, 453 DAYS AFTER THEY HAD BEGUN THE THERAPY. I CAN TELL YOU THAT THE ARMS IN THE STUDIED WERE PERFECTLY BALANCED. THEY ALL HAD EQUAL AMOUNT OF TUMOR COMING IN AND THEY ALL HAD COMPARABLE AMOUNTS OF TUMORS WHEN THEY LEFT THE STUDY. WHEN WE LOOKED AT THE PATIENTS WHO HAD GOTTEN IT, WE WOULD HAVE THOUGHT THEY K35E9D AT THE SAME PROJECTORY, SAME GREAT OF ROTE, THEY HAD 896 DAYS. OF COURSE THAT'S NOT GOING TO HAPPEN, THEY STOPPED. THEN THEY GOT NOTHING. HOW FAST DID THEIR TUMORS GROW WE KNEW THAT BECAUSE WE KNEW THOSE WHO HAD DONE PLACEBO HOW FAST THEIR TUMORS GREW. SO WE MODELED IN WHAT WOULD HAPPEN THOSE WHO GOT HIGH DOSE HAD THEIR TUMORS GO BACK TO GROWING AT A RATE THAT WAS COMPARABLE TO THE PLACEBO AND THEY SHOULD HAVE LIVED 627 DAYS. IN FACT THEY LIVED 495 DAYS. THEY CONCLUDED IN THE DATA THAT WAS ACCUMULATED SINCE THAT ENCOURAGES ME TO BELIEVE THIS IS TRUE THAT UNFORTUNATELY AFTER THE DRUG WAS DISCONTINUED THE PATIENT'S TUMOR HAPPENED ACCELERATION IN ITS GROWTH. WE THEN TURN TO PROSTATE CANCER. I HAVE A LOT OF DATA BUT I'LL ONLY SHOW YOU TWO SLIDES. WHAT WE DID IS WE WENT BACK AND LOOKED AT 15 YEARS OF CLINICAL TRIALS AND 12 YEARS OF PROSTATE CANCER CLINICAL TRIALS HERE AT THE NCI. THESE ARE IN CHRONOLOGICAL ORDER. HERE WHAT I'M SHOWING YOU IS FOR ALL THE PATIENTS ENROLLED IN THE STUDIED. EACH PATIENT REPRESENTED BY A DATA. WHAT THE RATE OF GROWTH OF THEIR TUMOR WAS WHILE THEY WERE BEING TREATED. AGAIN THIS IS A LOGARITHMIC SCALE. THIS IS SLOW, THIS IS FASTER. THESE PATIENTS DOWN HERE BASICALLY WENT INTO A COMPLETE REMISSION SO THEY HAD NO GROWTH. THIS IS BASICALLY ZERO. WHAT YOU SEE IS THAT OVER TIME THE THERAPISTS FOR PROSTATE CANCER GOT BETTER AND BETTER AND THE INVESTIGATORS WERE ABLE TO MORE GRADUALLY AND THEN MORE RAPIDLY DELAY THE GROWTH OF TUMOR. ONE THING WHICH WAS INTERESTING HERE AND UNFORTUNATELY I WON'T HAVE THE TIME TOOK INTO IT WAS THE VACCINE THAT SLOAN-KETTERING LAB DEVELOPED. AT THE END OF THE DAY WHILE THEY WERE ON STUDY RECEIVING. VACCINE THERE WAS NO INFORMATION ON THE RATE OF GROWTH BECAUSE THE IMMUNITY HAD NOT YET DEVELOPED. WHEN YOU LOOK AT ALL THE DATA THIS IN THE EVEN IS THE WINNER. PATIENTS WHO RECEIVED THIS VACCINE HAD THE LONGEST SURVIVAL. WE THEN TURN TO A DRUG CALLED -- I'LL TELL YOU ABOUT THE DRUG AND SPENT THE REST OF THE TIME ON THIS DRUG TO SHOW YOU HOW MUCH DATA THAT'S OUT THERE THAT WE NORMALLY DON'T LOOK AT AND DON'T EXTRACT. IT WAS TRIED IN A RANDOMIZED TRIAL AND COMPARED WITH THE DATA AT THAT TIME WHICH WAS INTERFERON. THIS WAS AN ANTI-BODY THAT BOUND THE CIRCULATING VEG F -- SMALL MOLECULE WITH THE TINY INHIBITORS THAT INHIBITOR THE VEG F RECEPTOR AND I'LL SHOW YOU THAT IN THE NEXT SLIDE. IN CANCER THAT WAS THOUGHT TO BE IMPORTANT BECAUSE IT WAS FELT THAT PATIENTS WHO HAD MUTATIONS DID NOT DEGRADE HERE IN THE INDUCIBLE FACTOR AND THIS IN TURN TURNED ON THE EXPRESSION OF VEG F AND AS A RESULT OF THIS SUMMERS WERE PRODUCING LARGE AMOUNTS OF VEG F WHICH THEN TURNED ON THE PRODUCTION OF VASCULATURE BY THE TUMOR ITSELF. SO BASICALLY NORMAL VASCULATURE WAS BEING PROMOTED VIA FACTOR IN THIS CASE VEG F THAT WAS BEING PRODUCED BY THE TUMOR [INDISCERNIBLE] ARE EXPRESSED IN TUMORS AND IN BLOOD VESSELS WHICH IS THE THEY ARE VEG F WHICH WAS EXPRESSED BUT SUBMITTING IT -- KINASE INDUCED WHERE THERE'S [INDISCERNIBLE] IT WAS THOUGHT THAT IT WOULD INHIBIT SIGNALING INTO BLOOD VESSELS AND LEAD TO THIS CLOTTING OF BLOOD VESSELS FOR INDID DEDUCTION OF BLOOD FLOW TO THE TUMOR. HERE AGAIN UNLIKE VEG F WHICH BINDS CIRCULATING AVASTEN -- BIND HERE AND INTERFERE WITH THE RECEPTORS, INTERFERE WITH SIGNALING AND WOULD THEREFORE HAVE ANTI-BLOOD VESSEL PRODUCTION EFFECT. NOW THIS IS AN INTERESTING DRUG. IT WAS DEVELOPED BY WHAT WAS CLEARLY ON COMPANY AHEAD OF ITS TIME AS MUCH AS JOHN DECKER WAS. THIS WAS DEVELOPED BY TWO INDIVIDUALS, CELESTING JURY AND WILL FRED MILLS AND -- THESE INDIVIDUALS HAD EGOS THAT COULD FILL THIS ROOM. THAT'S WHY SCHLESSINGER'S NAME WAS AT THE BEGINNING HERE AND ALL RICH IS THE SECOND NAME THERE. THIS WAS BACK IN THE 1990'S LONG BEFORE ANYBODY THOUGHT OF MAKING THIS THEY WERE GOING TO MAKE SMALL MALL QUEUES THAT WOULD INHIBIT KINASES. THEY MADE A BUNCH OF THEM BUT EVENTUALLY WENT OUT OF BUSINESS. ALL OF THEM FAILED AND THEY HAD NO SUCCESS BUT THEY HAD IN THEIR REPERTOIRE A COUPLE OF THEM LEFT OVER AND ONE OF THEM WAS SIGNIFICANT. NOW AS SOON AS THIS WAS DEVELOPED INHIBITORS THAT WAS EMERGING AS THE FAMILY OF KINASES AND THERE WERE SEVERAL HUNDRED OF THEM IN HUMANS. IT WAS THOUGHT MANY OF THEM WOULD BE IMPORTANT IN CANCER. BUT THIS IS, LOOK AT HOW MANY OF THE TYROSINE KINASES THEY TARGET AND YOU CAN SEE SOMETHING LIKE -- TARGETS VERY FEW OF THESE IN THE FAMILY TREE OF KINASES. IT WAS A REAL DIRTY DRUG. IT TARGETED -- THEY WERE AFRAID IT WOULD HAVE A LOT OF TOXICITY. WHAT IT NEEDED WAS A BRAVE FRENCH GUY BY THE NAME HOW FAR JOHN PIERRE, WHO DEVELOPED SOME OF THE MYTHS IN DRUGS IN CANCER AND SAID SURE I'LL TAKE THAT, WHY NOT. JOHN PIERRE DEVELOPED -- THE DRUG THAT WAS LEFT OVER. JOHN PIERRE SOON FOUND OUT IT HAD ACTIVITY IN KIDNEY TRIAL WHICH LED TO THE TRIAL I WILL BE DISCUSSING AND THIS WAS THIS TRIAL. WHAT THIS TRIAL DID WAS HARVEST AN ENORMOUS AMOUNT OF DATA. IT RANDOMIZED 750 PATIENTS, 375 -- IMAGINE YOU WERE TO DO -- WE WERE TALKING ABOUT RESOURCES AT THE NIH IN THOSE DAYS. IMAGINE BACK IN THE DAYS WHEN WE HAD SOME RESOURCES. NOWADAYS WE WORRY IF WE HAVE ENOUGH TO DO A SIMPLE EXPERIMENT. BACK IN THOSE DAYS WE HAD MORE RESOURCES THAT YOU DID A STUDY WITH 750 MICE AND YOU COLLECTED 24,000 DATA POINTS. AND THAT THE OUT PUT FROM THAT WAS THIS, OKAY, 750 PATIENTS WERE RANDOMIZED. THAT THE OUTPUT FROM THAT STUDY WAS YOU TOLD ME THE RESPONSE, RIGHT. YOU TOLD ME HOW LONG BEFORE THE TUMORS PROGRESSED AND THEN EVENTUALLY YOU PUBLISHED HOW LONG THEY SURVIVED. THAT'S IT. YOU COLLECTED 24,000 NATIVE POINTS IN 750 PATIENTS THAT WILL COST PFIZER PROBABLY 30-$40 MILLION AND ALL YOU DO WITH THAT DATA IS REPORT THESE. THAT'S ALL ANYBODY DOES THESE DAYS AND IT'S REMARKABLE THE AMOUNT OF DATA WE GATHER AND THAT WE DON'T MIND. I'M GOING TO SHOW YOU SOME OF THE THINGS WE HAVE DONE WITH THAT DATA AS WE LOOK NOT JUST AT THE RATE OF GROWTH BUT OTHER FACTORS. SO IN THE SUNITINIB TRIAL WE WERE ABLE TO SHOW AS WITH -- THAT THE FASTER THE GROWTH RATE, THE SHORTER THE SURVIVAL. AGAIN ON THE LOG HERE, THESE WERE FASTER GROWTH UP AT THE TOP, AND SLOWER GROWTH RATES HERE. THOSE ARE THE SLOWER GREAT RATE. AND SO WE WERE VALIDATING THIS OVER AND OVER AGAIN. WE'RE MEASURING THE RATE OF GROWTH WHILE THE PATIENT IS IN CLINICAL TRIAL AND THEN PREDICTING WHAT THE SURVIVAL WILL BE SOMETIMES YEARS DOWN THE LINE. AND IT'S REMARKABLE WE CAN DO THAT AND SOME DAY WE CAN TEST THAT IN MORE DETAIL. THE OTHER THING WE FOUND OUT WAS JUST AS AN ACCIDENT THAT WE DELIBERATELY WENT LOOKING FOR IT WAS ACTUALLY 24,000 TO 48 THOUSAND DATA POINTS HAVE BEEN GASHTD 24,000 BY THE INVESTIGATORS AND ANOTHER 24,000 BY RADIOLOGISTS THAT WERE PAID TO RATE THE DATA. WHEN WE LOOKED AT THE DATA GATHERED BY THE INVESTIGATORS AND THE DATA GATHERED BY THE RADIOLOGISTS, YOU SEE AN ENORMOUS CORRELATION BETWEEN THE DATA. SO INVESTIGATORS ARE AS GOOD AS RADIOLOGISTS. I LIKE TO SHOW THIS SO THAT ALL THE GOOD RADIOLOGISTS WON'T BE TEMPTED TO GO INTO THE PRIVATE ENTERPRISE AND DO THESE SORT OF ASSAYS. PRETTY SOON WE WON'T BE NEEDING RADIOLOGISTS THERE. WE NEED YOU HERE. THE PROBLEM WITH SUNITINIB HOWEVER WAS THAT IT'S ONLY SO GOOD. REGRETLY METASTATIC CANCER IS TO THIS DAY STILL LARGELY INCURABLE AND ALTHOUGH SUNITINIB WAS EFFECTIVE IN RENAL CANCER, SOON ENOUGH PATIENTS WERE PROGRESSING AND SOMETIMES FAST. IN FACT, EVERY YEAR THE AMERICAN CANCER SOCIETY PUTS OUT THIS BOOK. IT'S ACTUALLY A MONOGRAM AND THE DATA FROM HERE IS THE -- IT APPEARS IN THE JOURNAL OF CANCER AND HAS AN IMPACT OF OVER 1010. WHAT WE SEE WHEN WE LOOK HERE IS THE NUMBER OF PAGES THAT'S PROJECTED TO DIE EVERY YEAR AND THE AMERICAN CANCER SOCIETY UNFORTUNATELY HAS BECOME QUITE ACCURATE AT DOING THIS. AND IN 2013 IT'S EXPECTED THAT OVER 13,000 PATIENTS WILL DIE OF KIDNEY CANCER. IF YOU LOOK BACK TO 2000, THIS NUMBER HAS NOT CHANGED. SO ALTHOUGH WE HAVE MANY FOR KIDNEY CANCER THE MAJORITY OF PATIENTS ARE DYING FROM KIDNEY CANCER. SO WE WERE AWARE OF ALL OF THIS DATA AND HAD ON HAND ALL OF THE SUNITINIB DATA. SO WHAT DRUG COMPANIES AND PEOPLE ARE LOOKING FOR WHAT SHOULD WE DO AFTER SUNITINIB. WHY DO WE USE SUNITINIB FIRST BECAUSE WE RECOGNIZE THAT TO DO THE BEST DRUG FOR KIDNEY CANCER, BUT EVERYBODY WANTED TO KNOW WHAT DO WE DO AFTER THE PROGRESSION OF SUNITINIB. ONE OF THE DRUGS THAT WE EVALUATEDS THE DRUG CALLED -- A DRUG WHICH IS EXTREMELY DIFFICULT TO TAKE. AND THAT WAS APPROVED BY THE FDA, ALTHOUGH WE HAD NO ADVANTAGE AS FAR AS THE PATIENTS WERE CONCERNED IN TERMS OF OVERALL SURVIVAL. YOU CAN SEE HERE THE PLACEBO AND THOSE OVERALL SURVIVED WAS NO DIFFERENT. THERE'S NO STATISTICAL DIFFERENCE BETWEEN THESE TWO CURVES. IT WAS APPROVED IN PART BECAUSE OF A WATERFALL PLOT. THESE ARE THE PATIENT THAT GOT -- THESE ARE THE PATIENTS WHO GOT PLACEBO. YOU CAN SEE A LOT OF PATIENTS WHO GOT -- HAD MORE TUMOR REDUCTIONS. WE SEE THAT IN KIDNEY CANCER FOR. YEARS TIMES THESE CANCERS PROGRESS. IF YOU HAD A PATIENT IN CLINICAL TRIAL YOU SEE THEM PROGRESS WITH THE TUMOR. I ALSO TOLD YOU SEVERAL TIMES WHAT YOU NEED TO WORRY ABOUT IS WHAT'S LEFT BEHIND NOT WHAT DISAPPEARS. AND IF YOU PLOT THIS AS A WATERFALL PLOT IT'S THE AMOUNT OF TUMOR THAT WAS SET BEHIND THESE PATIENTS WHEN THEY DISCONTINUED THE STUDY. YOU CAN SEE THAT THERE'S NOT A WHOLE LOT OF DIFFERENCE BETWEEN THE PLACEBO AND THE -- AND NOW YOU CAN UNDERSTAND WHY OVERALL SUBVIVAL IS NO DIFFERENT. IN ANY CASE IT TOOK ITS PLACE AS A TREATMENT TO BE GIVEN AFTER YOU GAVE SUNITINIB. THE OTHER DRUG [INDISCERNIBLE] ALSO DEVELOPED BY PFIZER. IT WAS SHOWN IN A CLINICAL TRIAL THAT AGAIN RANDOMIZED 700 SOME ODD PATIENTS FOR EITHER SUNITINIB OR -- THAT IN PATIENTS WHO HAD 3RE6LY BEEN TREATED WITH SUNITINIB AND HAD DISCONTINUED SUNITINIB EITHER BECAUSE IT WAS TOXIC OR BECAUSE THE POSITION WAS NO LONGER EFFECTIVE [INDISCERNIBLE] SAID WHEN THE TUMOR IS 25% LARGER, IT'S NO LONGER EFFECTIVE. SO WE DISCONTINUED IT. MOST PATIENTS WENT ON [INDISCERNIBLE] AND THE TUMOR'S GROWTH WAS DELAYED 4.8 MONTHS. MEANING IT WAS 4.8 MONTHS BEFORE THEY MET THE CRITERIA FOR PROGRESSION THAT IT WAS 25% BIGGER. NOWADAYS IT'S 20% BIGGER BUT IT'S ACTUALLY DIAMETRICALLY A SIMILAR TUMOR. SO -- WAS THEN APPROVED BY THE FDA AS A SECOND LINE THERAPY. NOW WE HAD ALL OF THIS DATA AND WE WANTED TO ANALYZE IT. WE HAD IN THE LAB THIS YOUNG WOMAN JULIA. WHEN SHE REALIZED, SHE'S A VERY SMART WOMAN, WHEN SHE REALIZED WE WERE GOING TO HAVE TO AROUNDIZE THIS DATA SHE SAID I'M GOING TO BUY A BOOK AND LEARN HOW TO PROGRAM IT, I'M GOING TO LEARN CODE AND GET SOMETHING GOING BY LOOKING AT ALL THIS DATA BY THE CLICK OF A BUTTON. AND SHE DID THAT. WE HAVE A PROBLEM WITH DATA AND WE DO, WE'VE GOT MORE THAN WE CAN ANALYZE. THE ONLY SOLUTION I COME UP WITH IS WE OUGHT TO CLONE JULIA WOLFERSON. WITH THE BUDGET CRUNCH WE CAN NO LONGER DO THAT. WHAT YOU SEE HERE IS 24 PATIENTS RANDOMLY CHOSEN FROM THE SUNITINIB CLINICAL TRIAL. I COULD SHOW YOU 300 OF THOSE CYCLES. THERE'S NO SELECTION HERE. WHAT YOU SEE HERE IS MEASUREMENTS OF THEIR TUMORS AND YOU CAN SEE SOME HAVE SHRINKAGE AND THEN GROWTH, SOME SEEM TO GROW ALMOST FROM THE WORD GO. SOME HAVE MORE SHRINKAGE AND TAKE A LONGER TIME TO GROW. AND THEN WHAT JULIA HAS PLOTTED HERE FOR YOU IS AT EVERY POINT IN TIME BEGINNING WITH THE THIRD MEASUREMENT, SHE HAS CALCULATED THE GROWTH RATE CONSTANT. WHAT YOU SEE HERE IS THAT THE GROWTH RATE CONSTANT IS INDEED A CONSTANT. IT REMAINS INCREDIBLY CONSPHUNT, AND YOU CAN SEE THESE ARE PATIENTS THAT HAVE GONE ON FOR 1500 DAYS ON SUNITINIB. LOOK AT THE CONSTANT. IT'S NOT CHANGING. WHAT THAT MEANS IS THE RATE OF GROWTH OF THIS TUMOR IS NOT CHANGING. IT ALSO MEANS SEVERAL THINGS AND I WANT TO DEVIATED HERE A SECOND TO POINT THOSE OUT TO YOU. NUMBER ONE IF YOU EXTRAPOLATE BACK IT LIKELY HASN'T CHANGED FROM THE BEGINNING, OKAY. ALL THAT'S HAPPENING HERE AT THE BEGINNING YOU SEE LARGE ERROR BARS IS BECAUSE WE DON'T HAVE ENOUGH DATA. AND IT FINALLY SELLS DOWN INTO A STABLE VALUE. I WOULD TELL YOU THAT THIS ADDRESSES WHAT HAS BEEN OF INTEREST TO ME ALL MY LIFE, MY SCIENTIFIC LIFE AND IT IS DRUG RESISTANCE. WHAT THIS SHOWS IS IN FACT THE DRUG RESISTANCE IN THE TUMOR IS AN INTRINSIC PROPERTY. IT IS INHERIT IN THE TUMOR. FROM THE BEGINNING, IT'S GROWING AT A CERTAIN RATE WHILE BEING EXPOSED TO THE DRUG. IT WAS NOT ACQUIRED DRUG RESISTANCE. THAT'S WHAT I DID IN THE LAB FOR MANY YEARS DEVELOPED MODELS AND APPLIED DRUG RESISTANCE. THESE TUMORS COME TO YOU ALREADY RESISTENT. THERE ARE CLONES WITHIN THE TUMOR THAT ARE RESISTENT EVEN BEFORE GIVEN IN CHEMOTHERAPY. SO THIS IS CONSTANT. AND IT'S VERY PREDICTABLE. WHAT THIS MEANS IS THAT I CAN PREDICT WHAT WILL HAPPEN THE NEXT TIME WE MEASURE THIS, OKAY. BECAUSE AFTER 1500 DAYS, I THINK I KNOW WHAT THE NEXT GROWTH RATE, WHAT THE NEXT VALUE OF TUMOR WILL BE. THE THING TO KEEP IN MIND HERE THAT'S GIVEN THIS EXAMPLE ALL THE TIME. SAY YOU HAVE A PATIENT WITH PROSTATE CANCER AND YOU'RE MEASURING PSI. YOU COME IN AND YOU SEE A VALUE OF .1 . THEY COME BACK AND ITS .2. AND YOU SAY THAT'S OKAY. THREE MONTHS LATER IT'S .4. YOU THINK IT'S STILL OKAY. THREE MONTHS LATER IT'S .8, THREE MONTHS LATER 1.6, THAT'S NOT SO BAD. THREE MONTHS LATER IT'S .2. THEN THREE MONTHS LATER 6.4. THREE MONTHS LATER 12.8. AT THAT POINT EVERYBODY'S WORRYING. IF YOU'RE WORRIED WHEN IT WENT FROM .1 TO .2 YOU SHOULD BE WORRIED BECAUSE THE RATE OF GROWTH HASN'T CHANGED. WHAT'S HAPPENING IS THE QUANTITY OF TUMOR IS CHANGING. AND THAT'S WHAT HAPPENED IN HERE. THE RATE OF GROWTH HAS BEEN CHANGING. THERE IS MORE TUMOR BUT THE RATE OF GROWTH ISN'T CHANGING. CONSEQUENTLY, WE CAN VERY EASILY PREDICT WHAT WILL HAPPEN. AND BY THE WAY, THIS IS THE DATA I SHOWED YOU 24 EXAMPLES HERE. THIS IS THE RATE OF GROWTH IN NEARLY 300 OF THE PATIENTS. THEY'RE ALL CLUSTERED DOWN HERE AND ONLY IN 18 OVER 321 PATIENTS WAS EVER EVEN A HINT THAT THERE WAS ACCELERATION OF THE RATE OF GROWTH, AND I'M SHOWING YOU SOME OF THESE HERE WITH THE ARROW. BUT BECAUSE THE RATE OF GROWTH IS STABLE, YOU ACTUALLY CAN SAY NO, I CAN PREDICT WHEN AGAIN THAT PATIENT WILL HAVE PROGRESSION OF THEIR DISEASE AS DEFINED IN THIS DAY AND AGE CRITERIA WHICH IS NOW CALLED THE RESIST CRITERIA. WHEN IS THE TUMOR GOING TO BE 1 POINT TIMES BIGGER THAN NOW AND 1.2 DIVIDED BY THE GROWTH RATE CONSTANT FOR THAT PATIENT IS THE TIME TO PROGRESSION. SO WE CAN PREDICT BECAUSE WE'VE GOT THE DATA FOR 275 PATIENTS OF SUNITINIB WHAT WOULD BE TO THE TIME OF PROGRESS WHERE THEY WERE TO CONTINUE TAKING SUNITINIB AND IT WOULD HAVE BEEN 7.3 MONTHS. THAT COMPARES QUITE FAVORABLE WITH 3.9 MONTHS AND 3.4 MONTHS AND SUNITINIB AT 4.8 MONTHS. LISTED HERE IS -- WHICH IS ONE OF THE FELLOWS WORKING WITH US. WHAT THIS IS TELLING YOU IS THAT IN FACT THE BEST DRUG MAY CONTINUE TO BE THE BEST DRUG. I WOULD JUST SAY HERE HE HAD FORMIZING IF YOU WILL THAT THAT IS ONE OF THE PROBLEMS THAT WE HAVE IN ONCOLOGY. AND THAT IS THAT IT'S VERY DIFFICULT TO TELL A PATIENT THAT THEY HAVE PROGRESSIVE DISEASE. THAT THEIR DISEASE IS GROWING. WE USUALLY THEN TURN TO THE PATIENT AND SAY WE'RE GOING TO TRY SOMETHING ELSE. PATIENT WANTS TO HEAR THAT BECAUSE THEY'RE HOPING THAT NEXT ONE WILL BE THE ONE THAT WILL CURE THEM. BUT IN METASTATIC CANCER WHAT WE DON'T LACK OR WE LACK CURATIVE THERAPY, BUT WE STILL CAN'T CURE THE MAJORITY OF PATIENTS WHO HAVE METASTATIC CANCER. WE KNEW WHICH OF THE BEST DRUG FOR THIS PATIENT THAT'S GOING TO KEEP THE TUMOR GROWING AT THE SLOWEST POSSIBLE RATE AND PROLONG LIVES THE LONGEST. RATHER THAN CHANGING WE SHOULD BE LOOKING TO WHICH IS THE BEST DRUG. I WOULD ARGUE THAT SUNITINIB WOULD BE THE BEST DRUG TO CONTINUE. AND ACTUALLY, WE COULD MEASURE THE GROWTH RATE CONSTANT IN EVERY PATIENT AND HOPE TO BE ABLE TO ONE DAY DO THIS ON-LINE. THE PHYSICIANS WILL BE ABLE TO DO THAT AND THEY'LL KNOW WHETHER OR NOT IN THIS PARTICULAR PATIENT SUNITINIB WAS PERFORMING REALLY WELL AND IT SHOULD BE COMPLETED. AND I WOULD VERY MUCH TO GUESS THAT UNFORTUNATELY TODAY IN THE UNITED STATES, WE SOMETIMES TAKE PATIENTS FROM THE BEST THERAPY IN THE HOMES THAT WE WILL CURE THEM WHICH IS A FALSE HOPE SWITCHING TO ANOTHER THERAPY WHICH IS NOT AS GOOD, AND IN FACT I THINK PATIENTS ARE IN MANY CASES LIVING SHORTER THAN THEY WOULD HAD WE LEFT THEM ON THAT ONE THERAPY THAT EVEN THOUGH WAS NOT PREVENTING THE TUMOR FROM GROWING WAS KEEPING IT GROWING AT THE SLOWEST POSSIBLE RATE. AND SO CONSEQUENTLY, THAT'S WHAT DATA SUCH AS THIS TELLS US. NOW GOING TO WILLFRED WAS WHAT I THOUGHT WAS TRYING TO THINK OUT OF THE BOX. IF YOU WANT TO THINK OUT OF THE BOX YOU GOT TO LOOK OUTSIDE OF THE BOX AND WE D WILLFRED WASN'T IN THE CLINICAL BOX HE WAS IN A DIFFERENT BOX. I WAS IN MY OFFICE ONE DAY AND I GOT A CALL FROM THIS GENTLEMAN, A PHYSICIST WHO TOO IS OUT OF THE BOX. HE WAS INTERESTED IN SOME OF THE WORK WE HAD DONE WITH WILLFRED AND WANTED TO TALK TO ME. WHEN HE CAME I REALIZED WE WERE INTERESTED IN MANY THINGS IN THE SAME WAY. IN FACT WE HAD VERY SIMILAR INTEREST. EACH HAS HAD THE IDEA OF [INDISCERNIBLE] ONE OF THE THINGS THAT WE KNEW WAS THAT THIS PAPER HAD BEEN PUBLISHED IN CANCER CELLS. AND IT WAS A PAPER THAT SAID THAT SUNITINIB COULD ACCELERATE TUMORS. WE THOUGHT THIS MIGHT BE POSSIBLE. WE HAD DATA THAT SUGGESTED THAT -- HAD ACCELERATED TUMORS. MAYBE SUNITINIB COULD DO THE SAME THING. WE WERE SOMEWHAT SKEPTICAL ABOUT IT. IT WAS PUBLISHED BY A VERY BRIGHT INDIVIDUAL SO WE RESPECTED THE DATA. I BECAME CONCERNED WHEN ACTUALLY -- BEGAN TO WORRY ABOUT THIS AND I REMEMBER TWO YEARS AGO AT A MEETING -- ENCOURAGES THAT LUNCHTIME MEASURES AND DOCTOR INTERACT. I HAD TWO WOMEN INDEPENDENTLY COME UP TO ME AND THEY WANTED TO ASK ME SHOULD THEY USE SUNITINIB FOR THEIR TUMOR. THEY SHOWED ME THE PAPER AND PROBABLY PAID $35 TO HAVE IT PRINTED. THEY THOUGHT THIS WAS A WORTHWHILE INVESTMENT. THEY DIDN'T KNOW EACH OTHER AND THEY BOTH ZEROED IN ON THIS PAPER AND THEY WERE CONCERNED THAT THEIR TUMOR WAS GOING TO GROW. IT WAS REALIZED THEN WE HAD DATA THAT CAN ANSWER THERE AND WE SHOULD PUBLISH IT. IT WAS VERY SIMPLE. WE HAD ALL THIS DATA THAT NOBODY HAD BOTHERED TO ANALYZE ASKING THIS QUESTION. SO THE FIRST THING WE DID LOOK AT IT AND WELL, PATIENTS WHO GOT INTERFERON SEEMED TO LIVE LONGER AFTER THEY LEFT THE TRIAL THAN WITH PATIENTS WHO HAD SUNITINIB. COULD IT BE THAT SUNITINIB WAS ACCELERATING THE TUMOR AND PATIENTS WHO RECEIVED IT WERE DYING SOONER. WHEN YOU LOOKED FURTHER IN FACT EVERYBODY WHO GOT INTERFERON WHEN THEY LEFT THE TRIAL GOT SUNITINIB OR A SIMILAR DRUG. NOT EVERYBODY BUT 90% OF THE PATIENTS. WHAT HAPPENED WAS THEY HAD GONE ON TO GET AN EFFECTIVE -- AND THAT'S WHY THEIR SURVIVAL WAS LONGER. THESE PATIENTS STOPPED SUNITINIB AND DIDN'T GET ANOTHER DRUG THAT WAS AS EFFECTIVE AS SUNITINIB. SO THAT WASN'T THE ANSWER. WHEN WE LOOKED INTO IT AND WE SAY WELL, THE SUNITINIB IS BAD, THE SUNITINIB IS BAD, MORE IS WORSE. WHAT CAN WE SAY ABOUT ALL OF THIS. WELL, IF WE LOOKED AT THE TREATMENT AND YOU LOOKED AT THE POST PROTOCOL SURVIVAL, HOW LONG THEY SURVIVAL AFTER THEY LEFT THE STUDY IT DIDN'T MATTER HOW LONG THEY GOT SUNITINIB. IT HAD NO EFFECT ON HOW LONG IT SURVIVED. IT DID EFFECT HOW LONG IT DID SURVIVE, I'M SORRY HOW LONG IT SURVIVED AFTER THE PROTOCOL. IT DID AFFECT HOW LONG YOU SURVIVED. THE LONGER YOU WERE IN SOON -- SUNITINIB THE LONGER YOU LIVED. IT APPEARED IT WASN'T HAVING AN EFFECT. IF WE LOOKED HOW MUCH SHRINKAGE ON THE EFFECT OF THE SUNITINIB ON THE TUMOR, HAVING MORE EFFECT ON THE TUMOR MAKE IT WORSE, YOU FOUND THAT THOSE WHO HAD THE GREATEST EFFECT DIDN'T DO ANY WORSE, THOSE WHO HAD ALMOST MOW EFFECT IN TERMS OF THEIR SURVIVAL. IF YOU LOOKED AT THE OVERALL SURVIVAL, YOU COULD SEE THAT THOSE WHO HAD A GREATER EFFECT AS MEASURED BY THE WEIGHT OF GROWTH OF THE TUMOR HERE BY THE GENE COMPARED TO THOSE WHO HAD THE LEAST EFFECT, IN FACT THE GREATER EFFECT SURVIVED LONGER. SO FROM THIS AND OTHER DATE THAT WE HARVESTED FROM THIS STUDY, WE WERE ABLE TO CONCLUDE IN FACT IN THESE MEASURES WITH METASTATIC CANCER, SUNITINIB WAS NOT HARMFUL. I KNEW THE DATA AND CONVINCED TWO PATIENTS THEY SHOULD GO ON AND THEY DIDN'T NEED TO BE WORRIED ABOUT THAT. THE OTHER THING THAT -- AND I SHARED AN ANSWER IS CANCER STEM CELLS. THERE'S PROBABLY A LOT OF PEOPLE IN THE AUDIENCE THAT BELIEVE IN CANCER STEM CELLS. I DON'T SUBSCRIBE TO IT, BUT IT'S A MATTER OF DEBATE AND I'M FINE WITH THAT. BUT CANCER STEM CELLS WHICH ARE SHOWN HERE IN ORANGE ARE THOUGHT TO GENERATE TUMORS THAT WHEN YOU LOOKED AT THE MODELS FOR THIS, GROWTH IN THAT CASE IS LINEAR BECAUSE EVERY TIME A CANCER STEM CELL DIVIDES IT HAS TO REPRODUCE ITSELF SO THAT WE MAKE THE STEM CELL AND YIELD ONE -- BUT WE KNEW FROM ALL THE DATA WE ANALYZED WITH WILLFRED EVERY SINGLE TUMOR AT THIS POINT PROBABLY LIVED THROUGH 12 DIFFERENT TUMORS THE RATE OF GROWTH WAS EXPONENTIAL. EXPONENTIAL GROWTH IN TUMOR IS INCONSISTENT WITH THE CANCER STEM CELL HYPOTHESES. THE ANALYSES OF ALL OF THIS DATA IS THERE HAS TO BE A MODIFICATION OF THAT HYPOTHESES. WE LOOKED AT PROSTATE CANCER PATIENTS, WE LOOKED IN THIS REGION AT THE AREA IN WHICH THE TUMORS WERE GROWING. AND IF THE TUMOR GROWTH IS EXPONENTIAL AND THIS IS EAR MEAN GRAPH IF YOU WILL OF 60 PATIENTS WITH PROSTATE CANCER THE EFFECT OF THE LINE AT A 45 DEGREE ANGLE INDICATES THAT THE GROWTH IS EXPONENTIAL. OVER TIME IT'S DOUBLING IN ACCORDANCE WITH THE AMOUNT OF TIME THAT UNIT OBSERVING THE PATIENTS. SO ANALYSIS OF THE SUNITINIB DATA AS WELL AS PROSTATE DATA FROM THE INTRAMURAL TRIALS AND LOTS OF OTHER DATA FROM A LOT OF OTHER STUDIES SUGGESTS THAT IN FACT BOTH ARE EXPONENTIAL AND THERE HAS TO BE SOME ADJUSTMENT FOR THE CANCER CELL HYPOTHESES. AND THEN FINALLY LET ME TURN TO -- MAYBE WE'RE NOT SURPRISED OUR THERAPIES WEREN'T ABLE TO CURE THIS LARGE BURDEN. WE THOUGHT WE WOULD BE MORE SUCCESSFUL. NEO -- WHEN A SURGEON TELLS YOU ALL, JUST IN CASE I'M GOING TO GIVE A LITTLE BIT OF ADJUVANT THERAPIES IN CASE SOMETHING WAS LEFT BEHIND. WE THOUGHT THIS WOULD BE WHERE OUR THERAPIES WOULD PERFORM BEST BECAUSE THE BURDEN OF TUMOR WAS LESS. WE THOUGHT MAYBE THEY ARE LESS DIVERSE, WILL BE MORE SUCCESSFUL. HOWEVER, TIME AND AGAIN WHEN YOU FAKE A THERAPY THAT'S BEEN VALIDATED IN WHAT I WOULD SAY IS THE PROVING GROUND OF TUMOR THERAPY AT THE METASTATIC SETTING AND YOU TAKE IT TO THE ADJUVANT OR NEO ADJUVANT -- I SHOWED YOU THIS AT THE BEGINNING BUT I CHEATED. I SHOWED YOU THE RESISTENT TUMOR BEGINNING BASICALLY AT ZERO AND THE SENSITIVE BEGINNING AT 100. BUT IN FACT THAT'S NOT REAL LIFE. WILLFRED AND I, SUSAN BATES ALL WORKING ON THIS REALIZE THAT WE ALSO NEEDED TO CONSIDER THE FRACTION OF TUMOR. WHAT FRACTION WAS SENSESSIVE AND WHAT ONE WAS RESISTENT. I WON'T GO INTO DETAIL BUT WE CAN ESTIMATE IF WE HAVE SUFFICIENT DATA WHAT THE FRACTION OF THE TUMOR THAT WAS SENSITIVE AND WHAT WAS RESISTENT IS. AND THEN YOU CAN LOOK AT THE DATA AND WHETHER OR NOT YOU CONSIDER THE FRACTION THAT'S SENSITIVE IS ACTUALLY REMARKABLY THE RATE OF GROWTH AND THE RATE OF DECAY ARE VERY VERY SIMILAR. GENERALLY WE DON'T BOTHER CALCULATING, NOT BECAUSE IT'S A THING FOR JULIE, IT'S ANOTHER STROKE ON THE RETURN BINT, IT'S JUST THAT YOU NEED MORE DATA IN ORDER TO DO THAT BECAUSE YOU HAVE ONE MORE IN YOUR EQUATION. IF YOU NOW LOOK AT SUNITINIB IT ACTUALLY IS LIKE THIS. WE'RE MEASURING THE TOTAL TUMOR BUT THERE'S A FRACTION THAT'S DISAPPEAR AND A FRACTION THAT IS RESISTENT. IF WE START AT ZERO AND 1 THEY'RE VERY VERY VERY SIMILAR. SO WE USUALLY TAKE THE SIMPLER APPROACH. BUT WHAT THIS ALLOWS US TO THEN IS KNOW WHETHER THERAPIES ARE HAVING AN IMPACT PRIMARILY ON THE RATED OF DECAY, ON THE RATE OF GROWTH OR ON THE FRACTION OF TUMOR THAT THEY ARE KILLING. IF YOU LOOK AT PROSTATE CANCER, THERE ARE SOME THERAPIES IN WHICH YOU GET BOTH. THERE ARE SOME PATIENTS IN WHOM THERE IS NOT A WHOLE LOT OF TUMOR THAT IS SENSITIVE, AND IT COMES DOWN TO 5.5, LESS THAN .5 FOR THE TUMOR, 50% DISAPPEARING. BUT THERE ARE OTHERS WHERE THE AMOUNT OF TUMOR IN THIS CASE MEASURED BY MSA OR PROCESS STATE SPECIFIC ANTIGEN PRACTICALLY DISAPPEARS, IN SOME PATIENTS GOES BEYOND THE LEVEL OF PROTECTION. THESE PATIENTS HAVE VERY HAVE ROBUST RESPONSES TO THE THERAPY, A LOT OF THE TUMOR IS BEING KILLED. WHEN WE LOOK BACK AT SUNITINIB INTERFERON DATA WE SAW ACTUALLY IT WAS KILLING TUMORS, ITS MAJOR EFFECT WAS ACTUALLY IN SLOWING THE GROWTH OF TUMOR. AND THEN WHAT I WILL TELL YOU IS THAT IN THE METASTATIC SETTINGS, SOMETIMES WE GET A RESULT AND WE SEE THAT 14% OF PATIENTS IN THE CONTROL LINE HAVE SOME TUMOR SHRINKAGE AND 34% IN THE EXPERIMENTAL ARM HAVE SOME TUMOR SHRINKAGE. EVERYBODY SEES THAT AND SAYS I KILLED MORE TUMOR. THIS COMBINATION IS KILLING MORE TUMOR THE EXPERIMENTAL COMBINATION, THAT IS THE CONTROL LINE. IN FACT THAT'S NOT TRUE. IF YOU SAW THE GROWTH OF THE RESISTENT TUMOR AS WE HAVE DONE HERE, HOW DEEP THE CURVE GOES IS EFFECTIVE. IN THIS CASE, THE TUMOR THAT'S SENSITIVE IS CONSTANT. D, THE RATE OF DECAY IS CONSTUNTED. WE'VE DOUBLED THE AND HE IS OF THE RATE OF GROWTH. YOU CAN SEE IT CHANGES DRAMATICALLY. IT'S VERY SIMPLE. YOU HAVE THE AMOUNT OF TUMOR THAT'S DISAPPEARING. THE FASTER THE RESISTENT TUMOR GROWS, THE SOONER IT TURNS THAT CURVE AROUND. IF YOU SLOW THE RATE OF GROWTH, YOU ALLOW THAT SENSITIVE TUMOR THAT IS DECAYING AT A CERTAIN RATE TO MANIFEST ITSELF MORE CLEARLY. IN FACT IN THE METASTATIC SETTING OR WHAT THE FDA REQUIRES IS PROLONGED PATIENT SURVIVAL, NEARLY ALL OF OUR THERAPIES ARE WHAT WE WOULD CALL KEY THERAPIES. THEY AFFECT THE RATE OF GROWTH. THEY HAVE PRACTICALLY NO EFFECT ON THE FRACTION OF TUMOR THAT IS KILLED. AND YOU DON'T NEED THAT. YOU CAN PROLONG SURVIVAL BY TWO MONTHS MUCH. THE FDA WILL GRANT YOU AN APPROVAL. AND SO CONSEQUENTLY, WHAT WE ARE DEVELOPING AND AGAIN WHAT I WOULD CALL THE PROVING GROUND OF CANCER THERAPIES WHICH IS THE METASTATIC THERAPY, METASTATIC SETTING OF G THERAPIES THEY DELAY THE GROWTH OF TUMOR WERE NOT DEVELOPING IN WHAT WE LIKE TO CALL FIVE THEOREMS. THOSE ARE THE ONES WE NEED IN THE ADJUVANT AND NEO ADJUVANT. WHERE YOU HAVE VERY LITTLE TUMOR WE WANT TO KILL IT. YOU DON'T WANT TO ADMINISTER AN ADJUVANT THERAPIES. WHAT WE DO IS CALCULATE AN INDEX. I'M JUST SHOW YOU A COUPLE OF EXAMPLES HERE. THERE WAS A STUDY COMPARE -- THIS IS THE EXAMPLE I WAS CITING FOR YOU. 14% RESPONSE RATE, 34% RESPONSE RATE. SURELY WE KILLED MORE TUMOR. NO. IT HAS A DRAMATIC EFFECT ON THE RATE OF GROWTH OF THE TUMOR, A FRACTION THAT WAS KILLED WAS IDENTICAL. YOU MOVE THIS COMBINATION TO THE UP FRONT -- YOU MOVE IT TO THE ADJUVANT SETTING HE WILL HAVE NO BENEFIT. SIMILARLY IN MULTIPLE MYELOMA, WHEN WE'RE LOOKING AT THE CIRCULATING IMMUNOGLOBULIN, WE SEE THAT -- HAS BEEN IN THE NEWS BECAUSE WE CAN'T SEEM TO MANUFACTURE TWO VORTEX. THESE NO DIFFERENCE IN THE FRACTION OF TUMOR THAT IS SENSITIVE ALTHOUGH THE RESPONSE RATE HERE WAS AGAIN MORE THAN DOUBLE WHEN YOU ADDED THE COMBINATION. SO THAT'S WHAT THIS HAS TAUGHT US THAT WHAT WE'RE DEVELOPING ARE G THERAPIES AND IF WE'RE GOING TO SUCCEED WITH CONFERENCES THAT ARE MINUSCULE IN QUANTITY FROM THE ADJUVANT AND NEO ADJUVANT SETTING WE NEED FIVE THERAPIES. WE COLLECT DATA AND IGNORE IT OR WE CAN GO INTO THE DATA AND LEARN A GREAT AMOUNT. WE GAIN INSIGHT INTO WHICH THERAPIES SHOULD BE CONTINUED AND WHICH THERAPIES MIGHT BENEFIT HUMANS. WE HAVE ANIMAL MODELS THAT'S OCCURRING WITH SUNITINIB, WE HAVE EVIDENCE OF INTRINSIC -- INCONSISTENT WITH THE STEM CONTROL MOTHS. AND WE HAVE A PARADIGM THAT EXPLAINS WHERE NEO ADJUVANT AND ADJUVANT THERAPIES CONTINUE -- SO ARE WE DOING ALL WE CAN? I THINK NOT. SHOULD WE CONSIDER NEW PARADIGMS I THINK YES. SHOULD WE SERIOUSLY THINK ABOUT ALTERING OUR PARADIGMS I THINK YES. FOR THOSE OF YOU WHO AREN'T YET COMPLETELY SATISFIED SPEND THE LAST THREE MINUTES TRYING TO CONVINCE YOU THAT -- IS SOMETHING BY THE NUMBERS. SO 2001, THAT'S THE YEAR THE FDI APPROVED -- AND ENLARGED THE -- I WAS TALKING TO THERAPIES, WORKING ON THE THERAPIES FOR 20 YEARS. 552,200. THAT'S THE AMERICAN OF NUMBER DEATHS IN 2001 FROM CANCER. 580,350 THE PROJECTION FOR THE NUMBER OF DEBTS THIS YEAR A HIGH% INCREASE WHICH CONSIDERING HAVE A 10% LARGER POPULATION IS PROGRESS BUT NOT THE PROGRESS WE WOULD LIKE TO MAKE. 9.7. SO AVASTEN AND SUNITINIB WHICH IS MY FAVORITE WHIPPING BOY IS ACTUALLY A THERAPY THAT GENENTECH WOULD LIKE MEASURES WITH RECTAL CANCER TO TAKE FOREVER. 9.7 MONTH WHAT THEY SAID WITH THE ADVANTAGE IN OVERALL SURVIVAL IF YOU TOOK THIS THERAPY CONTINUOUSLY AS OPPOSED TO ONLY ONCE WITH YOUR FIRST LINE OF CHEMOTHERAPY. THIS WAS A RETROSPECTIVE TRIAL. 1.4 IS THE NUMBER OF MONTHS THAT YOU GAINED BY CONTAINING AVASTEN CONTINUE CONTINUALLY. WE NEVER GOT THIS DATA BUT YOU CAN TELL BY LOOKING AT IT THE TWO ARMS IN THE RETROSPECTIVE TRIAL ARE NOT THE SHAME. BY THE WAY I WOULD POINT OUT THAT THESE NUMBERS UNFORTUNATELY ARE NOT A WHOLE LOT DIFFERENT THAN 21.5 MONTHS WHICH WAS THE SURVIEFERL THAT WE HAD BACK IN 199 -- I'M SORRY, YES, 1994 TO 2004 IN COLORECTAL CANCER WITHOUT AVASTEN. SO 4,054 -- THESE ARE THE NUMBER OF PATIENTS THAT GENENTECH ENROLLED IN A CLINICAL TRIAL TRYING TO DEMONSTRATE THAT AVASTEN MIGHT BE EFFECTIVE IN THE NEW ADJUVANT SETTING. THEY WEREN'T HAPPY TAKING IT IN THE SETTING THEY WANTED TO ADMINISTER IT IN THE ADJUVANT AND NEO ADJUVANT SETTING. 27% IS THE HARM THAT WAS GOING TO BE COMING TO PATIENTS WITH AVASTEN. IT WAS HOW MUCH MORE LIKELY IT WAS A PATIENT GIVEN -- TO DIE OF CANCER. SO NOT ONLY DID IT NOT HELP IT HARMED. 3.2 AND 4.6 MONTHS THE TIME HOW MUCH MORE RAPIDLY IN MONTHS A PATIENT WILL RECEIVE IT DIED AFTER RECURRENCE. THIS IS LIKE THE RESULTS WE'VE HAD WITH KIDNEY CANCER. ZERO. THAT'S THE NUMBER OF PATIENTS WITH COLORECTAL CASUAL THAT WAS THOUGHT TO BE GIVEN SOON PARTICULAR AS THERAPY. THESE AND OTHER DATA WE DO NOT RECOMMEND USING -- IN THE TREATMENT OF PATIENTS. 95% OF CONSERVATIVE ESTIMATE OF THE PERCENT OF AGENTS IN PHARMACEUTICAL COMPANY FINDS ARE QUOTE TARGETED THERAPIES. AND I WOULD CAUTION THAT THE MAJORITY OF THESE ARE NEW TOO BECAUSE THAT'S WHAT WE CURRENTLY HAVE, THE MENTALITY THAT IS EXEMPLIFIED THAT THE FACT THAT MORE THAN 70 VEG FR INHIBITORS HAVE BEEN DEVELOPED BY PHARMACEUTICAL COMPANIES. SO THE CONCLUSION IS THAT WE NEED TO BEND THE EFFORTS IN THE COVER. WE NEED BETTER DRUGS WE NEED TO DO IT NOW AND IT WAS THE PARADIGM OF THE PAST DECADE AND WILL CONTINUE THE EFFICACY THAT WE HAVE AND WE WILL CONTINUE TO SOW THE SEEDS OF MEDIOCRITY -- STEVE ROSENBERG IS RESPONSIBILITY THAT THE FOUNDATION TODAY MAKES IT ALL EXCITED ABOUT THE NEW MODULES OF THERAPIES IN CANCER. IRA DEVELOPED NOT ONE BUT SEVERAL IMMUNOTOXINS THAT WILL BE VERY VALUABLE. JEFF SLOAN HAS SEVERAL VACCINES IN DEVELOPING BUT WILL EMERGE IN PATIENTS WITH PROSTATE CANCER. TOM -- ALSO NOTICED THERE'S MORE INTERLOOPING -- AND JAY AND NORM ARE WORKING FOR PROSTATE CANCER THAT WE'VE HAD THE OPPORTUNITY TO ANALYZE THE DATA. COUNTLESS IS THE NUMBER OF PEOPLE THAT I HAVE TO THINK AND THESE ARE THE ACKNOWLEDGEMENTS AND IT'S NOT EVERYONE THAT I WORKED WITH, IT DOESN'T INCLUDE -- WHO I LOVE DEARLY IT'S PEOPLE WITH WHOM I'VE WORKED IN WHAT I'VE BEEN DESCRIBING TO YOU TODAY. I MAY SPECIAL CLOSE ATTENTION TO WILLFRED STEIN, TO IRA WHO MENTORED MOW -- WHO ARE THE TWO MOST WONDERFUL INDIVIDUALS ONE CAN WORK WITH. MAUREEN IS THE RESEARCH CENTER I WORK WITH AND LYN MANAGES THE LAB REA. WITHOUT THAT I WOULDN'T BE ABLE TO DO ANY DATA. THANK YOU FOR COMING, I REALLY APPRECIATE THAT YOU CAME. [APPLAUSE]