THIS IS A PROGRAM OF THE
NATIONAL HUMAN GENOME RESEARCH
INSTITUTE AND IT IS MY ENORMOUS
PLEASURE TO WELCOME YOU TO THIS,
THE NINTH INSTALLMENT OF THE
2025 SEASON OF DEMYSTIFYING
MEDICINE.
A SERIES OF PRESENTATIONS THAT
BRIDGE THE EXCITING DEVELOPMENTS
IN BIOLOGY, ENGINEERING, AND
COMPUTER SCIENCE WITH MEDICINE.
AS ILLUSTRATED BY THE ICONIC
PHOTO OF THE CONSTRUCTION OF THE
BROOKLYN BRIDGE BACK IN THE LATE
19TH CENTURY, AND YOU CAN
PROBABLY SEE UP THERE ON THE
CATWALK THOSE TWO MEN, ONE OF
THEM PROBABLY FROM MANHATTAN, A
PHYSICIAN, I WOULD GUESS, AND
THE OTHER, A BASIC SCIENTIST
FROM BROOKLYN.
TALKING ABOUT ONE OF THE HOT
TOPICS OF THE DAY, PERHAPS THE
GERM THEORY OF DISEASE.
SO JUST AS THEY WERE BRINGING
TOGETHER BASIC SCIENCE WITH
CLINICAL MEDICINE, SO TOO THIS
AFTERNOON, WE ARE GOING TO BRING
TOGETHER BASIC SCIENCE WITH
CLINICAL MEDICINE TO TALK ABOUT
SOME OF THE GREAT EXCITING
ADVANCES IN THE UNDERSTANDING
AND TREATMENT OF LUNG CANCER.
THIS SERIES, DEMYSTIFYING
MEDICINE, TAKES PLACE ON TUESDAY
AFTERNOONS FROM JANUARY THROUGH
MAY THIS YEAR, 2025, FROM
3:00 TO 5:00 IN THE AFTERNOON.
YOU CAN WATCH IT ON THE LINK
SHOWN ON THE SCREEN.
YOU CAN GET CME CREDIT AVAILABLE
AND THE CODE IS 58788.
IF YOU HAVE QUESTIONS DURING THE
COURSE OF THE PRESENTATIONS, AND
WE'LL BE HAVING TWO, EACH OF
THEM ABOUT 35 MINUTES LONG AND
THEN THE OPPORTUNITY FOR A
QUESTION AND ANSWER SESSION AT
THE END, IF YOU HAVE QUESTIONS
THAT OCCUR TO YOU DURING THE
PRESENTATIONS, JUST USE THE
"SEND LIVE FEEDBACK" BUTTON ON
THE VIDEOCAST DISPLAY IN ORDER
TO GET THOSE QUESTIONS TO US
AHEAD OF TIME.
ALL OF THE PREVIOUS SESSIONS ARE
ARCHIVED, THE LINK IS ON YOUR
SCREEN AND FOR ADDITIONAL
INFORMATION, YOU CAN EMAIL
DEMYSTIFYINGMED@NIH.GOV.
THIS IS A SERIES THAT'S BEEN
GOING ON SINCE 2003, BRIDGING
SILOS AT THE NIH, AS ILLUSTRATED
BY THOSE SILOS THERE IN THE
LOWER RIGHT-HAND CORNER.
TODAY'S PRESENTATION IS GOING TO
BE ABSOLUTELY FANTASTIC.
WE ARE GOING TO HAVE FIRST
DR. ROY HERBST PRESENTING, AND
THE MAJOR TOPIC OF THIS SESSION
IS CANCER OF THE LUNG, PROGRESS
AND CHALLENGES.
DR. HERBST IS THE ENSIGN
PROFESSOR OF MEDICINE IN MEDICAL
ONCOLOGY, PROFESSOR OF
PHARMACOLOGY, AND CHIEF OF
HEMATOLOGY AND MEDICAL ONCOLOGY,
AND ALSO DEPUTY DIRECTOR OF THE
YALE CANCER CENTER.
HE'S ALSO THE ASSISTANT DEAN FOR
TRANSLATIONAL RESEARCH AT YALE
SCHOOL OF MEDICINE.
HE GOT HIS BACHELOR'S AND
MASTER'S DEGREES IN BIOCHEMISTRY
AND BIOPHYSICS AT YALE.
HE THEN DID HIS PH.D. IN
MOLECULAR AND CELL BIOLOGY AT
THE ROCKEFELLER UNIVERSITY
BEFORE GOING ON TO GET HIS
MEDICAL DEGREE AT CORNELL
MEDICAL SCHOOL, AND THEN A
MASTER'S DEGREE IN TRANSLATIONAL
RESEARCH AT HARVARD.
HE THEN WENT ON TO GET HIS
CLINICAL TRAINING IN MEDICAL
HEMATOLOGY/ONCOLOGY AT THE
HARVARD HOSPITALS AND THEN WENT
SOUTH TO HOUSTON, WHERE HE TOOK
POSITIONS AT THE UT MD ANDERSON
CANCER CENTER, EVENTUALLY RISING
TO THE ESTEEMED POSITION OF
BARNHART DISTINGUISHED
PROFESSOR.
HE'S THE RECIPIENT OF MANY
AWARDS AND RECOGNITION,
BEGINNING WITH PHI BETA KAPPA,
SUMMA CUM LAUDE, HE'S WON
NUMEROUS TOP DOCTOR AWARDS AND
HE WON THE DISTINGUISHED PUBLIC
SERVICE AWARD FROM THE AMERICAN
ASSOCIATION OF CANCER RESEARCH.
HIS LABORATORY SPECIALIZES IN
DEVELOPMENTAL THERAPEUTICS AND
PERSONALIZED THERAPY OF
NON-SMALL CELL LUNG CANCER, AND
LINKS CELLULAR GENETIC
ABNORMALITIES TO NOVEL
THERAPIES.
THEIR WORK HAS LED TO THE
APPROVAL OF SEVERAL THERAPIES
THAT HAVE REVOLUTIONIZED THE
FIELD.
HE'S ALSO A PIONEER IN THE USE
OF PD-L1 INHIBITORS IN LUNG
CANCER AND HAS BEEN A LEADER IN
THE UMBRELLA TRIALS OF TARGETED
THERAPIES.
OUR SECOND PRESENTER IS GOING TO
BE DR. KATERINA POLITI.
SHE IS THE JOSEPH A. AND LUCILE
MADRI PROFESSOR AT THE CENTER
FOR THORACIC CANCERS AT THE YALE
SCHOOL OF MEDICINE.
SHE RECEIVED HER UNIVERS
UNIVERSITY DEGREE, LAUREA, IN
BIOLOGICAL SCIENCES, CUM LAUDE,
FROM THE UNIVERSITY OF PAVIA,
AND THEN A PH.D. WITH
DISTINCTION FROM COLUMBIA
UNIVERSITY.
SHE WENT ON T TO DO A POSTDOC IN
GENETICS AND DEVELOPMENT AT
COLUMBIA AND THEN BECAME A
RESEARCH FELLOW IN HAROLD
VARMUS' LAB AT MEMORIAL SLOAN
KETTERING AND THEN A RESEARCH
SCIENTIST THERE AS WELL.
SHE THEN WENT ON, OF COURSE, TO
YALE WHERE SHE CURRENTLY IS THE
MADRI PROFESSOR OF PATHOLOGY.
SHE'S A MEMBER OF THE BOARD OF
DIRECTORS AND CHAIR OF THE
SCIENTIFIC ADVISORY BOARD OF THE
LUNG CANCER RESEARCH FOUNDATION.
SHE'S AN ELECTED MEMBER OF THE
PLUTO SOCIETY, WHICH IS A
SOCIETY OF ACADEMIC THAT POLL
GISTPATHOLOGISTS, AND ALSO A
RECIPIENT OF THE YALE CANCER
CENTER TRANSLATIONAL RESEARCH
PRIZE.
HER RESEARCH GROUP FOCUSES ON
THE MECHANISMS OF TUMORIGENESIS
AND SENSITIVITY AND RESISTANCE
TO TARGETED THERAPIES.
SHE WORKS ON ADENOCARCINOMAS
THAT HARBOR MUTATIONS IN THE
EGFR GENE, AND THEY STUDY LINKS
BETWEEN RESISTANCE, CANCER CELL
PLASTICITY, THE TUMOR
MICROENVIRONMENT, AND TUMOR
HETEROGENEITY.
SO AT THIS POINT, IT'S TIME TO
TURN THINGS OVER TO DR. HERBST
AND POLITI.
DR. HERBST, TAKE IT AWAY.
>> THANK YOU VERY MUCH.
THANK YOU FOR THAT WONDERFUL
INTRODUCTION.
WE'RE NOT USED TO USING TEAMS.
>> DON'T KNOW IF WE CAN MINIMIZE
THAT.
>> OKAY.
SO THANK YOU FOR HAVING US
TODAY, AND THANK YOU FOR THAT
WONDERFUL INTRODUCTION.
WHEN KATY AND I RECEIVED THIS
INVITATION, WE FIGURED OUT HOW
TO MAKE THIS WORK BECAUSE WE'RE
SO HONORED TO BE TALKING TO THE
NIH.
WE ACTUALLY JUST CAME FROM GRAND
ROUNDS, OUR CALABRAZI GRAND
ROUNDS GIVEN BY THE FORMER NCI
DIRECTOR, AND KATY AND I ARE
PIs TOGETHER ON A LUNG SPORE,
SO SOME OF THE WORKLOAD IS FROM
THAT, SO WE'RE VERY GRATEFUL FOR
ALL THE SUPPORT.
SO I THOUGHT I'D GIVE A
PERSPECTIVE CLINICALLY ON 20
YEARS OF PROGRESS IN THE
TREATMENT OF LUNG CANCER, MOSTLY
NON-SMALL CELL, TARGETED THERAPY
IMMUNOTHERAPY, AND HOW IT'S
IMPACTING THE TREATMENT OF EARLY
DISEASE.
HERE ARE MY DISCLOSURES.
SO LUNG CANCER IS THE NUMBER ONE
CAUSE OF CANCER DEATH WORLDWIDE.
MORE THAN 2 MILLION CASES
WORLDWIDE, NEW CASES, WITH
ALMOST AS MANY DEATHS.
IN THE U.S., WE HAVE ABOUT
228,000 NEW CASES EACH YEAR WITH
135,000 DEATHS.
84% OF LUNG CANCER IS NON-SMALL
CELL LUNG CANCER, ABOUT 15% IS
SMALL CELL, FOR WHICH THERE HAVE
BEEN, AGAIN, SPONSORED THROUGH
NIH AND NCI MANY RESEARCH
EFFORTS, BUT I'M GOING TO FOCUS
ON NON-SMALL CELL TODAY, AND YOU
CAN SEE THE PIE CHART ON THE
LEFT.
LUNG CAN SERL EXCEEDS BREAST,
COLON, PROSTATE, THE NUMBER ONE
CANCER BY DIAGNOSIS, OF COURSE,
IS SKIN CANCERS.
NOW THE CAUSES OF LUNG CANCER,
OF COURSE, TOBACCO IS THE SINGLE
LARGEST PREVENTABLE CAUSE OF
LUNG CANCER.
LEADING TO 30% OF ALL
CANCER-RELATED DEATHS AND 80% OF
LUNG CANCERS, BUT OF COURSE FOR
THE LAST 20-PLUS YEARS, WE KNOW
ABOUT THE NON-SMOKING LUNG
CANCER, OR THE LIGHT SMOKERS
WITH LUNG CANCER, AND OF COURSE
NOW THE FOCUS IS ON ACTIONABLE
MUTATIONS.
AS YOU CAN SEE FROM THIS FIGURE,
MOST OF THOSE TEND TO OCCUR IN
THE ADENOCARCINOMA IN THE BLUE
PART OF THE CIRCLE, WITH EGFR
BEING THE TOP ONE, ABOUT 10% OR
SO OF PATIENTS IN THE WESTERN
WORLD, 20 TO 30% IN ASIA, ALK,
MET, ERBB-2, ROS, RET, NTRK,
BRAF AND 12% KRAS G12C, ACTUALLY
A MUTATION THAT OCCURS MORE IN
SMOKERS.
FOR THE MOST PART THESE GENETIC
ALTD RANGE OF MOTIONS OCCUR IN
NON-SMOKERS.
NOW WHEN I WENT INTO THIS FIELD,
I WAS A STUDENT AS YOU HEARD, I
TRAINED AT DANA FARBER, I WAS
WORKING WITH THE LATE TOM FRYE,
ART SKERON, AND WE WERE STUDYING
THIS DISEASE.
THIS IS WHAT SURVIVAL LOOKED
LIKE.
IT'S HARD TO BELIEVE THAT HERE
IN 1995, WE'RE ALL EXCITED ABOUT
THESE DATA.
THESE WERE SOME OF THE NEWER
DRUGS THAT WERE BEING USED IN
LUNG CANCER, PACK BUT YOU CAN F
YOU LOOK AT THE LEFT THAT THESE
SURVIVAL CURVES ALL COME TO THE
BOTTOM.
NO ONE IS CURED, NO ONE HAS
LONG-TERM PLATEAU OR SURVIVAL
AND IT DOESN'T MATTER WHICH OF
THE DIFFERENT DRUGS ONE USED.
THE ONE YEAR SURVIVAL FOR THIS
DISEASE IN THE METASTATIC
SETTING WHEN PRESENTED MORE THAN
HALF THE TIME WAS 33% AND MEDIAN
SURVIVAL LESS THAN 8 MONTHS.
HERE'S THE PROGRESSION, EVEN
WORSE.
IT WAS CLEAR THAT A NEW PARADIGM
SHIFT WAS NEEDED.
NOW I'M GOING TO GIVE YOU THE
PUNCH LINE FIRST.
WE ARE MAKING A DIFFERENCE
THROUGH ALL OF OUR COMBINED
EFFORTS, SCIENCE, CLINIC, BACK
AND FORTH, YOU CAN SEE HERE'S
LUNG CANCER MORTALITY OVER TIME
WITH MEN, AND YOU CAN SEE THAT
IT PEAKED IN 1990, WHEN IT'S
COMING DOWN, AND FOR WOMEN, THE
PEAK IS A LITTLE BIT LATER.
INTERESTINGLY, WOMEN SMOKED --
THE PUSH TO ADVERTISE TO WOMEN
FOR SMOKING CAME AFTER MEN, SO
THE FEMALE PEAK IN LUNG CANCER
CAME A LITTLE LATER, IT'S ALSO
COMING DOWN.
YOU CAN SEE FROM THE AMERICAN
CANCER SOCIETY, THE ONE ON
PAPER, YOU CAN SEE THE INCIDENCE
COMES DOWN BY 2.6% A YEAR IN MEN
BUT THE MORTALITY OF 4.3, SO
IT'S NOT JUST INCIDENCE, COULD
OF COURSE BE AFFECTED BY
PREVENTION AND SCREENING, BUT
IT'S ALSO MORTALITY, COMING DOWN
FOR WOMEN, 1.2% IN INCIDENCE AND
3.1% IN MORTALITY.
I WOULD MAKE THE CASE THAT MOST
OF THIS IS TARGETED THERAPY
WORK, AND SOME OF THE EARLY
RESULTS OF IMMUNOTHERAPY, I'LL
SHOW YOU A LITTLE BIT ABOUT
BOTH.
SO I'M JUST GOING TO TRY TO KEEP
TO TIME BECAUSE KATY IS RIGHT AT
MY SIDE HERE, WE'RE SHARING THIS
PRESENTATION.
I WILL TELL YOU ABOUT SOME
ADVANCES IN TARGETED THERAPY,
THEN IMMUNOTHERAPY AND THEN SOME
THOUGHTS ON THE FUTURE, WHICH
REALLY IS WHAT WE'RE DOING IN
OUR SPONSORED RESEARCH.
SO TARGETED THERAPY, YOU SAW MY
BACKGROUND WHEN I STARTED OUT IN
MD ANDERSON, THAT WAS THE ADVENT
OF EGFR INHIBITORS.
EGFR, THE RECEPTOR WAS ACTUALLY
FIRST DESCRIBED AND THE
STRUCTURE FIGURED OUT 40 YEARS
AGO.
WE ACTUALLY JUST HAD A MEETING
AT THE ROYAL SOCIETY IN DECEMBER
COMMEMORATING THAT.
AND IN 1998, THE FIRST SMALL
MOLECULE TYROSINE KINASE
INHIBITORS WERE GOING INTO
CLINICAL TRIAL.
THIS WAS A DRUG WITH A DRUG
KNOWN AS ZD1839, AND YOU CAN SEE
THAT THIS DRUG TOOK PATIENTS
WITH WIDELY METASTATIC LUNG
CANCER, THIS IS A PATIENT SHOWN
HERE ON THE LEFT WHO WOULD
HARDLY HAVE BEEN ABLE TO
BREATHE, AND WITHIN WEEKS ON
THIS ORAL TKI, A WONDERFUL
RESPONSE.
THIS IS ACTUALLY ONE OF THE VERY
FIRST PHASE ONE TRIALS OF THESE
DRUGS ACTUALLY LED THIS TRIAL
WITH MY NOW YALE COLLEAGUE PAT
LARUSO.
IT WAS NOT UNTIL 2004, SO THAT
WAS 1998, SO FOR SIX YEARS, WE
KNEW THAT THESE SMALL MOLECULE
TGIs AGAINST THE EGFR RECEPTOR
WORKED BETTER IN SMOKERS AMONG
WOMEN AND ASIANS, BUP IT WASN'T
UNTIL IT WAS DESCRIBED BY GROUPS
IN BOSTON AND NEW YORK KNOWING
THAT IT HAS AN EXTERNAL DOMAIN,
TUMOR GROWTH FACTOR ALPHA, AND
THE INTERNAL TYROSINE KINASE
DOMAIN WHERE THE BINDING PACKETS
SHOWN HERE WHICH WHEN
PHOSPHORYLATED, ATP BOUND, THAT
SETS OFF SIGNAL TRANSDUCTION, IT
WAS FOUND CANONICAL EGFR
MUTATIONS WERE FOUND IN THESE
PATIENTS WHO RESPONDED WELL THAT
RESULTED IN A POCKET HERE WHERE
THE SMALL MOLECULES BOUND
ESPECIALLY WELL, AND RESULTED IN
THE TURNING OFF OF AN ADDICTED
RECEPTOR.
AT MD ANDERSON, WE HAD MANY
PATIENTS WHO WOULD FLY IN FOR
THESE CLINICAL TRIALS.
SECILY ON THE RIGHT WAS ONE OF
OUR VERY FIRST PATIENTS ON THIS
TRIAL WITH HER HUSBAND SHOWN
HERE.
THIS WAS AN ARTICLE WRITTEN FOR
"THE WALL STREET JOURNAL" IN
2003, WHY CURING YOUR CANCER MAY
NOT BE THE BEST IDEA.
THE WHOLE IDEA IS WHILE YOU MAY
NOT CURE LUNG CANCER WITH THESE
AGENTS, YOU CAN LIVE WITH THIS.
HERE'S SOMEONE LIVING QUITE
WELL, SO IT WAS A WHOLE NEW
PARADIGM FOR LUNG CANCER.
TARGETED THERAPY, ORAL THERAPY,
CHRONIC THERAPY.
WELL, AGAIN, A SHORT TALK HERE
TODAY, BUT THE CHEMISTRY HERE
WENT FROM FIRST GENERATION
DRUGS, WHICH WERE REVERSE
INHIBITORS THAT TARGETED WILD
TYPE EGFR.
MOSTLY SENSITIVE WERE THE X I-19
DELETION OR THE -- TO A SECOND
GENERATION OF DRUGS WHICH WERE
IRREVERSIBLE, SO TARGETING MORE
HER RECEPTORS, SO MAYBE A LITTLE
BIT MORE POTENT BUT CERTAINLY
MORE TOXIC TO THE THIRD
GENERATION DRUG SHOWN TO BE
SUPERIOR TO THE OTHERS, COVALENT
AND REVERSIBLE INHIBITOR BUT
IT'S EGFR MUTATION -- IT'S LESS
SPECIFIC, T790M, THE MOST COMMON
FORM OF PRIMARY EGFR RESISTANCE.
WE WERE A MD ANDERSON AT THE
TIME, ME AND MY GROUP AND WE
STARTED TO USE THESE DRUGS AS
WELL AS OTHER DRUGS IN LUNG
CANCER.
AND THE IDEA WAS THAT IF YOU'RE
GOING TO DO IT, TISSUE WAS THE
ISSUE.
YOU HAD TO HAVE BIOPSIES SO THIS
ASK A STUDY THAT ACTUALLY IS NOW
ABOUT 14 YEARS OLD FOR CALLED
THE BATTLE STUDY, WHICH REALLY
USED CORE TISSUE BIOPSIES INTO
LUNG TUMORS TO ACTUALLY USE
THOSE DATA TO DECIDE HOW TO
TREAT PATIENTS.
IT WAS LED BY A TEAM SHOWN HERE,
A SENIOR MEMBER WAS T AND JACK ,
OUR STATISTICIAN, WE USED
ADAPTIVE STATISTICS.
AND IT WAS BATTLE FOR LUNG
CANCER ELIMINATION.
WHAT HAPPENED BACK IN 14, 15
YEARS AGO IS WE REALIZED THAT
CORE BIOPSIES ARE FEASIBLE AND
SAFE.
WE CAN GET BIOMARKER RESULTS IN
A FEW WEEKS.
DRUGS CAN BE USED WITH MULTIPLE
STUDIES AND COMPANIES.
SO THIS WAS THE ERA OF TARGETED
THERAPY IN LUNG KUHN SER.
CANCER.
I'M GOING TO SHOW YOU SOME OF
THE DATA NOW.
ONCE WE HAD THE FIRST GENERATION
TKIs, THE SECOND GENERATION
TKIs WERE DEVELOPED AND THE
REASON WHY THEY WERE IMPORTANT
IS THEY WORKED IN PATIENTS WHO
HAD RESISTANCE TO THE FIRST
GENERATION AND AS I SAID ABOUT
HALF THE RESISTANCE IS DUE TO
C790M.
SO OSIMERTINIB IS A
T790-MILLIMETER SENSITIVE DRUG,
HERE'S A WATERFALL PLOT OF
PATIENTS ALL RESISTANT TO FIRST
GENERATION WITH WONDERFUL
RESPONSE TO THE OS MERT ANYBODY.
THIS DRUG BECAME APPROVED IN A
SECOND LINE SETTING INITIALLY
BUT STILL FEW IF ANY PATIENTS
WERE CURED BECAUSE RESISTANCE
DEVELOPS AS YOU'LL HEAR IN KATY
IN A LITTLE WHILE.
THIS WAS THE MAN WHO WAS NEXT TO
THE WOMAN BEFORE HE PASSED AWAY.
HE ALLOWED ME TO USE HIS PICTURE
10 YEARS LATER.
HE LIVED TO THE RIPE OLD AGE OF
95, YOU ALSO HAD LUNG CAN JER
AND GOT THE OSIMERTINIB AND HE
DID NOT DIE OF HIS LUNG CANCER.
THIS IS HIS 70-PLUS-YEAR-OLD SON
AND THIS IS, OF COURSE, ME.
SO I DON'T WANT TO TAKE TOO
LONG, BUT CUTTING TO THE CHASE,
IT WAS DETERMINED THAT
OSIMERTINIB WAS BETTER THAN THE
FIRST AND SECOND GENERATION
DRUGS.
THEN THE THING I WANT TO SHOW
YOU IS THE BIG ADVANCE IN THE
LAST FOUR YEARS IS THAT NOW THE
DRUG WAS TAKEN TO EARLIER STAGE
DISEASE.
SO IN LUNG CANCER, I'VE BEEN
TELLING YOU ABOUT ADVANCED
METASTATIC DISEASE, BUT IN EARLY
DISEASE, STAGE I DISEASE WHERE
YOU FIND A SMALL TUMOR AND IT'S
CUT OUT, STAGE II DISEASE WHERE
YOU HAVE A TUMOR ALSO CUT OUT
BUT SOME EARLY LYMPH NODES,
INTRAPARENCHYMAL LYMPH NODES OR
STAGE III, MORE DEEP MEDIASTINAL
LYMPH NODES, IN STAGE ONE THE
FIVE-YEAR SURVIVAL RATE IS ONLY
60%.
IN STAGE TWO IT'S 47%.
STAGE III, IT'S 38%.
SO ALL THESE PATIENTS, WHY WOULD
WE NOT USE AN EGFR INHIBITOR TO
PREVENT THEM FROM DEVELOPING
METASTASES?
THIS WAS A TRIAL WE STARTED
ABOUT 12 YEARS AGO.
WE HAVE PATIENTS WITH COMPLETELY
RESECTED STAGE I, B2 AND 3A
LOCAL LUNG CANCER WHO MAY OR MAY
NOT HAVE RECEIVED ADJUVANT
CHEMOTHERAPY, 5% IMPROVEMENT IN
SURVIVAL.
ALL THESE PATIENTS HAD THAT EGFR
MUTATION, THEY HAD TO HAVE BRAIN
IMAGING, THEY HAD TO HAVE
COMPLETED RESECTION AND THEY HAD
A CERTAIN AMOUNT OF TIME THAT
THEY COULD WAIT, 10 WEEKS
WITHOUT ADJUVANT THERAPY BEFORE
STARTING THE OSIMERTINIB OR 26
WEEKS WITH THE ADJUVANT THERAPY.
PRESSURE WAS STRATIFIED BY STAGE
SO EQUAL NUMBER OF EACH OF THE
THREE STAGES ON THE STUDY.
BY MUTATION TYPE, 19 OR 21.
SO BETWEEN THE TWO GROUPS, AND
RACE, ASIAN VERSUS NON-ASIAN,
EGFR MUTATIONS ARE ABOUT 30% IN
ASIA AND 10% PREVALENT IN THE
WESTERN WORLD, WE WANTED TO SORT
OF RANDOMIZE IN A WAY THAT THERE
WAS A STRATIFICATION.
SO EACH ARM HAD THE SAME NUMBER
OF ASIAN VERSUS NON-ASIAN
PATIENTS.
PATIENTS WERE RANDOMIZED 1 TO
1 THROUGH EITHER OSIMERTINIB AT
80 MILLIGRAMS OR A PLACEBO
BECAUSE EGFR INHIBITORS WERE
NEVER USED IN THE EARLY STAGE
SETTING.
THESE PATIENTS WERE AT HIGH RISK
OF RECURRENCE ESPECIALLY TO
BRAIN, LIVER AND BONE.
THE PLANNED TREATMENT DURATION
WAS THREE YEARS.
SHOULD THEY HAVE GOTTEN LONGER
OR LESS, I'LL SHOW YOU THAT IN A
MOMENT, AND WE FOLLOWED THEM UP
EVERY 12 AND 24 WEEKS.
NOW, THE STUDY WAS POWERED FOR
DISEASE-FREE SURVIVAL, FOR A
HAZARD RATIO OF .7, MEANING FOR
A 30% IMPROVEMENT.
AND ACTUALLY EXACTLY FIVE YEARS
AGO TODAY, BECAUSE OF THE
PANDEMIC, I GOT A CALL THAT THE
DEAFT SAFETY MONITORING
COMMITTEE WANTED TO STOP THIS
TRIAL.
I WAS LIKE OH, GOSH, IS IT
REALLY THAT BAD?
BECAUSE NORMALLY WHEN A TRIAL IS
STOPPED EARLY, IT'S A PROBLEM.
AND ACTUALLY THEY SAID NO, WE
ACTUALLY WERE DOING A SAFETY
ANALYSIS AND LOOKED AT THE
OUTCOME DATA AND IT'S LOOKING SO
POSITIVE, WE FEEL WE HAVE TO LET
YOU KNOW.
SO AFTER SOME DISCUSSION, WE
AGREED TO OPEN UP AND LOOK AT
THE DATA AND THE INVESTIGATORS,
I HAVE TWO OTHER PRINCIPAL
INVESTIGATORS ON THIS, ONE FROM
CHINA, DR. WU, ONE FROM JAPAN,
DR. SUBAI, WE UNBLINDED THE
TRIAL.
THIS IS WHAT WE SAW ON THE LEFT.
NOW LOOK, YOU'RE GIVING AN EGFR
INHIBITOR VERSUS A PLACEBO IN
THE ADJUVANT SETTING TO PATIENTS
YOU KNOW ARE GOING TO RECUR.
OF COURSE IT WAS GOING TO BE A
POSITIVE TRIAL.
WE EXPECTED THAT.
BUT DID WE EXPECT THAT THE
HAZARD RATIO WOULD BE .2, THAT
THE BLUE CURVE WHERE PATIENTS
GOT OSIMERTINIB VERSUS THE
YELLOW WHERE THEY HAD THE
CONTROL WOULD HAVE AN 80%
IMPROVEMENT?
IT EXCEEDED EXPECTATIONS.
THIS WAS AT AN EARLY MATURITY,
WE WERE WAITING FOR 50% OF THE
EVENTS, THAT WAS WHAT THE
STATISTICAL PLAN FOR CALLED FOR,
BUT EVEN THOAL ASCO WAS FIVE OR
SIX WEEKS AWAY, IT MADE TO THE
PLEP REOF ASCO THAT YEAR.
YOU CAN SEE EVEN WITH THE FULL
MATURITY NOW, 45-PLUS PERCENT,
THE HAZARD RATIO IS .27 OR 73%
IMPROVEMENT IN DISEASE-FREE
SURVIVAL FOR THE OSIMERTINIB IN
BLUE VERSUS THE CONTROL.
BUT THERE WERE STILL MANY
SKEPTICS WHO SAID WHERE'S THE
SURVIVAL?
WELL, WHILE WE WERE WAITING FOR
THE SURVIVAL DATA TO MATURE, WE
HAD A SECONDARY END POINT OF
BRAIN AS THE FIRST TYPE OF
RECURRENCE.
PATIENTS WITH EGFR MUTANT
DISEASE, ANYONE WITH TARGETED
THERAPY THE BIGGEST CONCERN IS
METASTASES AND TO THE BRAIN.
SO WE'RE LOOKING IN BLUE AS
BRAIN IS THE FIRST SITE OF
RECURRENCE VERSUS ON OSIMERTINIB
IN BLUE VERSUS BRAIN AT THE
FIRST SITE ON CONTROL IN THE
PLACEBO.
YOU CAN SEE THE HAZARD RATIO IS
.24 OR A 76% LESS CHANCE THE
PATIENT IS GOING TO DEVELOP THE
BRAIN AS THE FIRST SITE OF
RECURRENCE.
SO THIS WAS PRETTY GOOD, AND THE
DRUG WAS ALREADY APPROVED SINCE
2020, BUT THEN EVERYONE IS
SAYING WHAT ABOUT SURVIVAL?
NOW AS THE PI OF A TRIAL, A
CLINICAL TRIAL, SURVIVAL HAPPENS
WHEN YOU HAVE CERTAIN EVENTS SO
YOU DON'T WANT TO WISH IT ANY
FASTER THAN YOU HAVE TO, BECAUSE
PEOPLE WILL HAVE TO HAVE THEIR
SURVIVAL EVENT.
BUT IN TIME FOR AS CO2 YEARS
AGO, WE GOT THESE DATA AND THIS
WAS THE SURVIVAL CURVE AND AS
YOU CAN SEE, THE BLUE CURVE ARE
PATIENTS AND THIS IS OVERALL
SURVIVAL NOW, THE BLUE CURVE --
I'M SORRY -- THE BLUE CURVE ARE
THE PATIENTS WHO GOT THE
OSIMERTINIB VERSUS THE YELLOW IS
THE CONTROL, YOU CAN SEE THE A
FIVE YEARS, 88% VERSUS 78%
SURVIVING.
THE HAZARD RATIO .49.
AND YOU KNOW, THE GOAL OF THE
LAST NCI DIRECTOR OR TWO NCI
DIRECTORS AGO WAS 50% OR MORE
IMPROVEMENT IN CANCER SURVIVAL,
I THINK THAT WAS MONICA, SO WE
ACTUALLY HIT THAT IN THIS SMALL
SUBSET OF LUNG CANCER, .49 OR
51% IMPROVEMENT IN OVERALL
SURVIVAL.
SO THIS WAS THE PLENARY AT ASCO
TWO YEARS AGO.
I HAVE A FEW OTHER THINGS TO
TALK ABOUT TODAY SO I'M NOT
GOING TO BELABOR THIS, BUT
ALMOST ALL PATIENTS GOT IN THE
SECOND LINE SETTING AN EGFR TKI,
BUT ONLY ABOUT HALF GOT
OSIMERTINIB.
WHY?
BECAUSE WE DIDN'T FEEL THE
CROSSOVER UNTIL WE HAD THE
RESULTS IN 2020, AT WHICH TIME
ALMOST HALF THE PATIENTS HAD
ALREADY PROGRESSED.
IT WAS WELL TOLERATED, EASY FOR
ME TO SAY, BUT THERE'S ALWAYS
MORE TOXICITY WHEN YOU GIVE A
DRUG, OSIMERTINIB, VERSUS
PLACEBO, BUT YOU CAN SEE ANY
GRADE III TOXICITY, 23% VERSUS
14%.
IF YOU LOOK FOR CAUSALLY
RELATED -- THERE WERE NO DEATHS
IN EITHER ARM.
THERE'S ALWAYS CONCERN WITH
THESE TYROSINE KINASE INHIBITORS
WITH INTERSTITIAL DISEASE SO
THAT WAS REASSURING.
THIS IS NOW BEING DONE FOR OTHER
MUTATIONS.
ALK ARE WE GOING TO NEED --
SOMEONE JUST ASKED AT OUR GRAND
ROUNDS TODAY, ARE WE GOING TO
NEED SEPARATE STUDIES FOR ALL
THESE DRUGS?
PROBABLY NOT.
I THINK WE'LL NEED SMALL STUDIES
LOOKING AT THE TOXICITY AND
FEASIBILITY, BUT I WOULD SAY
THAT IN A FEW YEARS, MY
PREDICTION IS WE'LL BE USING
SPECIFIC ADJUVANT THERAPY FOR
PATIENTS IN A PERSONALIZED WAY
BASED ON THE DRIVER OF THEIR
TUMOR.
GIVEN THAT MOST OF THESE WILL
HAVE ORAL DRUGS.
I'D JUST LIKE TO SORT OF USE
THIS SLIDE, I TRAINED AT MD
ANDERSON WITH JOSH FIDDLER,
ALONG WITH -- ALWAYS SPOKE OF
TUMOR ANGIOGENESIS AND THE
CASCADE.
THE NEW PARADIGM NOW IN CANCER
WHICH IS WONDERFUL IS THAT YOU
DO YOUR BEST SURGERY,
CHEMOTHERAPY, PERHAPS RADIATION
THERAPY, AND THEN YOU ADD
TARGETED THERAPY IN, YOU KNOW,
AS ANOTHER MODALITY, AND YOU
BRING YOUR BEST THERAPIES TO
EARLY DISEASE, PREVENTING
METASTASES TO THE BRAIN, LIVER
AND BONE.
THIS DRUG WAS APPROVED IN 2020.
JUST LAST WEEK, THIS SUBSEQUENT
PAPER CAME OUT IN NATURE.
LOOLOOKING AT RESIDUAL DISEASE N
OSIMERTINIB IN THIS TRIAL.
WE LOOKED AT PLASMA ANALYSIS
USING A TUMOR-DERIVED ANALYSIS
TO LOOK AT CIRCULATING TUMOR
DNA.
SO BASICALLY WE HAD SAMPLES
EVERY THREE WEEKS, EVERY 24
WEEKS AFTER THAT, THEN WE HAD
PLASMA, WE CAN LOOK AT RESIDUAL
DISEASE, WE USE A TEST CALLED
RADAR, WE SEQUENCED THE TUMOR
AND FROM THE TUMOR, WE FOUND NOT
ONLY EGFR BUT THE 20 TO 25 MOST
FREQUENT ABNORMALITIES IN THAT
TUMOR, AND BASICALLY EVERY
PATIENT GETS THEIR OBSERVE SORTF
TEST MADE TO INCREASE
SENSITIVITY.
SO I CAN SHOW YOU QUICKLY SOME
OF THOSE RESULTS.
ONLY 8% OF PATIENTS POST SURGERY
AND CHEMOTHERAPY OR NOT
CHEMOTHERAPY HAD DETECTABLE
MUTATIONS.
ABOUT WHAT YOU WOULD EXPECT IN
EARLY STAGE CANCER.
NOWADAYS THERE ARE MORE TESTS
THAT ARE BEING DEVELOPED.
I KNOW WE'RE LOOKING AT
FRAGMENTATION ASSAYS AND OTHER
THINGS, ACTUALLY LOOKING A BIT
MORE SPECIFIC, BUT YOU CAN SEE
IN STAGE I B WE DIDN'T SEE ANY
MUTATION, ANY CELL-FREE DNA.
IN STAGE TWO, 7%, AND IN STAGE
THREE, WE HAD MORE, 13%.
AND THIS IS VERY INTERESTING.
SO THESE ARE PATIENTS -- THE
PATIENTS WHO HAD DETECTED MRD AT
THE BASELINE.
YOU CAN SEE THERE WERE ONLY 18
HERE, AND THIS IS VERY
INTERESTING SO HERE ARE THE
PATIENTS IN BLUE, THEY GOT
OSIMERTINIB, THEY CLEARED THEIR
CIRCULATING DNA, BUT YOU CAN SEE
AS THEY CAME OFF DRUG AT THREE
YEARS, 36 MONTHS, THEY ALL THEN
BECAME DETECTABLE.
THIS HAS NOT PROGRESSED YET.
THESE TWO PATIENTS PROGRESSED
LOCALLY.
SO NEED TO GET SOME RADIATION.
AND THEN YOU CAN SEE PATIENTS
WHO, OF COURSE, STARTED WITH
DISEASE AND THEN GOT PLACEBO, OF
COURSE THEY ALL PROGRESSED.
THEN THERE'S SOME PATIENTS, OF
COURSE, THAT HAVEN'T PROGRESSED
YET AT ALL.
THE MRD ASSAY WAS 4.7 MONTHS
EARLIER ON THE MEDIAN OF PICKING
UP PROGRESSION VERSUS RADIOLOGY.
SO PRESUMABLY IF WE HAD THINGS
THAT WE COULD DO EARLIER, THIS
FOUR OR FIVE MONTHS AT MEDIAN
COULD MAKE A BIG DIFFERENCE.
SO THE PARADIGM I JUST WANTED TO
SORT OF MAKE IN THE FIRST PART
OF THIS BRIEF OVERVIEW IS WE'RE
MAKING AMAZING PROGRESS WITH
TARGETED THERAPIES.
I SHOWED YOU ONE STORY OF EGFR.
CERTAINLY WE UNDERSTAND HOW TO
USE THOSE DRUGS AND BRING THEM
EARLIER.
BUT I'VE BEEN DOING THIS NOW,
DARE I SAY IT, SINCE 1996.
AND WHILE I'VE TREATED MANY,
MANY PATIENTS WITH EGFR DISEASE,
IS ANYONE TRULY CURED?
PERHAPS SOME OF THOSE PATIENTS
ON THE ODURA TRIAL, WE'LL HAVE
TO SEE HOW THEY'RE DOING EVERY
YEAR WITH LANDMARK ANALYSES.
RESISTANCE IS A BIG ISSUE AND
YOU'LL HEAR MORE ABOUT THAT FROM
KATY AND HER TALK.
IMMUNOTHERAPY IS ANOTHER BIG
PART OF OUR RESEARCH HERE IN OUR
LUNG SPORE.
CERTAINLY WE ALL KNOW THAT THE
IMMUNE SYSTEM IS SPECIFIC.
IT HAS MEMORY AND IT'S ADAPTIVE.
AND THE PARADIGM OF THE TUMOR
CELL AND THE CYTOTOXIC T-CELL,
WE KNOW THAT THE NEOANTIGENS
SHOWN IN RED AND THE CONTEXT OF
THE UNIQUE MHC1 IS RECOGNIZED BY
T-CELL RECEPTOR.
WHEN THAT INTERACTION OCCURS, WE
SEE ACTIVATION OF THE CYTOTOXIC
CD8 POSITIVE T-CELL, BUT IT ALSO
RESULTS IN PD-L1, THE ADAPTIVE
PRODUCTION OF PD-L1 THROUGH
INTERFERON ON THE TUMOR ITSELF
THAT INTERACTS WITH THE
PD-1 RECEPTOR ON THE T-CELL
OFFICE THIS FOS TO TASTE OR
NEGATIVE LOOP.
SO OF COURSE THE BIG REVOLUTION
IN CANCER MEDICINE IN THE LAST
DECADE HAS BEEN THE AVENT OF
THESE PD-1, PD-L1 INHIBITORS
THAT BLOCKS THAT INTERACTION.
IF IT WAS SO SIMPLE, IT WOULD BE
GREAT BUT WE HAVE SO MUCH GOING
ON IN THE MIC MICRO ENENVIRONME.
WE'VE MADE GREAT PROGRESS.
IF YOU LOOK AT THIS, WE'VE MADE
AMAZING PROGRESS IN CANCER
THERAPIES OVER THE LAST YEARS.
WE JUST NEED TO MAKE MORE.
AND I THINK IT'S IMPORTANT THAT
IN THIS TIME WE ALL GET THAT
MESSAGE OUT, THAT WE REALLY ARE
MAKING PROGRESS IN CANCER, AND
CERTAINLY I HOPE THAT WHEN
YOU'RE DONE WITH MY TALK, YOU'LL
SEE IN LUNG CANCER, WE'RE VERY
EXCITED BUT WE HAVE MORE TO DO.
THIS IS THE ONE OF THE FIRST
PATIENTS TREATED AT YALE
ACTUALLY BEFORE I GOT TO YALE.
BY SCOTT GE.
TINGER.
THEY BROUGHT THE TRIAL TO YALE.
SO HERE'S A PATIENT, MAUREEN,
AND SHE ALLOWS US TO USE HER
IMAGE, THIS IS ACTUALLY FROM
SOME OF OUR YALE MATERIALS.
THIS PATIENT HAD WIDELY
METASTATIC LUNG CANCER, SQUAMOUS
LUNG CANCER, NO MUTATIONS IN
SQUAMOUS LUNG CANCER OR IF THERE
ARE, IT'S VERY RARE.
AND WITHIN A COUPLE OF MONTHS
ACTUALLY ON THIS CLINICAL TRIAL,
NIVOLUMAB, YOU CAN SEE HER
DISEASE WENT NEARLY COMPLETELY
AWAY.
SHE HAD TO STOP DRUG AT TWO
YEARS BECAUSE THAT'S THE WAY THE
TRIAL WAS WRITTEN, BUT JUST SAW
HER RECENTLY, SHE'S DOING WELL.
SO THIS IS AN EXAMPLE OF IN
PATITHISPATIENT IS PROBABLY CURE
EVEN GOTTEN VINCE DAVITA TO
AGREE THIS PATIENT IS CURED, BUT
THIS ONLY HAPPENS IN 15% OF THE
PATIENTS.
THIS IS THE ACTUAL ACTUARIAL
SURVIVAL CURVE FROM THAT TRIAL.
YOU CAN SEE SCOTT IN THE UPPER
RIGHT.
IN FIVE YEARS, ABOUT 15% OF
PATIENTS ARE ALIVE.
IT'S THAT TAIL OF THE CURVE
WE'RE TRYING TO MAKE BE BETTER D
BETTER.
AGAIN TIME IS SHORT, BUT THERE'S
BEEN A WHOLE EVOLUTION OF
TRIALS, I KNOW THAT MANY ACROSS
THE WORLD HAVE ALLOWED THIS
WORK, NIH FUNDED HAS DONE TO
LOOK AT TRIALS, LOOKING AT NEW
DRUGS AND NEW IMMUNOTHERAPIES.
WE NOW USE IMMUNOTHERAPY UNLESS
CONTRAINDICATED IN MOST ALL
PATIENTS WITH LUNG CANCER,
EXCEPT THOSE THAT HAVE DRIVER
MUTATIONS BECAUSE FOR THEM WE
KNOW IT'S PROBABLY BETTER TO USE
A TARGETED THERAPY.
WE ALSO KNOW WITH A DRIVER
MUTATION, YOU'RE LESS LIKELY TO
HAVE MANY OTHER MUTATIONS THAT
COULD -- WITH MHC AND RESULT IN
IMMUNE RESPONSE.
FOR THEM WE'LL PROBABLY HAVE TO
WORK WITH VACCINES.
WE ACTUALLY ARE VERY PROUD OF
THIS, OUR GROUP AT YALE, HARRY
AND SARAH WORKING AS A TEAM WITH
VEVERONICA CHANG WHO DOES
RADIOSURGERY.
ABOUT 10 YEARS AGO AFTER WE DID
SOME EARLY TRIALS WITH
PEMBROLIZUMAB, THEY CONTACTED
MERCK AND SAID CAN WE DO AN
INVESTIGATOR INITIATED TRIAL TO
LOOK AT SMALL BRAIN METASTASES.
BECAUSE IF THESE IMMUNOTHERAPIES
WORK SO WELL IN LUNG CANCER, WHY
GIVE RADIATION AND PUT THAT
PATIENT THROUGH ALL THE
COGNITIVE IMPAIRMENT THAT MIGHT
ENSUE?
WHAT IF WE COULD JUST TREAT WITH
THE IMMUNOTHERAPY?
THIS WAS A TRIAL, AND YOU CAN
SEE JUST LOOK AT THE WATERFALL
PLOT, THE BRAIN RESPONSE IS
ORANGE AND THE EXTRA CEREBRAL,
SO THE REST OF THE BODY IS IN
BLUE, AND WHAT YOU CAN SEE IS
YOU CAN SEE THAT THE RESPONSES
IN THE BRAIN ARE ABOUT THE SAME
AS THE RESPONSES SYSTEMICALLY.
NOW WE WERE NERVOUS AND WE WERE
BEING CAREFUL, WE WERE BEING
FOLLOWED BY THE IRB BUT THEY NOW
DISAPPEARED.
WE NOW KNOW YOU CAN USE
IMMUNOTHERAPY IN PATIENTS WITH
BRAIN METS AS LONG AS YOU FOLLOW
IT CLOSELY.
THEY ACTUALLY CALLED HARRIET
WHEN JIMMY CARTER IN ATLANTA HAD
METASTATIC MELANOMA TO THE
BRAIN, AND WE SHARED OUR
PROTOCOL WITH THE GROUP DOWN
THERE AND LUCKY HE LIVED TO 100,
10 YEARS, WITH MELANOMA.
SO FRONT LINE TRIALS, WHAT
BROUGHT THE AGENTS TO THE FRONT
LINE WERE BIOMARKERS,
BIOMARKERS, BIOMARKERS.
SO IF YOU LOOK AT PD-L1 AS A
BIOMARKER AND JUST TAKE THOSE
PATIENTS, YOU CAN GET A 31.9%
SURVIVAL AT FIVE YEARS IN LUNG
CANCER.
RIR I SHOWED THOSE CURVES THAT
WENT DOWN TO HE BOTTOM AT THE
BEGINNING, THIS WAS PROGRESS.
STILL LET'S NOT KID OURSELVES,
AT THREE YEARS, 28% OF PATIENTS,
EVEN WITH A HIGH PD-L1, STILL
PROGRESS.
WE HAVE A LOT OF WORK TO DO.
HOW AM I DOING ON TIME, KATY?
>> FINE.
>> KATY IS RIGHT NEXT TO ME SO I
HAVE TO IK MA MAKE SURE I DON'TO
OVER TIME.
VERY IMPORTANT TO USE
BIOMARKERS.
HERE YOU CAN SEE THIS IS
PRODUCED BY DAVID RIM, ONE OF
THE CO-LEADERS OF OUR LUNG SPORE
PATHOLOGY CORE.
NOW I GUESS SEVEN, EIGHT YEARS
AGO.
WE HAVE PDL1, WHICH BINDS TO
PD-1 AS A BIOMARKER BUT IT'S NOT
THE BEST BECAUSE IF IT'S
NEGATIVE, IT DOESN'T MEAN MUCH,
BECAUSE HERE'S A PIECE OF TUMOR,
WE ACTUALLY DID THIS HERE AT
YALE TO MAKE THE POINT.
ONE AREA THAT'S STONE COLD
NEGATIVE FOR PD-L1 USING TWO
DIFFERENT ANTIBODIES AND ANOTHER
AREA THAT'S POSITIVE, AND YOU
CAN SEE THE DAB STAINING HERE,
AND DIFFERING LEVELS OF
POSITIVITY, AGAIN, DIFFERENT
ANTIBODIES.
SO THE SELECTION, WHERE YOU
STICK YOUR NEEDLE CAN MAKE A
DIFFERENCE.
NOW PEEL PEOPLE ARE DOING
THREE-DIMENSIONAL, THERE ARE ALL
SORTS OF WAYS AROUND THIS NOW.
SO AI AND DIGITAL PATHOLOGY, I
THINK WILL HELP IN THE FUTURE.
BUT HERE ON THE RIGHT, YOU CAN
SEE, WHERE DO YOU MEASURE IT?
SO THIS IS A FLUORESCENCE, GREEN
IS CYTOKERATIN, SO THIS IS
TUMOR, THE BLEUP BLUE IS DAPI, E
NUCLEI, AND THE RED IS PD-1 SO
YOU CAN MEASURE IT IN BOTH
PLACES.
IS IT 10%, 20%, 30%?
SO WHAT ARE THE CUTOFFS?
HOWL IS THE TUMOR AFFIXED?
WHEN DO YOU GET THE TUMOR?
THERE ARE LOTS OF UNKNOWNS.
BUT FOR THE MOST PART, A HIGH
PD-L1 USUALLY DOES MEAN THE
PATIENT IS MORE LIKELY TO
RESPOND BUP A NEGATIVE DOES NOT.
YOU DON'T WANT TO KEEP THAT
AMAZING THERAPY FROM THOSE
PATIENTS SO THAT'S SOMETHING
WE'RE VERY MUCH WORKING ON.
KATY WILL TALK MORE ABOUT THIS I
WAS VERY FORTUNATE THAT SHE AND
SCOTT GETTINGER -- YOU'VE HAD
THIS FOR 15 YEARS NOW OR MORE, A
REBIOPSY PROGRAM.
SO AT YALE, WE HAVE -- AND IT'S
BEEN A BIG PART OF OUR SPORE AND
OTHER R01 AND OTHER FUNDED
EFFORTS, U GRANTS, BECAUSE WE
HAVE ALL THIS TISSUE.
WHEN A PATIENT COMES IN EITHER
ON IMMUNOTHERAPY OR TARGETED
THERAPY, WE PUT THEM ON THIS
REBIOPSY PROTOCOL, SO UNDER
CONTROLLED CONDITIONS, WE CAN
GET A REBIOPSY, AND WE ALSO THEN
GO OUT AND GET THEIR
PRE-TREATMENT SPECIMENS SO THAT
WE CAN COMPARE.
AND WE ACTUALLY USE THIS
MECHANISM FOR -- THIS WAS
ACTUALLY AN INDUSTRY-FUNDED
TRIAL THAT WE DID WITH IRA
MELMAN AND DAN CHEN AND
GENENTECH, BUT WE HAD THE
INFRASTRUCTURE IN PLACE TO GET
PRE AND POST BIOPSIES.
THIS IS WHY THEY'RE SO
IMPORTANT, BECAUSE IT BRINGS
SCIENCE TO THE CLINIC.
HERE YOU CAN SEE A PATIENT WITH
LUNG CANCER FROM THE FIRST PHASE
ONE TRIAL OF ATEZOLIZUMAB.
THE PATIENT COMPLETELY
RESPONDED.
AND WITH PRE AND POST BIOPSIES
THAT WERE DONE, THIS IS AN 8 OR
9 SITE TRIAL THAT DID THE
BIOPSIES BUT WE DID MANY AT
YALE, HERE'S CD8, YOU CAN SEE
THE ADAPTIVE IMMUNE RESPONSE.
THIS PATIENT RESPONDED WITH A
LOT OF PD8 CELLS.
YOU CAN SEE ON THE RIGHT, THIS
IS AN IMMUNE CHIP LOOKING AT
EXPRESSION OF A NUMB BERL OF
T-CELL MARKERS, AND PREIS GREEN
AND -- TREATMENT IS YELLOW.
YOU CAN SEE THE DIFFERENT IN A
AND B, THE CELLS MAKE TO
PERFORATE INTO THE TEU ARE MO.
THIS IS AN EXAMPLE OF A VERY
POSITIVE ADAPTIVE IMMUNE
RESPONSE.
BUT AGAIN, ONLY 15, 20% IN THOSE
THAT DON'T RESPOND, WE KNOW WE
SEE THESE PATTERNS OF RESULTS
AND THIS IS PUBLISHED ACTUALLY
NOW EXACTLY 10 YEARS AGO.
YOU CAN SEE SOME TUMORS DON'T
HAVE ANY CD8 POSITIVE CELLS TO
BEGIN WITH, AND NONE AFTER THE
TREATMENT WITH THE IMMUNE
THERAPY, WE CALL THAT IMMUNE
IGNORANCE.
THESE TUMORS DON'T CARE THAT
YOU'RE TREATING THEM WITH IMMUNE
THERAPY.
A NON-FUNCTIONAL IMMUNE RESPONSE
WHERE YOU MIGHT GET A FEW MORE T
CELLS BUT IF YOU LOOK AT THE
IMMUNE CHIP, IT'S TOTALLY FLAT.
THIS IS SOMETHING THAT'S NOW
PART OF OUR MOST RECENT I GRANT
APPLICATION, EXCLUDED INFILTRATE
WHERE WE ACTUALLY HAVE TUMORS
WHERE THE CELLS ACTUALLY LINE UP
BUT THEY DON'T GET TO THE TUMOR.
THEY'RE EXCLUDED.
AND IT'S QUITE LIKELY THAT THERE
ARE FACTORS -- THERE ARE FACTORS
WITHIN THE MICROENVIRONMENT THAT
ARE KEEPING THIS FROM HAPPENING.
THE FIELD IS MOVING TO
NEOADJUVANT THERAPY.
IF YOU TREAT THE TUMOR BEFORE
IT'S OUT, YOU HAVE MUCH MORE
T-CELL AND OTHER IMMUNE CELLS IN
PLACE, SO THAT'S WHERE ALL THIS
IS GOING.
AND I'M JUST GOING TO INTRODUCE
THIS TO SAY THAT THERE HAVE BEEN
A NUMBER OF TRIALS THAT HAVE
LOOKED AT PATHOLOGIC COMPLETE
RESPONSE, AND HERE YOU CAN SEE
17% PATHOLOGIC COMPLETE
RESPONSES WHEN PATIENTS GET
CHEMO, I KNEW KNOW THERAPY
BEFORE SURGERY VERSUS 4.3% FOR
CONTROLLED CHEMOTHERAPY.
SO THIS IS WHERE IT'S GOING.
THIS IS A LITTLE REVIEW ARTICLE
WE WROTE HERE WHEN IMMUNOTHERAPY
MEET SURGERY.
SO LUNG CANCERS BECOME THE
DISEASE WHERE YOU NEED TO HAVE
THIS TUMOR BOARD WHERE EVERYONE
SITS AROUND, REVIEWS THE
RESULTS.
I ALREADY SHOWED YOU EARLY ON,
RESULTS FROM THE EGFR MUTATIONS,
SO WE NEED TO KNOW WHO HAS AN
EGFR MUTATION, WE NEED TO KNOW
BHO HAS PDL1 POSITIVE, WE NEED
TO KNOW ANYTHING ELSE THAT'S
GOING ON IN THAT TUMOR AND WE
HAVE TO USE THAT APPROACH.
TUMOR BOARDS ARE ESSENTIAL TO
BRING THE NEWEST SCIENCE TO THE
CLINIC, AND THIS IS WHAT THE
YALE TUMOR BOARD LOOKS LIKE,
BECAUSE WE'RE ALL DOING IT BY
ZOOM NOW, BUT THE PEOPLE THAT
HAVE TO GO SEE PATIENTS NEXT,
THIS IS OUR PULMONOLOGISTS, COME
IN.
BUT ZOOM IS GREAT.
WE'RE ON ZOOM RIGHT NOW.
IT ALLOWS US TO GET MORE PEOPLE
INVOLVED.
WE SEE PATIENTS HERE THE A YALE
IN CONNECTICUT AT 15 SITES SO
EVERYONE CAN JOIN THE TUMOR
BOARD.
SO A FEW NOTES ABOUT THE FUTURE.
WE NEED TARGETED IMMUNOTHERAPY.
THIS IS OUR PASSION HERE.
WE HAVE THE PATHOLOGY, WE HAVE
THE DRUGS.
THOUSANDNOW WE HAVE TO PULL IT L
TOGETHER.
BUT WHAT WE WANT TO UNDERSTAND
IS WE WANT TO UNDERSTAND IMMUNE
RESISTANCE.
ONE OF THE PROJECTS ON OUR LUNG
SPORE HAS BEEN WITH CHEN TO
TARGET IMMUNE RESISTANCE WITH A
NEW CHECKPOINT KNOWN AS
SIGLEC15, WHICH ACTUALLY CAME
OUT OF A SCREEN LOOKING FOR
HOMOLOGUES TO PD-L1.
IT WAS ACTUALLY INTERESTING, A
SHOTGUN APPROACH, MULTIPLE
MEMBRANE GENES, MORE THAN 6500
PROTEINS WERE PUT INTO A T-CELL
REPORTER SYSTEM LOOKING FOR
INHIBITION OF T-CELL FUNCTION.
AND FROM THAT, LIEPING FOUND
SIGLEC15 WHICH IS HOMOLOGOUS TO
PD-L1.
SIGLEC15 IS NOW ON THE SURFACE
OF MACROPHAGES, TUMORS, AND IT
ACTUALLY ALSO U.S. SPRESES SUPPF
IT HAS PD-L1, IT MIGHT HAVE
SIGLEC15.
WHILE INTERFERON UPGRADES PD-L1,
IT ACTUALLY DOWN REGULATES
SIGLEC15.
SO THOSE TWO MORES THAT ARE LOW
INTERFERON, THEY MIGHT BE
TARGETS FOR SIGLEC15.
SO THIS WAS A PHASE ONE STUDY
THAT WAS LED BY PAT LARUSO AND
TEAM.
WE CONDUCTED IT AND YALE AND
THESE ARE PATIENTS WITH LUNG
CANCER.
YOU CAN SEE TWO PATIENTS SHOWN
HERE, THE RED IS A CR AND THE
YELLOW IS A PR.
TWO PATIENTS HAD RESPONSE, IN
THE REFRACTORY SETTING.
HERE YOU CAN SEAL AN EXAMPLE OF
THE PATIENT WHO HAD A TUMOR
REFRACTORY TO A PD-L1 INHIBITOR
WHO HAD A NICE RESPONSE.
THIS WAS A PHASE ONE STUDY FIRST
IN HUMAN.
THEN WE DID AN IIT AS PART OF
OUR LUNG SPORE WHICH IS NOW
COMPLETING THIS YEAR.
WE HAVE AN AMAZING TEAM, AS I'M
GETTING TO THE END OF MY TALK
THAT I'M PRESENTING THE WORK OF
SO MANY PEOPLE, I'M VERY
FORTUNATE TO BE HERE.
KATY IS BY MY SIDE, WE LEAD THIS
TOGETHER.
YOU CAN SEE PAT LARUSO, CURRENT
AACR PRESIDENT WHO LEADS OUR
PHASE ONE GROUP I'M SURE KNOWN
TO MANY, THERE'S LIEPING, KATIE
COURIC WAS VISITING SO HE PUT ON
A TIE.
THIS IS THE ENTIRE PHASE 1 TEAM.
WE REALLY HAVE AN AMAZING TEAM
AND THE TEAM TAKES CARE OF THESE
PATIENTS FROM THE LAB TO THE
CLINIC.
BUT THIS WAS OUR INVESTIGATOR
INITIATED TRIAL, AND WE DID THIS
WITH SUPPORT FROM THE SPORE
GRANT WITH SUPPORT FROM THE
COMPANY, TWO COMPANIES, MERCK
AND A COMPANY CALLED NECCURE.
WE'RE IN THE PROCESS OF PUTTING
TOGETHER THE MANUSCRIPT NOW,
WHERE WE ACTUALLY TOOK PATIENTS
WHO HAD HAD PRIOR PD-L1 AND WE
TREATED THEM WITH EITHER NC318
WHICH IS AN ANTIBODY AGAINST
SIGLEC15, OR THE ANTIBODY IN
COMBINATION WITH PEMBROLIZUMAB.
FOR SAKE OF THIS SHORT TALK,
WE'VE SEEN RESPONSES.
HERE'S A PATIENT WHO WAS
REFRACTORY, THEY HAD A RESPONSE.
HERE'S ANOTHER PATIENT WITH A
RESPONSE.
HERE'S A PATIENT WHO GOT
MONOTHERAPY WITH A RESPONSE.
HERE'S A PATIENT WITH A COMBO
WITH RESPONSE.
WHAT WE'RE IN THE PROCESS OF
DOING IS USING RNA SEQ, USING
IMMUNOHISTOCHEMISTRY TO
UNDERSTAND WHO RESPONDED AND
WHY.
STAY TUNED.
LUNG MAP WAS A LABOR OF LOVE
WHICH I SHARED FOR ABOUT A
DECADE.
THE IDEA BEHIND LUNG MAP, AND IT
ALL BEGAN AT AN NCI MEETING IN
2012, FOLLOWED BY FRIENDS OF
CANCER RESEARCH MEETING, ELLEN
SIEGEL AND TER TEAM LATER THAT
YEAR, WAS THE IDEA THAT ALL THE
COOPERATIVE GROUPS AS PART OF
THE NEW NATIONAL CLINICAL TRIAL
NETWORK WOULD WORK TOGETHER AND
WE HAD SUCH AMAZING SUPPORT FROM
NCI, JEFF ABRAMS, KIM DOROSHOW,
MEGAN AND HER TEAM, WE STILL
CONTINUE TO HAVE AMAZING
SUPPORT.
ALL THE COOPERATIVE GROUPS
WORKING TOGETHER, GUIDANCE FROM
THE FDA, AND USING THE FNIH AS A
COMMON BROKER IN THIS
PUBLIC-PRIVATE PARTNERSHIP
WITHIN INDUSTRY.
THE REASON I WANT TO SHOW YOU
THIS IS AGAIN ANOTHER TEAM, THIS
IS A MEETING WE HAD ABOUT FOUR
OR FIVE YEARS AGO AT ELLEN
SIEGEL'S OFFICE, DOWNTOWN
WASHINGTON.
IT REALLY IS A TEAM EFFORT.
BUT THE IDEA WAS, IF YOU ASK
WHAT WE NEED NOW IN THIS TIME,
WHICH IS ARGUABLY -- THEY'RE
ALWAYS TOUGH TIMES BUT THIS IS A
TIME WHERE WE ALL HAVE TO PULL
TOGETHER, I THINK COLLABORATION
IS KEY.
SO WE HAD A COMMON SCREENING
PROTOCOL, TRIAL OPENED AT 700
SITES WHERE PATIENTS COULD GET
SCREENED WITH FOUNDATION
MEDICINE PROFILING FOR DIFFERENT
MUTATIONS.
WE COULD TEST WHAT WE CALLED THE
BIOMARKER-DRIVEN SUBSTUDY,
DIFFERENT MUTATIONS TO SEE IF
DRUGS THAT TARGET THOSE
MUTATIONS WORK.
YOU KNOW WHAT?
MANY OF THESE TRIALS WERE
NEGATIVE.
THEY WERE IMPORTANT NEGATIVE
TRIALS, BUT WHEN YOU USE -- IT
DIDN'T CAUSE ENOUGH ACTIVITY.
BUT NOW WE'RE ACTUALLY USING
THIS FOR WHAT WE CALL THE
NON-MATCHED TRIALS TO TEST
IMMUNOTHERAPY COMBINATIONS.
AND THIS IS AMAZING, LOOK AT ALL
THESE PATIENTS TREATED, ALL THIS
TISSUE SITS THERE IN COLUMBUS,
OHIO AT THE BIOBANK.
THIS IS ALL NOW AVAILABLE FOR
STUDY.
AND IT IMPROVED DIVERSITY, THIS
PAPER SHOWS THAT PATIENTS FROM
ALL OVER THE COUNTRY COULD GET
ON THIS BECAUSE THEY'RE TREATED
AT THE POINT OF CARE IN A TRIAL
THAT PROVIDES THEM THESE NEW
DRUGS.
THERE WAS A VERY NICE POSITIVE
TRIAL OUT OF WORK I INITIATED.
SOME OF YOU MIGHT KNOW IT AS
PRAGMATICA.
THIS WAS THE PRE-PRAGMATICA
WHERE WE HAD A HAZARD RATIO OF
.69, THE BLEUL CURVE -- THE RED
IS DEALER'S CHOICE CHEMOTHERAPY.
THESE ARE ALL PATIENTS WHO
FAILED IMMUNOTHERAPY BUT HAD
BEEN ON IMMUNOTHERAPY FOR AT
LEAST 12 WEEKS.
SO THEY WEREN'T STONE COLD
NEGATIVE TO THEIR RESULTS.
THEY HAD SOME ACTIVITY, AND THIS
TRIAL WAS POSITIVE BUT IT WAS A
ONE-SIDED P VALUE, ONLY A SMALL
PHASE TWO.
WE TALKED ABOUT DOING A BIG
PHASE THREE.
NO ONE WAS INTERESTED, THE
COMPANIES WEREN'T INTERESTED,
BUT THEN WE TALKED ABOUT PRAGUE
MATT KA.
SO THE IDEA WAS TO DO A TRIAL
JUST LOOKING AT SURVIVAL.
THAT'S SWAG 2302.
SO USING REAL WORLD DATA IN A
PROSPECTIVE WAY.
THIS WAS PROSPECTIVE, YOU
PRESPECIFY -- SELECTIVE
MONITORING.
THIS TRIAL IS ONLY LOOKING AT
SURVIVAL AS AN END POINT, YOU
DON'T NEED TO DO PET SCANS, YOU
DON'T NEED TO DO CAT SCANS.
REALLY TRYING TO LIMIT WHAT'S
BEING DONE SO IT CAN BE DONE
QUICKLY, ELEGANTLY IN THE
COMMUNITY SETTING, AND THIS
TRIAL, IT WILL BE UPDATED AT
ASCO, WE HEARD IT JUST GOT
ACCEPTED TO ASCO TODAY.
LOOK AT THIS ACCRUAL.
THIS IS A COOPERATIVE GROUP
TRIAL.
THIS IS 30, 44, IN A YEAR AND A
HALF THAT INCLUDED THE FULL 708
PATIENTS WITH A VERY NICE
DIVERSE POPULATION TOO, BLACK OR
AFRICAN AMERICAN, ALMOST 15%.
SO I'M AT THE END NOW.
I WANT TO TURN IT OVER TO KATIE.
BUT I TALKED QUICKLY BUT I HOPE
YOU'VE SHARED MY PASSION,
EXCITEMENT AND THE DATA.
AND WE NEED TO GET THESE DATA
OUT THERE.
WE ARE MAKING A DIFFERENCE.
CAN WE CURE METASTATIC LUNG
CANCER?
IN SOME CASES WITH
IMMUNOTHERAPY.
AND I SHOWED YOU 12-PLUS YEAR
SURVIVORS.
TREATMENT CAN BE WELL TOLERATED
AND RETREATMENT IS POSSIBLE.
I DIDN'T SHOW YOU THAT BUT IT
IS.
THE PROBLEM IS WE HAVE --
KNOWING IN ADVANCE OF WHO WILL
BE THOSE PATIENTS.
DO WE NEED TO PERSONALIZE
IMMUNOTHERAPY?
I WOULD SAY THAT'S THE GOAL.
WE HAVE SPENT PERSONALIZED --
IT'S TIME TO DO THE SAME FOR
IMMUNOTHERAPY.
IT REQUIRES BIOMARKERS AND
BETTER COMBO, WE NEED MORE
SCIENCE, INNOVATIVE TRIAL
DESIGN, COLLABORATION AND
PUBLIC-PRIVATE PARTNERSHIPS
WHERE THE FUTURE IS NOW.
THIS IS OUR CURRENT SPORE
APPLICATION.
WE'VE MORPHED A BIT, WE HAVE A
NEW DRUG THAT TARGETS PLA T2 10
WHICH IS ONE OF THOSE T-CELL
EXPLORERS I MENTIONED EARLIER
WHERE WE'RE LOOKING AT PRECISION
APPROACHES.
KATIE IS GOING TO TELL YOU ABOUT
THAT NOW, AND WE'RE VERY
INTERESTED IN WAYS TO TARGET
METASTASES INCLUDING THE BRAIN.
IT'S BEEN A PLEASURE TO BE HERE
TODAY.
MANY OF THE LUNG COMMUNITY WERE
HERE AT YALE LAST JUNE 12TH AND
13TH.
WE HAD A WONDERFUL MEETING THAT
KATIE AND I ORGANIZED WITH N.C.
DEPI, OUR SPORE ADMINISTRATOR,
AND WE HAD ALL THESE PEOPLE FROM
ALL OVER THE UNITED STATES, SOME
INTERNATIONAL, WORKING ON LUNG
CANCER, ALL AFFILIATED WITH THE
NCI FUNDED RESEARCH.
THANK YOU ALL VERY MUCH.
>> THANK YOU.
THANK YOU, ROY, FOR THAT AMAZING
PRESENTATION.
SO I'M GOING TO SHARE MY SLIDES
NOW.
AND TELL YOU ABOUT SOME OF THE
SCIENTIFIC EFFORTS THAT GO ALONG
WITH SOME OF THE AMAZING
PROGRESS THAT ROY HAS JUST TOLD
YOU ABOUT IN THE CLINICAL
EFFORTS.
I'M JUST GOING TO SHARE MY
SLIDES.
LET ME PUT THEM ON SLIDE SHARE.
ONCE I HAVE THEM, THEN I CAN GO
AHEAD AND GET STARTED.
SO THESE ARE MY DISCLOSURES.
SO AS YOU HEARD FROM ROY, LUNG
CANCER IS THE LEADING CAUSE OF
CANCER DEATHS IN THE UNITED
STATES AND WORLDWIDE, BUT WE DO
HAVE SOME REALLY GOOD NEWS IN
THAT WE ARE SEEING THAT THE
MORTALITY FROM LUNG CANCER HAS
DECLINED, AND I THINK SOME OF
THE NUMBERS ARE PRETTY STRIKING.
IF WE LOOK AT THE NUMBER OF LUNG
CANCER DEATHS TODAY COMPARED TO
20 YEARS AGO, WE SEE THAT THERE
ARE ABOUT 40,000 FEWER LUNG
CANCER DEATHS A YEAR NOW THAN
THERE WERE 20 YEARS AGO.
SO REALLY THERE HAS BEEN
TREMENDOUS PROGRESS IN ADVANCING
OF CARE OF PEOPLE LIVING WITH
LUNG CANCER.
THIS IS BECAUSE THERE REALLY,
OVER THE PAST TWO DECADES, HAVE
BEEN TREMENDOUS ADVANCES IN OUR
UNDERSTANDING OF BIOLOGICAL
PROCESSES THAT ARE INVOLVED IN
LUNG CANCER, AND ALSO REALLY THE
INTEGRATION OF THIS KNOWLEDGE OF
LUNG CANCER BIOLOGY WITH STUDIES
OF CLINICAL SPECIMENS AND
STUDIES OF DATA FROM PATIENTS
WITH LUNG CANCER.
THESE TOGETHER, BY INTEGRATING
THESE DATASETS, WE'VE REALLY
BEEN ABLE TO HAVE LEAD TO
DISCOVERIES THAT HAVE LED TO
CLINICAL TRIALS AND NEW
THERAPEUTIC APPROACHES FOR
PATIENTS, SOME OF WHICH YOU
HEARD ABOUT FROM ROY EARLIER
DURING HIS PRESENTATION.
STO WHAT ARE SOME OF THESE
INSIGHTS AND WHAT ARE SOME OF
THESE ADVANCES?
I THINK ONE OF THE THINGS THAT
REALLY HAS EMERGED OVER THE PAST
TWO DECADES IS THAT WHEN WE
THINK OF LUNG CANCER, WE CAN'T
REALLY THINK ABOUT IT AS ONE
ENTITY.
THERE ARE MULTIPLE DIFFERENT
HISTOLOGICAL SUBTYPES AND THERE
ARE MULTIPLE DIFFERENT MOLECULAR
SUBTYPES.
SO WE THINK OF NON-SMALL CELL
LUNG CANCER WHICH REALLY
REPRESENTS OTHER HISTOLOGICAL
SUBCATEGORIES INCLUDING LARGE
CELL CARCINOMA, SQUAMOUS CELL
CARCINOMA AND LUNG
ADENOCARCINOMAS, WHICH LUNG
ADENOCARCINOMAS ARE THE MOST
COMMONLY OBSERVED HISTOLOGICAL
TYPE OF LUNG CANCER.
LUNG CANCER ALSO REPRESENTS
ABOUT 15% OF ALL LUNG CANCER
CASES.
SO WHEN WE TAKE LUNG
ADENOCARCINOMAS, ONE OF THE
THINGS THAT HAS HAPPENED OVER
THE PAST TWO DECADES, AND THIS
REALLY IS IN PART BECAUSE OF THE
STUDIES THAT HAVE GONE ON TO
REALLY UNDERSTAND, TO SEQUENCE
THE CANCER GENOMES AND TO REALLY
UNDERSTAND THE MOLECULAR BASES
OF THESE TUMORS IS THAT NOW WE
KNOW THAT THERE ARE SPECIFIC
MOLECULAR ALTERATIONS, GENETIC
MUTATIONS THAT ARE PRESENT IN
MANY LUNG ADENOCARCINOMAS THAT
ARE PRESENT IN GENES WHICH
REALLY LEADS TO DRIVE
TUMORIGENESIS IN THOSE CONTEXTS.
AND SO ROY TOLD YOU ABOUT SOME
OF THOSE WHEN HE SPOKE ABOUT THE
EGF RECEPTOR MUTATIONS IN LUNG
CANCER, AND WE'LL TALK ABOUT
THOSE ALSO A LITTLE BIT MORE
EXTENSIVELY IN THIS
PRESENTATION, BUT HERE YOU CAN
SEE IF WE LOOK AT THIS CHART
HERE, YOU CAN SEE THAT THE EGF
RECEPTOR MUTATIONS IN THE
EPIDERMAL GROWTH FACTOR
RECEPTOR, I'LL TELL YOU A LITTLE
ABOUT THAT IN A LITTLE WHILE,
THOSE ARE QUITE COMMONLY
OBSERVED IN ADENOCARCINOMAS AS
ARE MUTATIONS IN THE KRAS
ONCOGENE, AND THEN THERE ARE A
NUMBER OF OTHER GENES WHERE
MUTATIONS ARE FOUND IN THESE
SORT OF SMALLER SLICES OF THIS
PIE CHART.
YOU CAN SEE THEM LISTED BELOW.
ONE OF THE REALLY IMPORTANT
THINGS TO THINK ABOUT IS THAT
WITH THIS KNOWLEDGE OF THESE
SPECIFIC ALTERATIONS AND THE
KNOWLEDGE THAT THESE MUTATIONS
THEN DRIVE LUNG CANCER
TUMORIGENESIS, IN PARALLEL,
THERAPIES WERE DEVELOPED THAT
COULD COUNTERACT THE ONCOGENIC
ACTIVITY OF THESE DIFFERENT
VARIANTS.
SO WE'VE SEEN SOME TREMENDOUS
ADVANCES OVER THE PAST COUPLE OF
DECADES BECAUSE AS A RESULT OF
THESE OBSERVATIONS, AND HERE YOU
CAN SEE THIS TIMELINE OF FDA
DRUG APPROVALS, OF DRUGS WITH
UNIQUE MECHANISMS OF ACTION THAT
HAVE HAPPENED OVER THE PAST FEW
YEARS.
I'LL SHOW YOU ACTUALLY SOME
OTHER TIMELINES AND OTHER GRAPHS
THAT REALLY CAN HIGHLIGHT HOW
THESE AGENTS TARGET DIFFERENT
MOLECULAR SUBSETS OF LUNG CANCER
BUT YOU CAN SEE HERE IN BLUE,
THESE ARE ALL TARGETED THERAPIES
AND AS WELL, WHAT HAS HAPPENED
DURING THESE PAST COUPLE OF
DECADES IS THIS HAS GONE HAND IN
HAND WITH THE DEVELOPMENT OF
IMMUNOTHERAPIES AND THOSE ARE
SHOWN HERE IN YELLOW HERE.
I THINK THIS IS HIGHLIGHT IN A
SLIGHTLY DIFFERENT WAY, BUT ALSO
MORE EXTENSIVELY FOR SOME OF THE
DIFFERENT MOLECULAR SUBSETS OF
LUNG ADENOCARCINOMAS THAT HARBOR
DIFFERENT GENETIC ALTERATIONS.
YOU CAN SEE HERE FOR EXAMPLE
TUMORS WITH EGFR MUTATIONS,
THESE ARE ALL OF THESE DIFFERENT
TARGETED THERAPIES AND APPROVALS
THAT HAVE BEEN DEVELOPED OVER
THE PAST FEW YEARS FOR TUMORS
THAT HARBOR EGF RECEPTOR
MUTATIONS, ALL THESE GREEN
BOXES.
THERE ALSO ARE TUMORS THAT HAVE
REARRANGEMENTS IN THE ANAPLASTIC
LYMPHOMA -- HERE IN ORANGE ARE
BOXES INDICATING AGENTS THAT
WERE APPROVED DURING THIS TIME
FRAME FOR -- LUNG CANCERS.
SO REALLY EXPLOSION OF THERAPIES
THAT HAVE BEEN DEVELOPED AS A
RESULT OF THESE FINDINGS AND
THESE MOLECULAR ANALYSES OF THE
TUMORS.
I REALLY LIKE TO SHOW THIS CHART
FROM THE LUNG CANCER RESEARCH
FOUNDATION WHICH SHOWS IF WE
LOOK AT LUNG CANCER, THESE FDA
DRUG APPROVALS OVER THE YEARS,
OVER THE DECADES, AND YOU CAN
SEE THAT THERE REALLY HAS BEEN A
REVOLUTION, I'D SAY, SINCE THE
EARLY 2000s WITH THE ADVENT OF
TARGETED THERAPIES, MANY OF THEM
APPROVED OVER THE PAST TWO
DECADES, AND YOU CAN SEE THOSE
ARE REPRESENTED BY THESE BLUE
AND WHITE PILLS HERE, AND THEN
IMMUNOTHERAPIES ALSO REPRESENTED
HERE BY THESE HELICES.
SO REALLY PARADIGM SHIFT IN THE
USE AND THE TREATMENT OF LUNG
CANCER.
SO THIS IS ALL WONDERFUL, WE'VE
TOLD YOU ABOUT ALL THESE NEW
THERAPIES, WE'VE TOLD YOU ABOUT
ALL OF THESE ADVANCES OF
DECREASES IN LUNG CANCER
MORTALITY.
SO HAND IN HAND WITH THAT GOOD
NEWS, HOWEVER, WE REALLY ALSO DO
HAVE TO POINT OUT THAT THERE IS
A MAJOR CHALLENGE IN THE FIELD
THAT REALLY IS HAMPERING THE
ABILITY TO CURE PATIENTS WITH
METASTATIC LUNG CANCER WITH
THESE TYPES OF THERAPEUTIC
APPROACHES.
AND THAT IS BECAUSE TUMORS CAN
BECOME RESISTANT TO THERAPY.
AND SO HERE IF WE HAVE A TUMOR,
THIS IS A TUMOR ILLUSTRATED HERE
PRE-TREATMENT, WE GIVE IT A
THERAPY, WHETHER IT BE AN
IMMUNOTHERAPY OR TARGETED
THERAPY, FOR EXAMPLE.
IF THE TUMOR DOESN'T SHRINK AT
ALL, THAT'S WHAT'S CALLED
PRIMARY RESISTANCE.
THE TUMOR CAN ALSO SHRINK AND
RESPOND INITIALLY BUT THEN GROW
OUT AGAIN.
BECAUSE IT DEVELOPS SECONDARY OR
ACQUIRED RESISTANCE.
AND HERE JUST TO ILLUSTRATE FOR
EXAMPLE THAT ACQUIRED RESISTANCE
IS COMMON BOTH TO TARGETED
THERAPIES AND TO I
IMMUNOTHERAPIES.
YOU CAN SEE HERE IN THE CONTEXT
OF KRAS G12C-DRIVEN LUNG TUMORS,
WE HAVE TUMORS THAT ARE
PRE-TREATMENT, YOU CAN SEE IN
THESE SCANS, YOU HAVE THE
TUMORS.
THESE TUMORS ARE TREATED WITH A
KRAS -- TARGETED THERAPY THAT
TARGETS KRAS DIRECTLY.
THE TUMORS SHRINK BUT THEN
EVENTUALLY THE TUMORS COME BACK.
EVEN HERE IN THE CONTEXT OF
IMMUNOTHERAPIES, YOU CAN SEE
THAT SORT OF THE NUMBER OF
PATIENTS AT RISK OF RELAPSE --
OVER TIME, WHEN PATIENTS DEVELOP
PROGRESSIVE DISEASE, EVEN ON
IMMUNOTHERAPY.
SO ACQUIRED RESISTANCE IS A
MAJOR CHALLENGE.
SO WHAT I'D LIKE TO DO IS TALK
TO YOU A LITTLE BIT ABOUT SOME
OF THE WAYS IN WHICH WE'RE
STUDYING RESISTANCE, THINKING
ABOUT RESISTANCE, FIRST OF ALL
IN THE CONTEXT OF EGFR LUNG
CANCER, LABORATORY HAS SERVED AS
A PARADIGM FOR UNDERSTANDING
RESISTANCE TO TARGETED
THERAPIES.
SO I'LL ALSO TOUCH ON A LITTLE
BIT SOME OF THE WORK IN THE
COUCONTEXT OF IMMUNOTHERAPIES.
SO FIRST OF ALL WHEN WE THINK OF
EGFR RECEPTOR DRIVEN LUNG
CANCER, EGF RECEPTOR IS RECEPTOR
TYROSINE KINASE SO IT'S ON THE
CELL SERVICE, YOU CAN SEE HERE
THIS IS THE NUCLEUS, THIS BLUE
CIRCLE, AND E TBGF RECEPTOR NEEA
LIGAND THAT HAS TO BIND EGF
RECEPTOR TO BRING IT TOGETHER,
BRING DIFFERENT MONOMERS OF EGF
RECEPTOR TOGETHER AND LEAD TO
DIMERIZATION AND THEN ACTIVATION
OF EGF RECEPTOR.
SO YOU CAN SEE THIS LIGAND
REPRESENTED HERE BY THIS PINK
CIRCLE.
ONCE EGF RECEPTOR IS ACTIVE, IT
CAN TELL THE CELLS ESSENTIALLY
ONCE IT'S LIGAND BOUND TO DIVIDE
AND TO SURVIVE.
SO THAT'S WHAT HAPPENS IN NORMAL
HOMEOSTASIS, YOU REALLY HAVE TO
HAVE THOSE LIGANDS PRESENT TO
ACTIVATE THE EGF RECEPTOR.
WHEN A MUTATION IS PRESENT IN
LUNG CANCER, ONE OF THE THINGS
THAT CAN HAPPEN AND THE MUTATION
IS REPRESENTED BY THIS LIGHTNING
BOLT IS THAT THEN THE TUMOR
DOESN'T REALLY NEED -- THE EGF
RECEPTOR DOESN'T NEED THE LIGAND
TO GET ACTIVATED, IT GETS
ACTIVATED IN THE ABSENCE OF ANY
SPECIFIC SORT OF REAL EXOGENOUS
CONTROLS.
AND SO ONE WAY OF THINKING ABOUT
IT IS LIKE -- IT'S LIKE A LEAKY
FAUCET, RIGHT?
SO NORMALLY YOU CAN TURN THE
FAUCET ON, YOU CAN TURN THE
FAUCET OFF, CAN YOU CONTROL
THAT, BUT WHEN YOU HAVE THE EGFR
MUTATION OR THE MUTATION, IT'S
LIKE -- IT'S ALWAYS ON A LITTLE
BIT AND DRIPPING.
SO ONE OF THE THINGS THAT HAS
BEEN DEVELOPED OVER THE YEARS,
THESE TARGETED THERAPIES AGAINST
MUTATED EGF RECEPTOR HAVE BEEN
REALLY EFFECTIVE BECAUSE THEY
CAN ACTUALLY STOP THE LEAK.
SO YOU CAN GIVE THESE AGENTS,
THEY CAN STOP THAT LEAKY FAUCET,
THEY CAN ESSENTIALLY CLOSE THAT
FAUCET AGAIN AND STOP IT FROM
FUNCTIONING.
SO THAT'S HOW THEY WORK.
THEY WORK REALLY WELL, THEY WORK
VERY WELL AT THE BEGINNING, AND
THERE ARE NOW A NUMBER OF AGENTS
AND COMBINATIONS OF AGENTS THAT
ARE USED TARGETED THERAPIES THAT
ARE USED FOR THE TREATMENT OF
EGF RECEPTOR-DRIVEN LUNG CANCER.
SO HERE ON THE LEFT, YOU CAN SEE
A LIST OF SOME OF THESE
THERAPIES THAT ARE APPROVED FOR
THE TREATMENT OF ADVANCED EGFR
DN DRIVEN LUNG CANCER THAT NAIVE
TO TYROSINE KINASE INHIBITORS,
SOME OF THESE TYROSINE KINASE
INHIBITORS, OSIMERTINIB CAN ALSO
BE USED IN COMBINATION WITH
CHEMOTHERAPY OR ANOTHER THIRD
GENERATION TYROSINE KINASE
INHIBITOR, LAZERTINIB, CAN BE
USED WITH AN ANTIBODY TARGETING
EGF RECEPTOR AND THE MET
RECEPTOR IN COMBINATION.
SO THEY CAN BE USED TO TREAT
DISEASE IN THE METASTATIC
SETTING.
THERE'S ALSO OSIMERTINIB THAT
YOU HEARD FROM ROY THAT CAN BE
USED IN EARLIER STAGE DISEASE.
AND SO ONE OF THE THINGS THAT I
DID WANT TO TOUCH ON A LITTLE
BIT AND TALK ABOUT IN ONE OF THE
THINGS THAT REALLY HAS EMERGED
IN THE FIELD IN RECENT YEARS IS
OUR UNDERSTANDING THAT NOT ALL
EGF RECEPTOR MUTATIONS ARE
ALIKE, AND THEY CAN HAVE
DIFFERENT SENSITIVITIES TO THESE
TARGETED THERAPIES TO THESE
TYROSINE KINASE INTIB TORES SO
THAT'S A REALLY IMPORTANT
COMPONENT OF UNDERSTANDING HOW
BEST TO USE THESE AGENTS AND
WHETHER WE NEED TO THINK ABOUT
ALTERNATIVE STRIKE T STRATEGIES.
SO WE'VE TALKED ABOUT EGF
RECEPTOR MUTATIONS SORT OF AS --
IN BULK AS ONE ENTITY BUT ONE OF
THE THINGS WE KNOW, YOU CAN LOOK
HERE AT THIS PIE CHART IN THE
CENTER, IS THAT E I THEY'RE ACTY
QUITE HETEROGENEOUS.
YOU HAVE A POINT MUTATION THAT
IS PRETTY COMMONLY OBSERVED, OR
SMALL IN FRAME DELETIONS IN EXON
19 AND BETWEEN THE L858R AND
EXON 19 DELETIONS ARE THE
COMMONLY OBSERVED MUTATIONS AND
THEN WE HAVE ANOTHER SUBSET OF
OTHER MUTATIONS THAT ARE ALSO
OBSERVED THAT ARE RARE.
BUT ONE OF THE THINGS THAT WE
ALSO KNOW IS THAT IF WE TAKE
THESE EXON 19 DELETIONS, THEY'RE
NOT ALL THE SAME.
THERE'S ONE THAT IS THE MOST
COMMONLY OBSERVED DELETION
MUTATION, BUT THEN THERE ARE A
LOT OF OTHER ONES AS WELL.
SO SOME OF THE THINGS THAT WE
AND OTHERS HAVE BEEN FINDING
OVER THE YEARS IS THAT ACTUALLY
NOT ALL MUTATIONS, EGFR
MUTATIONS ARE ALIKE.
SO I JUST WANTED TO POINT OUT
HERE ON THE LEFT, FOR EXAMPLE,
IF WE LOOK AT THE EGFR EXON 19
DELETIONS ON TREATMENT WITH
OSIMERTINIB, FOR EXAMPLE, ONE OF
THE THINGS WE CAN SEE IS THAT
OVERALL SURVIVAL FOR PATIENTS
TREATED WITH OSIMERTINIB WHOSE
TUMORS HARBOR THE DELETION IS
ABOUT 14 MONTHS.
BUT IF WE LOOK IN THAT SAME
CLINICAL TRIAL AND LOOK AT THE
SUBSET OF TUMORS WITH THE L858R
MUTATION, THE OVERALL SURVIVAL
IS ABOUT 33 MONTHS.
THIS IS SEEN WITH OSIMERTINIB
BUT ALSO WITH OTHER TYROSINE
KINASE INHIBITORS.
WE KNOW THE L858R TUMORS SEEM TO
BE A SUBSET THAT DOES A LITTLE
WORSE WITH TYROSINE KINASE
INHIBITOR MONOTHERAPY.
ONE OF THE THOUGHTS IS THAT
MAYBE THOSE ARE TUMORS THAT ONE
MIGHT WANT TO THINK ABOUT FROM
SOME OF THESE OTHER COMBINATION
THERAPIES OR THAT ARE POSSIBLE
IN THE FIRST LINE SETTING LIKE
OSIMERTINIB PLUS CHEMOTHERAPY.
ONE OF THE OTHER THINGS THAT
WE'VE BEEN WORKING ON AND OTHER
GROUPS HAVE ALSO BEEN WORKING ON
IS REALLY UNDERSTANDING MORE
ABOUT THE BIOLOGY AND THE
BIOCHEMISTRY OF THESE DIFFERENT
EGFR EXON 19 DELETION MUTATIONS
AND ONE OF THE THINGS THAT WE
FOUND SEVERAL YEARS AGO IS THAT
ACTUALLY FOR EXAMPLE THERE'S
THIS ONE EXON 19 DELETION
MUTATION THAT COMPARED TO THE
MORE COMMON ONES SEEMS TO HAVE
WORSE OUTCOMES UPON TREATMENT
WITH TYROSINE KINASE INHIBITORS,
THIS PURPLE LINE.
AND IN FACT, WE'VE DONE WORK
TOGETHER WITH MARK LEMON AND
SARAH GOLDBERG TO REALLY LOOK AT
THE BIOCHEMISTRY AND MOLECULAR
FEATURES OF THESE MUTANTS AND
FOUND A DIFFERENT AFFINITY FOR
ATP OF THE KINASE IN THIS
UNCOMMON EXON 19 DELETION
MUTATION COMPARED TO THE MORE
COMMON ONE.
SO REALLY BEGINNING TO
UNDERSTAND HOW THE MOLECULAR
FEATURES OF THESE INDIVIDUAL
MUTATIONS CAN ACTUALLY TELL US
SOMETHING ABOUT THE SENSITIVITY
TO THE TYROSINE KINASE
INHIBITORS AND I THINK THIS IS
REALLY WHERE WE'RE HEADING IN
THE FIELD OF PRECISION MEDICINE,
IS REALLY UNDERSTANDING THESE
FINE DETAILS BECAUSE NOW WE HAVE
SO MANY DRUGS AND SO MANY
POSSIBILITIES FOR TREATMENT WITH
DIFFERENT AGENTS.
SO WITH THAT, I'D LIKE TO MOVE
ALONG AND TELL YOU ABOUT SOME OF
THE CHALLENGES AND WHAT OUR
KNOWLEDGE IS ABOUT MECHANISMS OF
ACQUIRED RESISTANCE TO TARGETED
THERAPIES.
SO HERE YOU CAN SEE IN THESE
SCANS, THIS IS AN EXAMPLE OF
LUNGS WHERE YOU SEE THE TUMOR IS
PRESENT AT THE BEGINNING, BEFORE
TREATMENT WITH THE TYROSINE
KINASE INHIBITOR.
AFTER TREATMENT WITH THE
TYROSINE KINASE INHIBITOR, THE
TUMOR REALLY SHRINKS AWAY, BUT
THEN WHEN WE LOOK EVENTUALLY THE
TUMOR COMES BACK, AND THIS IS
REALLY THE EMERGENCE OF
RESISTANCE TO TYROSINE KINASE
INHIBITORS.
AND WITH SOME OF THE EARLY
GENERATION DRUGS, RESISTANCE
EMERGED ABOUT A YEAR AFTER
TREATMENT WITH SOME OF THESE
NEWER GENERATION DRUGS, LIKE
OSIMERTINIB, IT REALLY IS MOVED
TO MORE 1 1/2, 2 YEARS FOLLOWING
TREATMENT WITH THE AGENTS.
YET, RESISTANCE IS REALLY
INEVITABLE.
AND SO I THINK ONE OF THE THINGS
WE'VE LEARNED OVER THE YEARS
WITH THESE DIFFERENT EGFR
TYROSINE KINASE INHIBITORS AND I
SHOULD SAY THAT THESE SORT OF
CATEGORIES OF RESISTANCE
MECHANISMS CAN ALSO BE
EXTRAPOLATED TO DIFFERENT
TARGETED AGENTS.
SO I'M GOING TO TELL YOU ABOUT
WHAT WE KNOW IN THE CONTEXT OF
EGF RECEPTOR DRIVEN LUNG CANCER
BUT WE CAN EVEN LOOK AT THIS
MORE BROADLY AND THINK ABOUT IT
IN THAT CONTEXT.
SO FOR EXAMPLE, WE KNOW THAT ON
TARGET MUTATIONS IN EGF RECEPTOR
CAN OCCUR TO CONFER RESISTANCE.
SO -- AND THIS IS -- THERE ARE
VARIOUS DIFFERENT TYPES OF
MUTATIONS BUT I THINK ONE OF THE
MORE COMMON ONES WITH THE NEW
GENERATION DRUG OSIMERTINIB,
ACTUALLY ASSISTING A POSITION AT
WHICH EGF RECEPTOR BINDS
COVALENT -- OSIMERTINIB BINDS
COVALENTLY EGF RECEPTOR.
SO YOU CAN IMAGINE THAT IF YOU
MUTATE THAT SITE WHERE THE DRUG
BINDS THE PROTEIN, THEN THAT IT
CAN'T BIND ANYMORE.
AND SO -- AND SOME OF THESE
OTHER ALTERATIONS CAN, FOR
EXAMPLE, CREATE STERIC HINDRANCE
AND PREVENT REALLY THE DRUGS
FROM WORKING.
SO THESE ON-TARGET MUTATIONS ARE
ONE CATEGORY OF RESISTANCE
MECHANISMS.
WE ALSO CAN HAVE OFF-TARGET
MECHANISMS OF RESISTANCE.
AND THESE CAN BE CONSIDERED, FOR
EXAMPLE, BYPASS PATHWAY
ACTIVATION, SO WE CAN HAVE
ACTIVATION OF PATHWAYS THAT THEN
HAVE SIMILAR EFFECTS TO THE
EFFECTS OF MUTATED EGF RECEPTOR
IN THE LUNG CANCER CELLS.
SO YOU COULD IMAGINE ACTIVATION
OR HIGHER LEVELS IN ACTIVATION
OF ANOTHER RECEPTOR TYROSINE
KINASE THAT CAN ACTIVATE MANY OF
THE SIMILAR PATHWAYS, LIKE MET
OR HER-2, WHICH ARE ALSO
RECEPTOR TYROSINE KINASES.
SO THESE CAN GET AMPLIFIED, THEY
CAN GET ACTIVATED IN TUMORS THAT
ARE RESISTANT, OR WE CAN HAVE
ACTIVATION OF DOWNSTREAM
MOLECULES THAT ARE DOWNSTREAM OF
EGF RECEPTOR THAT ACTIVATE THOSE
SAME PATHWAYS THAT ARE ACTIVATED
BY EGFR.
AND SO THIS IS ANOTHER MECHANISM
OF ACQUIRED RESISTANCE, AND SO
IN THIS CASE, EVEN IF YOU'RE
BLOCKING THE ACTIVITY OF EGF
RECEPTOR WITH A TARGETED
THERAPY, THERE ARE OTHER
PATHWAYS THAT CAN GET AROUND IT.
ONE OF THE OTHER MECHANISMS OF
RESISTANCE THAT IS PERHAPS THE
MOST MYSTERIOUS THAT THERE'S A
LOT OF WORK THAT IS HAPPENING TO
REALLY UNDERSTAND THE BASIS FOR
IT IS THAT WE CAN SEE THAT SOME
OF THESE TUMORS CAN CHANGE THEIR
HISTOLOGIC FEATURES.
SO WE CAN START FROM THESE
ADENOCARCINOMAS THAT HAVE EGFR
MUTATIONS, FOR EXAMPLE, TREAT
THEM WITH A TYROSINE KINASE
INHIBITORS, AND THEN WHEN YOU
LOOK AT RESISTANCE, THE TUMORS
ARE DIFFERENT HISTOLOGICALLY.
SO FOR EXAMPLE, THEY CAN HAVE
ACQUIRED FEATURES OF SMALL CELL
LUNG CANCER, WHICH AS IF YOU
REMEMBER FROM ONE OF MY FIRST
SLIDES, ONE OF THE SUBSETS --
ONE OF THE SMALLER SUBSETS OF
LUNG CANCER, SO TOTALLY
DIFFERENT TUMOR TYPES, OR CAN
ACQUIRE FEATURES OF SQUAMOUS
CELL LUNG CARCINOMAS, OR CAN
ALSO UNDERGO WHAT'S CALLED
EPITHELIAL TO MESENCHYMAL
TRANSITION AND LOOK SORT OF MORE
MESENCHYMAL, MORE MUSCLE-LIKE
CELLS IN A PROCESS CALLED
SARCOMATOID DIFFERENTIATION.
SO THE TUMOR CELLS ARE CHANGING
THEIR DEPENDENCE.
THEY DON'T DEPEND ON EGF
RECEPTOR ANYMORE.
OR REALLY HAVE SHIFTED THEIR
HISTOLOGY SO THERE ARE OTHER
WAYS ON WHICH THEY'RE GROWING
OUT.
I THINK THAT ONE OF THE THINGS
THAT WE ARE OBSERVING NOW IS
THAT WITH SOME OF THESE NEWER
GENERATION AGENTS AND
GENERATION -- NEW DRUGS LIKE
OSIMERTINIB THAT IS REALLY USED
A LOT IS THE FIRST LINE
TREATMENT FOR EGF RECEPTOR
DRIVEN LUNG CANCER IS NOT ONLY
DO WE SEE THESE MECHANISMS OF
RESISTANCE THAT I JUST TOLD YOU
ABOUT, BUT ONE OF THE THINGS
THAT HAS BEEN HAPPENING IS THAT
ESPECIALLY WHEN IT'S USED IN THE
FIRST LINE TREATMENT, WE STILL
DON'T KNOW WHAT THE MECHANISMS
OF RESISTANCE ARE IN MANY OF
THOSE TUMORS.
ALMOST 50% IN THIS DATASET,
ANALYZED HERE.
SO THIS REALLY REPRESENTS A
MAJOR CHALLENGE BECAUSE IT'S
TELLING US, WELL, ALTHOUGH WE
KNOW ABOUT SOME OF THE
MECHANISMS OF RESISTANCE, WITH
SOME OF THESE NEWER DRUGS,
THERE'S JUST SO MUCH THAT WE
DON'T UNDERSTAND AND THERE
AREN'T OBVIOUS GENETIC
ALTERATIONS THAT ARE TELLING US
WHAT THE MECHANISM OF RESISTANCE
IS.
AND SO WITH THAT, I DID WANT TO
TOUCH A LITTLE BIT ON SOME OF
THE CHALLENGES THAT THE FIELD
FACES TO REALLY TACKLE THE
PROBLEM OF DRUG RESISTANCE, AND
TO FIGURE OUT WAYS IN WHICH WE
CAN OVERCOME THIS RESISTANCE OR
PREVENT THIS RESISTANCE, REALLY
WE CAN GET CLOSER TO CURES IN
THESE ONCOGENE-DRIVEN LUNG
CANCERS.
I SHOW YOU THIS PAINTING HERE,
BECAUSE ONE OF THE THINGS THAT I
THINK ABOUT IS THAT WE'VE REALLY
MADE TREMENDOUS PROGRESS, WE'VE
LEARNED SO MUCH OVER THE YEARS,
AND WE REALLY -- THE FRUITS AT
THE BOTTOM OF THE TREE, BUT
THERE ARE LOTS OF FRUITS AT THE
TOP HERE AND WE HAVE TO REALLY
PICK THEM AND FIGURE THESE --
DID GET TO THEM IF WE WANT TO
MAKE SORT OF MORE EXPONENTIAL
PROGRESS IN THE FIELD.
AND SO WHAT ARE SOME OF THE
THINGS THAT WE THINK ABOUT AND
WHAT ARE SOME OF THE CHALLENGES?
I THINK ONE OF THEM HERE IS THE
TARGETED AGENTS ARE CLEARLY NOT
SUFFICIENT.
WE NEED TO DISCOVER NEW UNTAPPED
VULNERABILITIES OF
ONCOGENE-DRIVEN LUNG CANCERS.
TACKLING RESISTANCE REQUIRES NEW
KNOWLEDGE OF THE LINKS BETWEEN
CANCER CELL PLASTICITY, THE
TUMOR MICROENVIRONMENT AND TUMOR
HETEROGENEITY.
WE JUST DON'T KNOW ENOUGH ABOUT
DRUG RESISTANCE YET, AND WE
REALLY NEED TO UNDERSTAND IT
BETTER.
AND THEN ONE OF THE THINGS THAT
IS STILL MYSTERIOUS IS WHEN WE
TREAT WITH A TARGETED AGENT,
WHAT MAKES SOME CANCER CELLS
SURVIVE THE TREATMENT WHILE THE
TARGETED THERAPIES CAN
ERADICATE, CAN GET RID OF THE
OTHER CELLS.
ANOTHER MYSTERY, AND I'LL TALK A
LITTLE BIT ABOUT THAT.
SO ONE OF THE THINGS THAT I
WANTED TO DO IS I JUST WANTED TO
HIGHLIGHT HOW WE ARE MAKING SOME
PROGRESS IN UNDERSTANDING SOME
OF THESE PREVIOUSLY UNKNOWN
MECHANISMS OF DRUG RESISTANCE,
AND THIS IS TO HIGHLIGHT A PAPER
THAT WE PUBLISHED A COUPLE OF
YEARS AGO, PART OF SOME OF THE
WORK THAT WE'RE DOING IN THE
CONTEXT OF OUR LUNG CANCER SPORE
AND REALLY NICE COLLABORATION
WITH THE HARVARD SPORE AND LUNG
CANCER AND PASIANA AND KADOSH IN
WHICH WE IDENTIFIED A ROLE FOR
THE SWISNF COMPLEX AND PROMOTING
TYROSINE KINASE INHIBITORS.
IT'S A CHROMATIN-REMODELING
COMPLEX, AND HERE INSTEAD OF
MUTATIONAL CHANGES THAT ARE
CONFERRING RESISTANCE, ONE OF
THE THINGS WE FOUND IS THAT
THERE ARE SOME TUMORS, SOME EGFR
MUTANT TUMORS THAT AT THE TIME
OF RESISTANCE REALLY RELY ON
THIS COMPLEX FUNCTIONING IN THE
CELLS SO THAT FOR EXAMPLE, IT
CAN ACTUALLY KEEP CHROMATIN OPEN
AT SITES THAT ARE IMPORTANT FOR
THE PROLIFERATION OF CELLS AND
FOR THE CELLS TO WITHSTAND
TREATMENT WITH A TARGETED AGENT.
HERE YOU CAN SEE AN EXAMPLE OF
SOME DATA HERE WHERE IF WE KNOCK
OUT SM ACA4 AND TREAT WITH
OSIMERTINIB, IT ACTUALLY
RESENSITIZES THESE TUMORS TO
TREATMENT AND HERE IN PATIENT
DERIVED XENOGRAPHED MODEL, WE
ACTUALLY USE A DRUG THAT TARGETS
THE COMPLEXES IN COMBINATION
WITH OSIMERTINIB, WE CAN KIND OF
SEE A PLATEAU IN TUMOR GROWTH.
SO THESE ARE SOME OF THE
MECHANISMS THAT WE'RE STARTING
TO UNCOVER AND REALLY THAT ARE
ALLOWING US TO UNDERSTAND NEW
APPROACHES TO -- NEW MECHANISMS
OF RESISTANCE BUT THEN NEW
POTENTIAL WAYS OF OVERCOMING
RESISTANCE, AND PERHAPS ALSO
PREVENTING RESISTANCE THAT COULD
BE REALLY IMPORTANT TO TAKE TO
THE CLINIC EVENTUALLY.
I THINK YOU KNOW, ONE OF THE
OTHER AREAS THAT I DID WANT TO
TOUCH ON BECAUSE I THINK IT IS A
MAJOR CHALLENGE AND SOMETHING
THAT WE'RE REALLY BEGINNING TO
LEARN SOMETHING ABOUT IS AS I
MENTIONED, IN A SUBSET OF TUMORS
THAT BECOME RESISTANT TO
TARGETED AGENTS, WE ACTUALLY
HAVE THIS SHIFT FROM THE TUMOR
LOOKING LIKE LUNG
ADENOCARCINOMA, ONE TUMOR TYPE,
ACTUALLY SHIFTING AND YOU CAN
SEE HERE'S AN EXAMPLE OF A LUNG
ADENOCARCINOMA, THIS IS WHAT IT
LOOKS LIKE, THEN AFTER TREATMENT
IT HAS COMPLETELY CHANGED AND
HAS FEATURES OF SMALL CELL LUNG
CANCER, SO A TOTALLY DIFFERENT
TUMOR TYPE.
THIS WAS FIRST DESCRIBED
ACTUALLY IN 20 2006, AND THEN
REALLY VALIDATED AND VERIFYING
LARGER DATASETS FROM SEVERAL
DIFFERENT GROUPS, AND WHAT WE
KNOW IN THESE TUMORS THAT IS
REALLY INTERESTING THAT THESE
TUMORS INITIALLY HAVE THE E DP.
F RECEPTOR MUTATION, THEY
EXPRESS ONCOGENIC EGFR WHICH IS
REALLY IMPORTANT FOR THE
SURVIVAL OF THESE CELLS, BUT
THEN MAP WHAPS WHEN THE
TUMORS -- WHEN THE SMALL CELL
LUNG CANCERS EMERGE, EXPRESSION
OF MUTATED EGF RECEPTOR IS LOST.
SO THE MUTATION IS STILL THERE,
BUT THE MUTANT IS NOT EXPRESSED,
AND ONE OF THE OTHER THINGS THAT
WE KNOW IS THAT THESE TUMORS ARE
CHARACTERIZED BY MUTATIONS IN
THE TUMOR SUPPRESSOR GENES P53
AND RETINOBLASTOMA, WHICH ARE
ALSO CHARACTERISTIC OF SMALL
CELL LUNG CANCERS.
WE KNOW THAT IF YOU LOOK AT
BASELINE, EGFR MUTANT TUMORS
THAT AT BASELINE HAVE P53
MUTATIONS AND RB1 MUTATIONS ARE
MORE LIKELY TO EMERGE AS SMALL
CELL LUNG CANCER AT THE TIME OF
RESISTANCE.
IN THIS CASE WE'RE IDENTIFYING
FEATURES UP FRONT THAT ARE
DISPOSED TO RESISTANCE EMERGING.
THINK ONE OF THE BIG QUESTIONS
IN THE FIELD IS WHAT ARE THE
CELLULAR AND MOLECULAR BASIS FOR
THIS TRANSFORMATION, AND I'D
JUST LIKE TO POINT OUT A COUPLE
OF THINGS RELATED TO THAT.
THERE ARE A LOT OF GROUPS
WORKING ON IT BUT ONE OF THE
THINGS THAT IS REALLY
FASCINATING IS THAT THE PROCESS
FOR THIS NEUROENDOCRINE
DIFFERENTIATION THAT WE SEE IN
LUNG CANCER THAT IS
TREATMENT-RESISTANT IS ANALOGOUS
OR HAS A PERIL LEL I A PARALLELT
OF PROSTATE CANCERS TREAT.
YOU CAN SEE IN THE TOP IN BLUE,
THIS SCHEMATIC FROM A FEW YEARS
AGO WHERE YOU HAVE LUNG CANCERS
WITH EGF RECEPTOR MUTATIONS.
EFFICIENTLY YOU CAN HAVE THE
EMERGENCE OF SMALL CELL LUNG
CANCER, YOU CAN ALSO HAVE
NEUROENDOCRINE DIFFERENTIATION
FOR PROSTATE CANCER SHOWN HERE
IN YELLOW.
AND SOME OF THE ALTERATIONS THAT
OCCUR, THE P53 MUTATIONS, RB
MUTATIONS, SOME OF THE OTHER
THINGS THAT CAN OCCUR THAT
HAPPEN IN THESE TUMORS THAT
UNDERGO THIS DIFFERENTIATION ARE
ANALOGOUS, SO WE HAVE THESE
PARALLELS BETWEEN DIFFERENT
CANCER TYPES TREATED WITH
TARGETED THERAPIES AND I THINK
WE CAN LEARN A LOT BY LEARNING
FROM BOTH OF THESE SYSTEMS.
I'D JUST LIKE ALSO TO POINT OUT
THAT SOME RECENT WORK THAT A
WHOLE LOT OF PROGRESS HAS BEEN
GOING INTO MODELING THE
REQUIREMENTS FOR THIS SMALL CELL
TRANSFER PLASTICITY IN VIVO FROM
HAROLD HA HAR MUST'S LAB FOR
EGFR -- IN WHICH YOU CAN -- IN
WHICH THEY'VE BEEN ABLE TO
ACTUALLY FOLLOW THE TUMOR CELLS
WHEN YOU FOR EXAMPLE GET RID OF
EGF RECEPTOR SO YOU DON'T HAVE
IT ANYMORE, AND THEN YOU LOOK AT
THE RESIDUAL DISEASE, SEE WHAT
HAPPENS AND IN THE PRESENCE, YOU
CAN ACTUALLY SEE THIS TRANSFORM
SMALL CELL LUNG CANCER EMERGE.
SO WE'RE BEGINNING TO LEARN
ABOUT THE REQUIREMENTS FOR THIS
TRANSFORMATION TO OCCUR THROUGH
MODELING.
I THINK WE'LL CONTINUE TO SEE
MANY ADVANCES IN OUR
UNDERSTANDING OF THIS TYPE OF
PLASTICITY IN THE COMING YEARS.
JUST TO HIGHLIGHT HOW -- THE
THINGS THAT WE'RE OBSERVING AND
LEARNING WITH EGF RECEPTOR
INHIBITORS ALSO HAVE SOME
PARALLELS AND SOME DIFFERENCES
IN THE CONTEXT OF KRAS
INHIBITORS.
SO AS I MENTIONED AT THE
BEGINNING OF MY TALK, KRAS IS
ANOTHER ONCOGENE THAT IS MUTATED
IN LUNG CANCER, AND THERE HAS
BEEN THE DEVELOPMENT, LARGELY
CONSIDERED UNDRUGGABLE UNTIL A
FEW YEARS AGO, WHEN THERE WERE
DRUGS THAT WERE DEVELOPED THAT
CAN TARGET ONCOGENIC KRAS, AND
WE NOW NOW FROM MANY GROUPS, I'M
SHOWING YOU SOME DATA FROM ONE
OF THE PAPERS SHOWING HOW
RESISTANCE EMERGES IN THE
CONTEXT OF TREATMENT WITH KRAS
INHIBITOR, SO OTHER TARGETED
AGENTS, AND WE CAN SEE HERE WE
CAN HAVE ACQUIRED KRAS
ALTERATIONS SO THESE ON-TARGET
MUTATIONS CAN ALSO HAPPEN HERE.
WE CAN ALSO SEE ACTIVATION OF
BYPASS SIGNALING PATHWAYS HERE
HIGHLIGHTED IN YELLOW, FOR
EXAMPLE, THAT HAPPEN IN THE
RESISTANT TUMORS.
AND ONE OF THE THINGS THAT CAN
ALSO HAPPEN AND HIGHLIGHTED IN
THESE TWO CASES HERE REALLY IN
PINK IS THAT WE HAVE HERE ALSO
AN EXAMPLE OF LINEAGE
PLASTICITY, WHERE LUNG
ADENOCARCINOMAS CAN CHANGE TO
ANOTHER HISTOLOGICAL SUBTYPE OF
SQUAMOUS CELL CARCINOMA.
AND THERE'S A LOT OF WORK IN THE
FIELD REALLY TRYING TO
UNDERSTAND WHY SOME TUMORS THAT
RESISTANCE WILL SHIFT FROM THESE
ADENOCARCINOMAS TO SQUAMOUS CELL
LUNG CARCINOMAS, AND JUST WANTED
TO SHOW YOU HERE THAT SOME WORK
HAS SHOWN THAT IF YOU ACTUALLY
TAKE A TUMOR AT BASELINE AND IT
HAS A SIGNATURE OF A SQUAMOUS
CELL CARCINOMA, THOSE CAN HAVE
WORSE OUTCOMES ON TREATMENT WITH
THESE KRAS INPIB HIB TORES
COMPARED TO TUMORS THAT DON'T
HAVE THIS SIGNATURE.
AND WORK HAS GONE INTO -- THIS
IS REALLY SHOWING THAT IN THE
CONTEXT SPECIFIC GENOMIC
CONTEXT, YOU ACTUALLY AT
RESISTANCE CAN SEE THIS CHANGE
FROM ADENOCARCINOMA TO SQUAMOUS
CELL CARCINOMA THAT YOU DON'T
SEE NECESSARILY IN OTHER GENOMIC
CONTEXTS.
SO WE'RE REALLY BEGINNING TO GET
A SENSE OF WHEN THESE TYPES OF
TRANSITIONS, WHEN THIS TYPE OF
PLASTICITY HAPPENS IN THE
CONTEXT OF KRAS G12C INHIBITORS,
TRANSFORMATION OCCURRING.
SO I'D JUST LIKE TO TAKE A FEW
MORE MINUTES IN THIS
PRESENTATION AND TELL YOU ABOUT
SOME OF THE WORK THAT WE'VE
BEEN -- WE AND OTHERS HAVE BEEN
DOING TO REALLY UNDERSTAND --
I'VE TOLD YOU ABOUT RESISTANCE,
I'VE TOLD YOU ABOUT PRIMARY
RESISTANCE, I'VE TOLD YOU ABOUT
ACQUIRED RESISTANCE, BUT ALL OF
THIS IS SORT OF PREDICATED OR
RELIES ON THE FACT THAT WHEN WE
FIRST USE THE TARGETED
THERAPIES, THEY'RE NOT GETTING
RID OF ALL OF THE CELLS FROM THE
GET-GO.
AND THIS IS A BIG PROBLEM.
IT'S A BIG PROBLEM WITH ALL OF
THE TARGETED AGENTS BUT YOU CAN
SEE HERE IN THIS SLIDE IF WE
HAVE A PRE-TREATMENT TUMOR WITH
A CT SCAN POST TREATMENT SIX
MONTHS LAY TE YOU STI LATER, YOA
LITTLE BIT OF ACTUAL MORE LEFT
OVER.
IF WE LOOK AT THESE --
OSIMERTINIB, YOU SEE MANY TUMORS
SHRINK BUT THERE'S REALLY A LOT
OF VARIABILITY IN HOW MUCH EACH
OF THESE TUMORS SHRINKS.
SO WE HAVE A LOT OF CELLS THAT
ARE LEFT OVER, AND SO SOME OF
THE WORK THAT IS HAPPENING IN
THE FIELD, I THINK SOME OF THE
VERY EXCITING WORK IS REALLY TO
UNDERSTAND WHAT THE MECHANISMS
OF THIS DRUG TOLERANCE ARE, AND
WE KNOW MANY OF THESE CELLS CAN
HAVE REDUCED RATES OF
PROLIFERATION, THESE PERSISTERS,
WE DRAW THEM DRUG TOLERANT
PERSISTERS IN THE FEEL, THEY CAN
HAVE DIFFERENCES IN METABOLIC
CHANGES, THEY CAN ACTIVATE, FOR
EXAMPLE, PROTECTIVE ANTIOXIDANT
MECHANISMS.
THEY CAN ALSO SHIFT, AND SHIFT
STATES, AND UNDERGO, FOR
EXAMPLE, EPITHELIAL TO
MESENCHYMAL TRANSITION, CHANGE
THESE -- THESE PROPERTIES OF THE
CELLS CAN CHANGE SO THAT THEY
DON'T REALLY CARE WHETHER A
TARGETED AGENT IS AROUND OR NOT.
AND THEN THE MICROENVIRONMENT
CAN, OF COURSE, INFLUENCE THE
SURVIVAL OF THESE DIFFERENT
CELLS.
SO THERE ARE LOTS OF DIFFERENT
PROCESSS THAT CAN HAPPEN, AND
WE'RE STARTING TO UNCOVER SOME
OF THAT.
I'D JUST LIKE TO POINT OUT SOME
DATA FROM OUR GROUP THAT WE
PUBLISHED LAST YEAR IN WHICH WE
SAW THAT IN PATIENT DERIVED
XENOGRAPHS, SO THESE ARE TUMORS
FROM -- PATIENT TUMORS IN WHICH
WE WERE ABLE TO MODEL THIS DRUG
TOLERANCE STATE, ONE OF THE
THINGS THAT WE SAW IS WE SAW
THAT YOU COULD HAVE ACTIVATION
OF EXPRESSION OF A HELIX PIONEER
TRANSCRIPTION FACTOR ASCL1 IN
THESE RESIDUAL CELLS.
YOU CAN SEE ON THE RIGHT, THESE
ARE EXAMPLES OF THE UNTREATED
TUMORS, WHERE YOU SEE EGF
RECEPTOR IS THERE AND YOU SEE
UN -- PHOSPHORYLATION OF EGF
REAP ACCEPTOR, WHEN YOU ACTUALLY
BLOCKAGETIVITY OF THE RECEPTOR,
IT'S SHUT OFF, BUT THEN YOU TURN
ON ASCL1 AND ACTUALLY ALL OF
THESE OTHER GENES THAT ARE
DOWNSTREAM TARGET.
SO YOU REALLY ARE TURNING ON
THIS PROGRAM, AND WHEN WE WENT
IN AND LOOKED MORE IN DETAIL AND
DID MORE FUNCTIONAL STUDIES, WE
SAW ASCL1 IN THESE TUMORS COULD
ACTUALLY TURN ON AN EPITHELIAL
TO TRANS ENG MALL TRANSITION
STATE THAT ALLOWS THE CELLS TO
SURVIVE.
THIS IS REALLY FASCINATING
BECAUSE IT TELLS US IF THIS ASCL
GENE GOES ON AND IS ON IN THESE
RESIDUAL CELLS, IT CAN THESE EMT
GENES, AND WHEN THEY'RE TREATED
WITH THE TYROSINE KINASE
INHIBITOR, THEY DON'T DIE, THEY
STAY ALIVE.
BUT IT ONLY HAPPENS IN CERTAIN
CELLS AND THERE ARE OTHER CELLS
WHERE EVEN IF YOU HAVE
ASCL1 THERE, THEY ARE JUST NOT
PERMISSIVE.
THAT DOESN'T HAPPEN, AND THEY
WILL STILL UNDERGO APOPTOSIS AND
DIE UPON TKI TREATMENT.
BUT THIS IS A NOVEL MECHANISM
THAT WE'RE WORKING TO UNDERSTAND
BETTER NOW.
IN THE LAST COUPLE OF MINUTES OF
THE PRESENTATION, I'D JUST LIKE
TO TELL YOU ABOUT SOME OF THE
WORK THAT WE'RE DOING TO
UNDERSTAND THE WORK WE'RE DOING
WITH IMMUNE CHECKPOINT
INHIBITORS, AND HERE AS YOU
HEARD FROM ROY, THE GREAT
ADVANCES.
WE SEE THAT MANY PATIENTS
SURVIVE FOR QUITE -- WE SEE A
NICE REALLY TAIL OF THE CURVE
IMPROVEMENTS IN SURVIVAL FOR
PATIENTS TREATED WITH IMMUNE
CHECKPOINT INHIBITORS, BUT ONE
OF THE THINGS THAT WE LEARNED
OVER THE YEARS AND WE'RE ABLE TO
LEVERAGE OUR BIOPSY PROGRAM THAT
ROY TOLD YOU ABOUT EARLIER,
SEVERAL YEARS AGO, WITH REALLY
WE KNEW THAT PATIENTS WERE
DEVELOPING ACQUIRED RESISTANCE
TO IMMUNE CHECKPOINT INHIBITORS
AS WELL.
SO SEVERAL YEARS AGO, WHAT WE
DID IS WE COLLECTED SPECIMENS
FROM PATIENTS WHO DEVELOPED
ACQUIRED RESISTANCE TO IMMUNE
CHECKPOINT INHIBITOR, WE WERE
ABLE TO COMPARE THEM TO THE
PRE-TREATMENT TUMOR SPECIMENS,
AND HERE YOU CAN SEE AN EXAMPLE
OF THIS IS ONE CASE WHERE
PATIENT WAS TREATED WITH A
COMBINATION OF IMMUNOTHERAPEUTIC
AGENTS, HAD AN AMAZING INITIAL
RESPONSE TO IMMUNOTHERAPY, BUT
EFFICIENTLY RESISTANCE DEVELOPED
THE IMMUNOTHERAPY.
AND WE WERE ABLE TO THEN GO
AHEAD AND WE DID WHOLE EXOME
SEQUENCING ON THESE TUMORS.
AND IN THIS CASE, WE FOUND
HOMOZYGOUS LOSS OF BETA 2 MICRO
GLOBULIN.
NOW, BETA 2 MICRO GLOBULIN IS A
FUNDAMENTAL COMPONENT OF THE HLA
ANTIGEN PRESENTATION MACHINERY.
SO WHAT HAPPENS IS THAT IN ORDER
FOR OUR CELLS TO BE RECOGNIZED
BY THE IMMUNE SYSTEM, THEY NEED
TO PRESENT ANTIGENS ON THE CELL
SURFACE.
WHEN THEY DO THAT, T CELLS WILL
THEN RECOGNIZE THOSE CELLS,
THOSE ANTIGENS.
SO THAT'S REALLY IMPORTANT FOR A
T-CELL TO REACT TO A TUMOR CELL.
AND SO WHEN YOU LOSE BETA 2 --
WHAT HAPPENS IS THAT HLA COMPLEX
CANNOT BE FORMED, SO THOSE
CANCER CELLS THEN CANNOT PRESENT
ANTIGEN.
SO THEY BECOME INVISIBLE TO THE
IMMUNE SYSTEM.
INVISIBLE TO THE T CELLS, WHICH
IS A REALLY GOOD WAY OF EVADING
THE IMMUNE SYSTEM.
AND SO THERE'S A SUBSET OF
TUMORS THAT DEVELOP ACQUIRED
RESISTANCE TO THESE IMMUNE
CHECKPOINT INHIBITORS BY
ACTUALLY BECOMING INVISIBLE TO
THE IMMUNE SYSTEM.
AND OTHER GROUPS HAVE GONE ON TO
DO MORE WORK AND THEY SEE A
SUBSET OF TUMORS, A SMALL SUBSET
OF TUMORS THAT HAVE MUTATIONS,
FOR EXAMPLE, IN BETA 2 MICRO
GLOBULIN, HERE IS AN EXAMPLE
FROM A STUDY THAT WAS PUBLISHED
LAST YEAR, BUT ONE OF THE THINGS
THAT WE'RE REALLY LEARNING, AND
I JUST WANT TO HIGHLIGHT THIS,
IS THAT WE CAN LEARN THIS FROM
THE GENETICS, FROM LOOKING AT
THE TUMORS, WE SEE A SMALL
SUBSET THAT HAVE THESE
ALTERATIONS.
BUT ONE OF THE THINGS THAT'S
REALLY IMPORTANT IS THESE
PATHWAYS, ANTIGEN PRESENTATION,
CAN ALSO BE REGULATED IN
DIFFERENT WAYS.
IT DOESN'T HAVE TO BE GENETIC.
IT CAN ALSO BE, FOR EXAMPLE,
SIGNALING THAT CAN LEAD TO --
CAN SHUT IT OFF OR TURN IT DOWN,
AND YOU CAN SEE HERE IF YOU
ACTUALLY LOOK AT THE LEVELS OF
THE PROTEINS, OF HLA PROTEIN,
YOU CAN SEE IN THE TUMORS
RESISTANT TO IMMUNE CHECKPOINT
INHIBITORS, PLU CHEMOTHERAPY THE
LEVELS ARE LOWER THAN IN TUMORS
ONLY TREATED WITH CHEMOTHERAPY
OR TARGETED THERAPY.
SO WE MAKE THE ARGUMENT HERE
THAT WE REALLY NEED TO LOOK MORE
BROADLY, GO BEYOND LOOKING AT
MUTATIONS BUT LOOK ACTUALLY AT
THE PROTEIN LEVEL AND I THINK
WE'LL PROBABLY SEE A LARGER
FACTION OF TUMORS WITH
RESISTANCE THAT HAVE DEFECTS IN
THIS PATHWAY.
A LOT OF WORK IS GOING ON TO
UNDERSTAND OTHER MECHANISMS OF
RESISTANCE.
SO I'D LIKE TO CLOSE REALLY
WITH -- CLOSE WITH TALKING ABOUT
HOW WE'VE REALLY, I THINK, GONE
A LONG WAY IN THE PAST COUPLE OF
DECADES, REALLY UNDERSTANDING
THE IMPORTANCE OF PARTNERING OUR
HISTOLOGICAL DIAGNOSIS,
IMMUNOHISTOCHEMICAL DIAGNOSIS OF
TUMORS WITH MOLECULAR PROFILING
WITH UNDERSTANDING OF THE
BIOLOGY OF THE TUMORS, WITH THE
HOPES THAT WE CAN REALLY TREAT
TUMORS IN A MORE TAILORED
FASHION, BUT THEN DISEASE
PROGRESSION, IF WE CAN DO REPEAT
BIOPSIES, WE CAN STUDY THE
MECHANISMS OF RESISTANCE AND
INCORPORATE THERAPEUTIC STUDIES,
FUNCTIONAL STUDIES, TO REALLY
CONTINUE TO IMPROVE THE
TREATMENT OF LUNG CANCER FOR
PATIENTS.
I'D LIKE TO SHOW HERE PICTURES
OF MEMBERS OF MY LAB, AND THE
TEAM, AND THE MANY COLLABORATORS
AND PEOPLE WE WORK WITH.
AND THANK YOU VERY MUCH.
>> WELL, KATARINA, THANK YOU
VERY MUCH FOR THAT INCREDIBLE
PRESENTATION AND ALSO THANK YOU
TO ROY FOR HIS SPECTACULAR
PRESENTATION AS WELL.
THIS HAS JUST BEEN ABSOLUTELY
INCREDIBLE, HEARING THE TWO OF
YOUR PRESENTATIONS.
JUST SEEING THE BREATHTAKING
PROGRESS THAT'S BEEN MADE IN THE
LAST TWO OR THREE DECADES IN
THIS FIELD.
IT'S REALLY AMAZING.
SO JUST TO START THINGS OFF, ONE
OF THE MEMBERS OF OUR AUDIENCE
WAS STRUCK BY THE FACT THAT MANY
OF THE THINGS THAT YOU'RE
TALKING ABOUT WITH REGARD TO
LUNG CANCER PROBABLY APPLY TO
MANY OTHER KINDS OF CANCERS.
>> I'M HERE TOO.
DO YOU SEE ME?
>> PARDON ME?
>> THIS IS ROY.
I JUST WANTED TO MAKE SURE -- I
WAS ON A DIFFERENT COMPUTER --
THAT YOU SEE ME.
>> YES, YES, WE DO SEE YOU.
YES, INDEED.
SO ANYWAY, THE QUESTIONER WAS
POINTING OUT THAT MANY OF THE
THINGS THAT YOU'VE SO NICELY
DEMONSTRATED IN LUNG CANCER
PROBABLY HAPPENED IN OTHER FORMS
OF CANCER AS WELL.
ARE THERE TUMORS FOR EXAMPLE IN
OTHER ANATOMIC SITES THAT HAVE
EGFR MUTATIONS AND COULD THE
EGFR INHIBITORY DRUGS BE USED IN
THOSE FORMS OF CANCER?
>> SO I THINK JUST TO -- THERE
ARE -- SO ONE OF THE THINGS,
THESE TYPES OF MUTATIONS I WAS
TELLING YOU ABOUT ARE MOSTLY
LUNG CANCER ASSOCIATED MUTATIONS
IN EFF RECEPTORS, VERY
INTERESTING BUT THEY'RE REALLY
EXCLUSIVELY FOUND IN LUNG
CANCERS.
THERE ARE OTHER TYPES OF
MUTATIONS IN EGF RECEPTOR FOUND
IN OTHER TUMOR TYPES.
YOU CAN HAVE MUTATIONS, FOR
EXAMPLE, IN GLIOMAS, THERE ARE
THESE EGFR B3 MUTATIONS, THERE
ALSO CAN BE SOME CHANGES IN THE
LEVELS OF EGF RECEPTOR THAT CAN
BE FOUND IN DIFFERENT TUMORS,
AND ALSO THERE ARE DIFFERENT
THERAPEUTIC STRATEGIES TO TREAT
THEM.
SO THERE ARE COLON CANCERS, FOR
EXAMPLE, THAT CAN BE TREATED
WITH EGF RECEPTOR ANTIBODIES AND
ACTUALLY YOU CAN HAVE RESISTANCE
TO THOSE EGFR ANTIBODIES DEVELOP
AND THE RESISTANCE, THOUGH, IS
MORE LINKED THAN TO THE
ANTIBODIES THAT WORK AGAINST E
GMENT F RECEPTORS.
SO FOR EXAMPLE, YOU'D HAVE MORE
THE MUTATIONS THAT ARE IN THE
EXTRACELLULAR DOMAIN OF EGF
RECEPTOR THAT WOULD CONFER
RESISTANCE TO THE ANTIBODIES.
WE DIDN'T TALK TOO MUCH ABOUT
ANTIBODIES TODAY AGAINST EGF
RECEPTOR, BUT SO THERE ARE
PARALLELS, I THINK, WITH REGARD
TO EGF RECEPTOR PLAYING A ROLE
IN OTHER CANCER TYPES AS WELL.
SOME OF THESE TYROSINE KINASE
INHIBITORS DON'T NECESSARILY
WORK AS WELL IN THESE OTHER
CANCER TYPES.
THEY SEEM TO WORK PARTICULARLY
WELL ON THESE LUNG CANCER
ASSOCIATED MUTATIONS.
>> SO IT WOULD BE OVERSIMPLIFIED
THEN TO SAY THAT WELL, WE COULD
JUST REORGANIZE OUR TAXONOMY OF
CANCER BY SAYING, WELL, THESE
ARE JUST ALL EGFR TUMORS AND
THEN WE HAVE THESE OTHER TUMORS
THAT ARE WHATEVER, KRAS TUMORS
OR WHAT HAVE YOU.
THEY DIFFER ACTUALLY IN THEIR
CHARACTERISTICS, NOT ONLY BY THE
KINASE INVOLVED, BUT BY THE
ANATOMIC ORIGIN OF THE TUMOR AS
WELL.
>> YES, ABSOLUTELY.
I THINK IT DEFINITELY -- I THINK
ACTUALLY IF ANYTHING, WE'RE KIND
OF GOING IN THE OTHER DIRECTION
OF REALLY SAYING WE'RE REALLY
UNDERSTANDING MORE ABOUT THE
DETAILS ABOUT HOW YOU HAVE THESE
DIFFERENT MUTATIONS OR DIFFERENT
INVOLVEMENT OF THE PATHWAYS AND
DIFFERENT TUMORS AND HOW THEY
CONTRIBUTE DIFFERENTLY IN
DIFFERENT ANATOMIC SITES.
AND THAT'S IMPORTANT TO KEEP IN
MIND AND THINK ABOUT.
>> OKAY.
ALL RIGHT.
WELL, NOW WE HAVE ANOTHER
QUESTION, JUST GOING BACK TO DR.
ARE THERE ANY CASES OF INCREASED
INTRACRANIAL PRESSURE IN
PATIENTS WITH BRAIN METASTASES
TREATED WITH IMMUNE CHECKPOINT
INHIBITORS?
>> THAT'S A GOOD QUESTION.
CERTAINLY INCREASED INTRACRANIAL
PRESSURE WOULD BE A SIGN OR A
SYMPTOM OF BRAIN METASTASES.
I GUESS THEIR THINKING IS
THEY'RE AN IMMUNE REACTION AND
SWELLING.
THAT, I THINK HAS BEEN REPORTED
BUT VERY RARELY.
I THINK WHAT WE'VE FOUND IS THAT
THESE DRUGS APPEAR TO GET ACROSS
THE BLOOD BRAIN BARRIER, THE
IMMUNE CHECKPOINT INHIBITORS,
AND THE IMMUNE EFFECT OCCURS AND
IT OCCURS IN AN EFFICACIOUS WAY
WITHOUT CAUSING SYMPTOMATIC OR
PROCESSES IN THE BRAIN THAT
REQUIRE INTERVENTION.
SO WE'RE VERY MUCH EVEN WITH
BIGGER LESIONS NOW TREATING
PATIENTS WITH IMMUNOTHERAPY IN
LUNG CANCER RIGHT NOW, THE MOST
COMMONLY USED THERAPY IS
CHEMOTHERAPY WITH PEMBROLIZUMAB
FOR PATIENTS WITH METASTATIC
DISEASE.
ANY -- WE DO IT FOR ALL
PD-L1 STATUS, EVEN THE ZEROS
BECAUSE IT'S THE BELIEF THAT
THERE WAS ACTIVITY, ZERO DOESN'T
ALWAYS MEAN YOU'RE ZERO, AND WE
ARE USING IT, YOU KNOW, WITH THE
BRAIN, BUT YOU WATCH CAREFULLY
AND YOU LOOK FOR CLINICAL SIGNS
AND YOU FOLLOW MRIs QUITE
FREQUENTLY.
>> OKAY.
WELL, THANK YOU VERY MUCH.
SO ANOTHER MEMBER OF THE
AUDIENCE IS ASKING THE QUESTION,
THE TUMOR MICROENVIRONMENT IS
VERY INTERESTING AND CANCER
METAMORPHOSIS IS VERY
INTERESTING AS WELL.
DOES IT CHANGE WITHOUT TREATMENT
AS WELL?
HAVE SPECIFIC DIETS DESCRIBED TO
BE CLINICALLY MEANINGFUL OTHER
THAN THE TYPICAL TEU AMER TURMER
CRUCIFEROUS VEGETABLES, THAT
LUNG CANCER PATIENTS SHOULD BE
ON TO POTENTIATE THEIR RESPONSE?
>> YOU WANT TO START, KATY,
ABOUT THE MICROENVIRONMENT?
>> I CAN COMMENT ON THE
MICROENVIRONMENT.
SO THE TUMOR MICROENVIRONMENT
CHANGES AS TUMORS PROGRESS.
SO YOU CAN HAVE CHANGES IN THE
MICROENVIRONMENT AS THE TUMOR
GETS LARGER, GETS MORE ADVANCED,
AND ALSO WHEN YOU HAVE
METASTASIS FOR EXAMPLE, I THINK
THAT'S ONE OF THE SITUATIONS IN
WHICH THE TUMOR MICROENVIRONMENT
CHANGES A LOT, BECAUSE SUDDENLY
A LUNG TUMOR IS NOW GROWING IN
THE CONTEXT OF THE LIVER OR THE
CONTEXT OF THE BRAIN.
I THINK ONE OF THE THINGS THAT
WE SEE FROM DIFFERENT THERAPIES,
YOU CAN SEE A LOT OF CHANGES IN
THE TUMOR MICROENVIRONMENT AND
ALSO THE ARCHITECTURE OF THE
TUMOR CHANGES.
SO YES, DEFINITELY THE TUMOR
MICROENVIRONMENT CHAIRNTION OVER
TIME, AND IT CHANGES EVEN WITH
DIFFERENT THERAPIES, NOT JUST
WITH IMMUNOTHERAPIES, RIGHT?
THE TUMOR MICROENVIRONMENT IS
COMPOSED OF BLOOD VESSEL CELLS,
IT'S COMPOSED OF SMOOTH --
DIFFERENT FIBROBLASTS, DIFFERENT
CELLS THAT HOLD EVERYTHING
TOGETHER.
SO YES, THERE ARE LOTS OF
CHANGES THAT HAPPEN.
>> SORRY, DANIEL.
>> NO, I WAS JUST GOING TO SAY
THAT IT SOUNDS LIKE THEN AS THE
TUMOR METASTASIZE, IT BECOMES
JUST MORE AND MORE DIFFICULT TO
USE A TARGETED THERAPY BECAUSE
OF THE FACT THAT THE TUMOR IS
RESIDING IN MULTIPLE DIFFERENT
MILIEUS.
>> AND I THINK ONE OF THE THINGS
THAT WE'RE TRYING TO UNDERSTAND
AT THE EXPERIMENTAL LEVEL NOW AT
LEAST IS HOW DIFFERENT MICRO
ENVIRONMENTS CONTRIBUTE TO THE
RESPONSE TO DIFFERENT TARGETED
THERAPIES, FOR EXAMPLE.
THERE MIGHT BE SOME MICRO
ENVIRONMENTS THAT ARE BETTER
THAN OTHERS.
SO WE JUST HAVE TO UNDERSTAND
THAT.
I THINK THERE'S STILL A LOT OF
WORK TO DO IN THAT ARENA.
>> I WAS GOING TO SAY, THAT'S
THE OLD SEED AND SOIL HYPOTHESIS
FROM YEARS AGO, AND TUMORS DO
BEHAVE DIFFERENTLY IN DIFFERENT
AREAS.
I THINK THE FACT THAT THE
MICROENVIRONMENT CAN CHANGE AND
WE HAVE TO THINK WHEN WE DO
COMBINATION THERAPIES WHAT IS
THE OTHER THERAPY DOING TO THE
MICROENVIRONMENT, THAT'S
IMPORTANT TO CONSIDER.
AND ACTUALLY WE JUST HAD A TALK
TODAY WHERE METABOLISM CAN HAVE
AN EFFECT ON THE
MICROENVIRONMENT.
I GUESS NUTRITION COULD AFFECT
METABOLISM, SO YES, I WOULD SAY
THIS IS DEFINITELY GOING TO BE
AN AREA IF WE THINK TO THE
FUTURE AND INNOVATION THAT COULD
BE IMPORTANT.
RIGHT NOW IN -- THERE ARE THINGS
I WOULD RECOMMEND LIKE TURMERIC
OR OTHER SUPPLEMENTS, BUT
SCIENTIFIC STUDY AND I'M SURE
THERE IS A BASIS TO HOW
AFFECTING THE METABOLISM AND
THAT ENVIRONMENT CAN HAVE AN
EFFECT ON THE MICROENVIRONMENT.
>> OKAY.
ANOTHER MEMBER OF THE AUDIENCE
IS ASKING WHY DON'T ALL SMOKERS
GET CANCER?
WHY ARE SOME PROTECTED?
>> THAT'S A GREAT QUESTION.
FIRST OF ALL, ONE THING I DIDN'T
MENTION BUT I'LL TELL YOU ABOUT
IS WITH IMMUNOTHERAPY WHICH
ACTUALLY I BELIEVE CAN CURE SOME
PATIENTS IT REALLY ONLY WORKS IN
SMOKERS.
SO SOMETIMES I'LL GIVE A LECTURE
AND PEOPLE LIKE SHOULD I HAVE
SMOKED OR SHOULD I START
SMOKING, THAT'S SORT OF IRONIC.
BUT BASICALLY WHY SOME SMOKERS
DON'T HAVE LUNG CANCER, IT'S ALL
GENETICS.
I HAD A GRANDMOTHER WHO LIVED TO
99, SHE SMOKED LIKE A CHIMNEY.
SHE HAD A LOT OF THINGS BUT SHE
NEVER HAD LUNG CANCER.
WE DON'T KNOW.
BUT STILL IF YOU SMOKE, YOUR
CHANCE OF GETTING LUNG CANCER IS
ENORMOUSLY HIGHER.
BY THE WAY, ONE THING I WANT TO
MAKE A CASE FOR, THIS CAME OUT
OF NIH AND NCI SPONSORED
RESEARCH IS SCREENING.
SO PEOPLE WHO SMOKE OR ARE
FORMER SMOKERS WITHIN 15 YEARS
SHOULD GET SCREENED.
ACTUALLY IT'S 20 YEARS NOW.
IT'S 20 PACK YEARS OF SMOKING.
BUT PEOPLE WHO SMOKE, SCREENING
SAVES LIVES AND WE NEED TO DO
MORE SCREENING FOR THAT.
I WORKED WITH THE LATE KEY HAHN,
WE MUST WORK ON SMOKING
CESSATION BUT THOSE PATIENTS WHO
STOP, WE NEED TO SCREEN THEM AND
FOLLOW THEM.
SO SOME PEOPLE, UR KNOW, SOME
PEOPLE DON'T HAVE GOOD DIET AND
THEY DON'T GET HEART DISEASE.
YOU GET LUCKY.
BUT SMOKING -- BY THE WAY, I'VE
BEEN VERY INVOLVED WITH AACR AND
OTHER ORGANIZATIONS ON THE
SMOKING TASK FORCES AND WE WORK
VERY CLOSELY WITH NCI.
TOBACCO STILL IS TOO HIGH.
WE'VE GOT IT DOWN, 13, 14% OF
THE POPULATION, CERTAIN PART OF
THE COUNTRY, CERTAIN SOASH YOAL
ECONOMIC GROUPS, SO SMOKING IS
DEFINITELY SOMETHING TO NOT DO.
>> AND YOU MENTIONED SCREENING,
SO OF COURSE ONE OF THE WAYS OF
SCREENING WOULD BE BY IMAGING
BUT WOULD THERE BE ANY UTILITY
FOR SCREENING BY LOOKING FOR
CELL-FREE DNA IN THE BLOOD?
>> KATY AND I WERE JUST
DISCUSSING THAT AT A MEETING
RECENTLY.
DO YOU WANT TO GO FIRST, KATIE?
>> I THINK THAT'S AN EMERGING
TECHNOLOGY, RIGHT?
AND I THINK PEOPLE ARE WORKING
ON USING CELL-FREE DNA FOR
SCREENING.
I THINK IF WE COULD, THAT WOULD
BE A REALLY IMPORTANT ADVANCE
AND PERHAPS A WAY OF GETTING
ACCESS TO MORE PEOPLE.
I MEAN, I THINK EVENTUALLY IT
WOULD BE IDEAL IF WE COULD USE
CELL-FREE DNA OR BLOOD-BASED
BIOPSY TECHNOLOGIES.
IT SOUNDS LIKE A BIOPSY BUT IT'S
ACTUALLY JUST DOING A BLOOD TEST
TO SCREEN FOR LUNG CANCER AND
OTHER CANCERS AS WELL
EVENTUALLY.
I DON'T THINK WE'RE QUITE THERE
YET, A LOT OF WORK TO DO BUT
HOPEFULLY THAT'S THE DIRECTION
THE FIELD IS GOING IN.
>> THERE ARE TWO TYPES OF WAYS
OF DOING THIS.
YOU HAVE A PATIENT WHO THAT'S'
'S HAD ATUMOR RESECTED, SHOULD T
ADJUVANT THERAPY OR NOT?
IN THE ADORA TRIAL, THERE WE CAN
DO A TUMOR INFORMED ASSAY, IT'S
MORE SENSITIVE BECAUSE YOU'RE
LOOKING AT MORE MUTATIONS,
DIFFERENT ASSAYS, METHYLATION
FRAGMENTATION.
THE ASSAYS ARE CONTINUING TO GET
BETTER AND BETTER.
CERTAINLY IF SOMETHING IS
POSITIVE IN SOMEONE WITH KNOWN
CANCER, I THINK THAT IS
CONCERNING, AND THAT'S SOMETHING
WE CAN FOLLOW.
THEN THERE'S THE SCREENING, THE
PEOPLE WHO DON'T HAVE CANCER
YET.
ONE OF THE REASONS WHY LUNG
CANCER SCREENING IS NOT AS
POPULAR AND THAT IS THE UPTAKE
HAS BEEN LOWER, IS IT'S NOT AS
EASY TO DO AS SCREENING FOR
BREAST CANCER OR COLON CANCER.
WITH COLON CANCER, YOU DO THE
PROCEDURE, YOU GO AND YOU
USUALLY DO THE PROCEDURE AND
YOU'RE DONE.
WITH BREAST CANCER, IT'S A LOT
EASIER TO DO THE BIOPSY.
SO NOT ALWAYS.
BUT IN LUNG CANCER, IF YOU SEE
SOMETHING THAT YOU DON'T KNOW,
YOU HAVE TO DO AN OPEN
PROCEDURE.
VIDEO-ASSISTED PROCEDURE.
IT'S A BIGGER DEAL.
THERE ARE TESTS NOW, YOU CAN
LOOK AT CELL-FREE DNA, MAYBE MAY
NOT BE POSITIVE.
THERE ARE ALSO COMPANIES OUT
THERE NOW THAT HAVE THESE
CLASSIFIERS THAT CAN LOOK AT
DIFFERENT PROTEOMIC CLASSIFIER
OR SOME SORT OF GENOMIC TEST TO
HELP DETERMINE YES OR NO IF THE
RISK IS HIGH.
ALL THESE THINGS NEED TO BE
STUDIED.
THE ONLY WAY THEY'RE GOING TO BE
STUDIED IS THROUGH, I WOULD SAY,
COLLABORATIONS.
I'D LIKE TO SEE THIS DONE
PERHAPS THROUGH THE SPORES, MOVE
TO EARLIER DISEASE, WE CAN
COLLECT THESE SAMPLES AND PULL
THEM TOGETHER.
IT'S SOMETHING THAT I'M VERY
DRIVEN TO DO IN THE NEXT PHASE
OF MY CAREER.
HAVING DONE THIS NOW FOR OVER 30
YEARS, I CAN TELL YOU, WE'LL DO
MUCH BETTER BY FINDING THESE
LUNG CANCERS EARLIER, SCREENING,
EITHER PREVENTING OR TREATING
THEM EARLY, EVEN WITH EVERYTHING
I'VE SHOWED WITH THE ADVANCES IN
METASTATIC DISEASE.
>> I THINK ANOTHER USE OF
CELL-FREE DNA IS ALSO EVEN IN
THE METASTATIC SETTING WHERE YOU
CAN IDENTIFY PATIENTS WHOSE
TUMOR IS NOT RESPONDING TO
TREATMENT, AND THEN CAN FOR
EXAMPLE ADD OTHER AGENTS OR
OTHER DRUGS.
SO YOU COULD START, FOR EXAMPLE,
IN THE CASE OF A PATIENT WITH E
IM. FR DRIVEN LUNG CANCER, START
WITH -- OSIMERTINIB BUT IF YOU
SEE THE CELL-FREE DNA IS STILL
THERE, THE MUTATION IS STILL
THERE IN THE BLOOD AFTER A
CERTAIN PERIOD OF TIME, THEN
MAYBE THAT IS THE SUBSET OF
PATIENTS FOR WHOM YOU'D LIKE TO
ADD ADDITIONAL THERAPY TO SEE
RESPONSES.
SO PEOPLE ARE EVALUATING THESE
TYPES OF CONCEPTS IN CLINICAL
TRIALS NOW, AND I THINK THEY'LL
BE VERY HELPFUL.
BECAUSE OF COURSE THERE'S
TOXICITY WITH ADDED TREATMENT SO
YOU ONLY WANT TO GIVE IF
NECESSARY.
>> ANOTHER MEMBER OF THE
AUDIENCE IS COMMENTING ON RADON.
AND COMMENTING THAT NO ONE TALKS
ABOUT RADON ANYMORE.
USED TO BE A BIG ISSUE.
WONDER WHY.
>> IT'S AN ISSUE FOR US HERE IN
CONNECTICUT.
YOU HAVE A BASEMENT, RADON IS A
CAUSATIVE FACTOR OF LUNG CANCER.
AS IS ASBESTOS.
I HAD BOTH IN MY BASEMENT.
YOU HAVE THESE RADON DETECTORS
AND THEIR ABATEMENT SYSTEMS.
LUNG CANCER -- SMOKING IS BY FAR
THE NUMBER ONE CAUSE WI BUT YOUE
GOT RADON, ASBESTOS, THEN OF
COURSE YOU'VE GOT POLLUTION.
THINGS IN THE AIR.
SOMETHING WE'VE HEARD A LOT
ABOUT FROM CHARLIE SWANTON AND
THE WORK HE'S REALLY LEADING OUT
OF ENGLAND.
SO NO, I THINK ONE DOES NEED TO
KEEP AN EYE OUT FORAY DONE, AND
CERTAINLY IF YOU LIVE IN AN AREA
WHERE IT'S PREVALENT, I WOULD
HOPE IT'S PART OF AN INSPECTION
FOR A HOME.
WHAT DO YOU THINK ABOUT, KATIE,
FORAY DONE?
>> I THINK IT'S BEEN DIFFICULT
TO STUDY, ESPECIALLY TO MODEL
THAT AND REALLY BE ABLE TO STUDY
THE EFFECTS OF RADON ON LUNG
CANCER.
I KNOW THERE ARE GROUPS THAT ARE
WORKING ON THIS.
SO SOMETHING THAT PEOPLE SHOULD
CERTAINLY BE AWARE OF AND MAKE
SURE THEY CHECK IN THEIR HOUSES.
>> OKAY, ANOTHER OF THE MEMBER
OF OUR AUDIENCE COMMENTS, GREAT
WORK, THANK YOU.
IS TUMOR HISTOLOGICAL
TRANSFORMATION TRIGGERED BY
TREATMENT WITH TYROSINE KINASE
INHIBITORS OR KRAS INHIBITORS,
OR IT MAY HAPPEN INDEPENDENTLY
OF THESE THERAPIES.
>> I THINK THAT'S A GREAT
QUESTION.
IT CAN ALSO HAPPEN INDEPENDENTLY
OF THE THERAPIES.
OCCASIONALLY YOU WILL SEE TUMORS
THAT HAVE A MIX OF HISTOLOGY.
SO ADENOCARCINOMA AND SQUAMOUS
CELL CARCINOMA OR ADENOCARCINOMA
AND SMALL CELL LUNG CANCER
INDEPENDENT OF THERAPIES.
WE'RE JUST SI SEEING THIS
TRANSFORMATION AND DETECTING
THAT IS ASSOCIATED WITH
TREATMENT, SORT OF MORE COMMONLY
NOW WITH THESE AGENTS.
>> I WOULD AGREE.
IT'S IMPORTANT TO KNOW BECAUSE
THE THERAPIES ARE VERY
DIFFERENT.
>> AND WOULD IT BE FAIR TO SAY
THAT ACTUALLY THE SUPRE SORT OF
ANCESTRAL CELL TYPE THAT GIVES
RISE TO THESE DIFFERENT LUNG
CANCERS IS THE SAME GOING TO
SMALL CELL TUMORS VERSUS
ADENOCARCINOMA VERSUS SQUAMOUS
CELL CARCINOMAS?
THEY SEEM TO BE AT LEAST CAPABLE
OF METAMORPHOSING FROM ONE TO
THE OTHER.
>> THE WAY WE THINK ABOUT IT, WE
THINK ABOUT DIFFERENT CELLS
GIVING RISE TO, SAY, SMALL CELL
LUNG CANCER AND DIFFERENT CELLS,
MORE PERIPHERAL ALVEOLAR CELLS
GIVING RISE TO LUNG
ADENOCARCINOMAS, FOR EXAMPLE,
BUT I THINK WE'RE LEARNING THAT
THERE ARE CELLS THAT HAVE A LOT
MORE -- ARE A LOT MORE PLASTIC.
THERE'S A LOT MORE OF AN ABILITY
TO SHIFT SORTD OF IN SORT OF ID
CELL STATE THAN I THINK WE
ORIGINALLY MIGHT HAVE THOUGHT.
>> AND THIS WOULD PRESUMABLY BE
AT LEAST IN PART DUE TO
EPIGENETIC CHANGES RATHER THAN
MUTATIONAL CHANGES?
>> YEAH, I THINK THERE'S A
COMBINATION OF THINGS THAT ARE
HAPPENING, SO THERE'S SOME
MUTATIONAL CHANGES THAT I THINK
SET THE STAGE FOR THEN THIS TYPE
OF HIS HIT OR MISS TOE LOGICAL
TRANSFORMATION TO BE ABLE TO
HAPPEN, IN PART THROUGH
EPIGENETIC CHANGES AS WELL.
SO I THINK IT'S PROBABLY A
COMBINATION OF FACTORS THAT
REALLY LINE UP.
AND YOU PROBABLY HAVE CELLS THAT
ARE POISED IN A CERTAIN
SITUATION, RIGHT, TO GO INTO ONE
DIRECTION OR GO IN A DIFFERENT
DIRECTION.
>> ANOTHER OF OUR MEMBERS OF THE
GROUP HERE IS ASKING, IS THERE A
ROLE FOR ENDO STATIN INHIBITORS
OF BLOOD SUPPLY IN LUNG CANCER?
THE SORT OF THING THAT JUDAH
FOLKMAN DISCOVERED YEARS AGO.
>> I'LL LET RAY ANSWER THAT
QUESTION.
HE'S WORKED A LOT WITH THESE.
>> I ACTUALLY DID NCI FUNDED
STUDIES OF ENDOSTATIN AND WORKED
WITH JUDAH.
YOU KNOW, ANGIOGENESIS IS
CLEARLY INVOLVED IN TUMOR
METASTASIS AND DRUGS THAT TARGET
ANGIOGENESIS ARE IMPORTANT, AND
THEY'RE USED IN A NUMBER OF
TUMOR TYPES, SMALL MOLECULES
THAT TARGET VEGF.
THE TYPE OF AMAZING RESPONSE
WHERE IT'S DESCRIBED IN MICE
WITH ENDOSTATIN WAS NEVER REALLY
SEEN IN PATIENTS.
SO THE IDEA THAT YOU COULD USE
AN AGENT THAT WAS WITHOUT
CHEMOTHERAPY THAT COULD TARGET
TUMOR BLOOD VESSELS AND MU TORES
WOULD SHRINK AND METASTASES
WOULD SHRINK WOULD NEVER BE
SEEN.
BUT I WILL TELL YOU THAT
CERTAINLY IN LUNG CANCER, I'LL
JUST FOCUS ON THAT, VEGF
INHIBITION HAS ACTUALLY BECOME
UP WITH OF THE MOST HOT TOPICS,
I'M ACTUALLY WRITING AN
EDITORIAL ON IT RIGHT NOW, NEWS
AND VIEWS, BECAUSE THEY'RE RIGHT
NOW SPECIFIC AGENTS THAT TARGET
PD-1 AND VEGF THAT ACTUALLY
STUDIES ALBEIT IN CHINA BEING
REPEATED IN THE U.S. HAVE SHOWN
SUPERIOR PROGRESSION-FREE
SURVIVAL IN METASTATIC LUNG
CANCER OVER IMMUNOTHERAPY ALONE.
WHY IS THAT WORKING?
IT IS KNOWN THAT VEGF DOES HAVE
SOME EFFECT ON IMMUNE
PRESENTATION, SO THAT COULD BE
ONE OF THE THINGS.
I DON'T KNOW IF SHE'S ON THE
LINE BUT MY OLD MENTOR AND
FRIEND BEV TYSHIRE WHO I WORKED
WITH AT DANA FARBER YEARS AGO
SHOWED THAT YOU HAVE AN EFFECT
ON TUMOR BLOOD VESSELS AND YOU
ACTUALLY EYE WRONGLY INCREASE
FLOAL, SO IT COULD BE A WAY TO
INCREASE T-CELL INFILTRATION
INTO TUMORS.
A NUMBER OF APPROACHES WE'RE
LOOKING AT HERE IN OUR LAB WITH
LEIPING CHEN AND OTHERS TO DO SO
AS WELL.
SO YES, I THINK THERE'S PROMISE,
CERTAINLY IN MACULAR
DEGENERATION, WE USE VEGF
INHIBITORS.
SO VEGF IS THERE BUT I REMEMBER
WHEN I WAS A FELLOW AT DANA
FARBER AND JUDAH CAME AND TALKED
AND MADE GRAND ROUNDS, WE ALL
RAN UP, WE ALL WANTED TO WORK
WITH HIS LAB AND WORK WITH HIM
AND THE CONCEPT IS RIGHT, IT'S
JUST DIFFERENT AGENTS THAT WILL
GO FORWARD.
>> ALL RIGHT.
I THINK AT THIS POINT, ALL GOOD
THINGS HAVE TO COME TO AN END
AND THIS IS YET ANOTHER REALLY
SPECTACULAR GREAT THING THAT
WE'RE GOING TO HAVE TO CALL TO A
CLOSE.
THIS WAS REALLY, REALLY
WONDERFUL.
THANK YOU BOTH SO MUCH FOR THE
SPECTACULAR PRESENTATIONS.
WE'RE NOW TWO MINUTES AWAY FROM
OUR DEADLINE.
I GUESS I COULD THROW IN THAT
OBLIGATE QUESTION FOR ANY OF
THESE PRESENTATIONS, WHAT'S THE
ROLE OF THE MICROBIOME IN YOUR
WORK?
[LAUGHTER]
WE'LL WAIT FOR THE NEXT
PRESENTATION.
WE'LL INVITE YOU BACK FOR THAT,
I GUESS.
>> THAT WOULD BE GREAT.
THERE ARE A LOT OF PEOPLE
WORKING ON THE MICROBIOME IN
LUNG CANCER.
BUT WE HAVEN'T DONE WORK
DIRECTLY IN THAT AREA.
>> WELL, DR. KASTNER, YOU'RE A
WONDERFUL MODERATOR FOR A
PRINCETON GUY.
>> YES, WELL, THANK YOU!
YOU HAVE A GOOD AFTERNOON, AND
AGAIN, THANK YOU FOR EVERYTHING
THAT YOU'VE DONE.
AND ALL OF THE WORK THAT YOU'RE
DOING AND CONTINUING TO DO.
>> THANK YOU VERY MUCH.
>> WE APPRECIATE ALL THE SUPPORT
OF THE NCI AND NIH AND THE SPORE
GROUP BECAUSE IT'S BEEN A BIG
PART OF OUR WORK.