>>I'M NINA SCHOR, THE ACTING
DEPUTY DIRECTOR FOR INTRAMURAL
RESEARCH, AND IT TRULY IS MY
PLEASURE TO LAUNCH THIS ACADEMIC
YEAR'S NIH DIRECTOR'S SEMINAR
SERIES.
OUR SPEAKER THIS AFTERNOON IS
DR. ANDREA APOLO FROM NCI.
AS YOU KNOW, THE NIH DIRECTOR
SEMINAR SERIES PRESENTS
INVESTIGATORS WHO ARE NEWLY
TENURED, AND WE ARE IN FOR A
REAL TREAT THIS AFTERNOON.
DR. APOLLO I APOLO IS AN INTERNATIONALLY
RECOGNIZED RESEARCHER IN BLADDER
CANCER RESEARCH.
SHE GOT HER UNDERGRADUATE DEGREE
SUMMA CUM LAUDE FROM LEHMAN
COLLEGE, CITY UNIVERSITY IN
NEW YORK, WITH A BACHELOR OF
SCIENCE IN CHEMISTRY AND
BIOCHEMISTRY.
SHE THEN GOT HER MEDICAL DEGREE
AT ALBERT EINSTEIN COLLEGE OF
MEDICINE AND COMPLETED RESIDENCY
TRAINING IN INTERNAL MEDICINE AT
NEW YORK PRESBYTERIAN
HOSPITAL/WEILL CORNEL MEDICAL
CENTER IN NEW YORK CITY.
SHE THEN WENT ON TO A MEDICAL
ONCOLOGY FELLOWSHIP AT MEMORIAL
SLOANE-KETTERING CANCER CENTER
AND IN 2010 WAS RECRUITED TO THE
NATIONAL CANCER INSTITUTE AND
ITS PHYSICIAN-SCIENTIST EARLY
INVESTIGATOR PROGRAM,
SPECIFICALLY TO BUILD A
TRANSLATIONAL BLADDER CANCER
PROGRAM.
DR. APOLO SERVES HERE AT NIH AS
THE HEAD OF THE BLADDER CANCER
SECTION OF THE GENITOURINARY
MALIGNANCIES BRANCH AND THE
DIRECTOR OF THE BLADDER CANCER
JU TUMORS MULTIDISCIPLINARY
CLINIC.
SHE REALLY HAS BEEN INSTRUMENTAL
IN BUILDING CLINICAL TRIALS THAT
GO ALL THE WAY FROM FIRST IN
HUMAN STUDIES THROUGH PHASE III
CLINICAL TRIALS.
SHE'S A PROLIFIC SPEAKER,
MENTOR, AUTHOR.
SHE HAS WON MANY, MANY AWARDS,
BOTH HERE AT NIH AND NATIONALLY,
INCLUDING THE 2020 ARTHUR S.
FLEMMING AWARD FOR LEADERS WHO
MAKE AN IMPACT IN PUBLIC
SERVICE.
SHE RECEIVED TENURE FROM NIH IN
2021, AND IT'S WITH GREAT
PLEASURE THAT I INTRODUCE
DR. APOLO'S TALK ENTITLED:
DEVELOPMENT OF TARGETED AND
IMMUNE-BASED THEARPIES FOR
UROTHELIAL CARCINOMAS AND RARE
GENITOURINARY TUMORS.
DR. APOLO, WELCOME.
>> THANK YOU, DR. SCHOR, FOR
THAT WONDERFUL INTRODUCTION.
AND I'M ALSO VERY HONORED TO
HAVE DR. GOTTESMAN ON THE LINE,
WHO CAME ON A LITTLE EARLIER TOO
TO SAY HELLO.
SO THIS IS A TRUE HONOR TO BE
HERE TODAY.
I WANT TO TALK TODAY ABOUT DRUG
DEVELOPMENT AND RESEARCH WITHIN
OUR BLADDER CANCER PROGRAM AND
OUR RARE G.U. TUMORS PROGRAM
HERE AT THE NCI.
BUT I WANTED TO START OFF BY
ACKNOWLEDGING A PROGRAM THAT IS
DEAR TO MY HEART.
THIS IS THE NIH UNDERGRADUATE
SCO LASCHOLARSHIP PROGRAM.
I WOULDN'T BE WHERE I AM TODAY
WITHOUT THIS PROGRAM.
THIS PROGRAM WAS DEVELOPED FOR
MINORITIES OF DISADVANTAGED
BACKGROUNDS, AND THIS PROGRAM
PROVIDED ME A SCHOLARSHIP DURING
COLLEGE AND THE OPPORTUNITY TO
WORK AT THE NIH.
I WORKED HERE FOR THREE SUMMERS
DURING COLLEGE THROUGH THIS
PROGRAM, AND I WAS FIRST
INTRODUCED TO BIOMEDICAL
RESEARCH, AND MY LIFELONG
COMMITMENT TO RESEARCH FIRST
STARTED THROUGH THIS PROGRAM.
SO I JUST WANTED TO START OFF
WITH THAT ACKNOWLEDGMENT.
AND NOW I'LL GO AHEAD AND START
TALKING ABOUT BLADDER CANCER,
AND I WANTED TO GIVE YOU A
BACKGROUND ABOUT BLADDER CANCER
JUST TO KIND OF PUT OUR RESEARCH
INTO CONTEXT AND KIND OF WHERE
IT FALLS INTO THE PARADIGM AND
TREATMENTS OF BLADDER CANCER.
BLADDER CANCER IS ACTUALLY A
VERY COMMON CANCER IN THE UNITED
STATES WITH AN ESTIMATED 81,000
PATIENTS DIAGNOSED WITH BLADDER
CANCER IN THE UNITED STATES THIS
YEAR AND 17,000 PATIENTS WILL
DIE WITH THIS DISEASE.
THE MAJORITY OF THE TUMORS ARE
LOCALIZED TO THE BLADDER AND
MANAGED BY THE UROLOGIST, AND
THERE IS A PREDOMINENCE O -- A
MALE TO FEMALE PREDOMINENCE TO
THE DEVELOPMENT OF BLADDER
CANCER.
FOR METASTATIC DISEASE, THE
TREATMENT INCLUDES CHEMOTHERAPY,
IMMUNOTHERAPY WITH CHECKPOINT
INHIBITORS, ANTIBODY DRUG
CONJUGATES, TYROSINE KIE NICE
INHIBITOR TARGETING FGFR, BUT
THE AVERAGE SURVIVAL IS 14 TO 20
MONTHS, SO WE DEFINITELY HAVE A
LOT OF ROOM FOR IMPROVEMENT IN
TERMS OF THE TREATMENTS THAT WE
OFFER OUR PATIENTS.
THE RISK FACTORS FOR BLADDER
CANCER ARE MANY.
THE MAJORITY -- THE BIGGEST RISK
FACTOR IS SMOKING.
ANOTHER RISK FACTOR IS AROMATIC
AMINES THAT ARE ASSOCIATED WITH
CERTAIN OCCUPATIONS, LEATHER,
RUBBER, PAINTING WITH ANALINE
DYES, ALSO PRIOR PELVIC
IRRADIATION, SCHISTOSOMIASIS,
INDEMIC IN AFRICA, CAN LEAD TO
SQUAMOUS SELL OR UROTHELIAL CELL
CARCINOMA OF THE BLADDER.
CHRONIC CYSTITIS, CHRONIC
INFLAMMATION OF THE BLADDER IN
PATIENTS THAT HAVE, FOR EXAMPLE,
INDWELLING CATHETERS, PATIENTS
THAT ARE PARAPLEGIC.
IT CAN ALSO BE ASSOCIATED WITH
LYNCH SYNDROME OR HNPCC, AND
THIS IS GENERALLY UPPER TRACT
TUMORS.
SO PATIENTS OFTEN PRESENT WITH
PAINLESS HEMATURIA OR BLOOD IN
THE URINE, AND THEY UNDERGO A
CYSTOSCOPIC EVALUATION BY THE
UROLOGIST.
AND THIS IS A LITTLE CAMERA TO
TAKE A LOOK AT THE BLADDER, AND
THERE COULD BE -- FROM THERE,
THERE SHOULD BE A TRANS URETHRAL
RESECTION OF THE BLADDER TUMOR
THAT CAN BE DONE WHICH IS BOTH
DIAGNOSTIC AND CAN BE
THERAPEUTIC TOO.
AND THEN WE STAGE -- ONCE WE GET
THE TUMORS REMOVED, WE LOOK AT
THEM UNDER THE MICROSCOPE AND WE
STAGE THE GRADE OF THE TUMOR AND
THE DEPTH OF INNOVATION.
NON-MUSCLE INVASIVE BLADDER
CANCER INCLUDES TA, T1 AND
CARCINOMA IN SIGH TUT SITU, GENERALLY
SCRAPING OR RESECTION.
MUSCLE INVASIVE TUMORS, THESE
INCLUDE T2, T3, T4 TUMORS, ARE
REALLY MANAGED AS A
MULTIDISCIPLINARY APPROACH WITH
THE UROLOGIST, THE MEDICAL
ONCOLOGIST, AND EVEN THE
RADIATION BLADDER,
THE URETER, THE RENAL PELVIS AND
THE URETHRA.
SO THIS SCHEMA HERE SUMMARIZES
THE MANAGEMENT OF BLADDER CANCER
PATIENTS BASED ON THEIR STAGE,
AND IT DIVIDES IT BY NON-MUSCLE
INVASIVE, MUSCLE INVASIVE AND
METASTATIC DISEASE.
SO LIKE I WAS MENTIONING BEFORE,
NON-MUSCLE INVASIVE BLADDER
CANCER IS PREDOMINANTLY MANAGED
BY THE UROLOGIST WITH THE
SCRAPINGS, THE TURBTs, AND
THEN INTRAVESICAL THERAPY.
THE INTRAVEST CAL THERAPY THAT
IS MOST COMMONLY USED IS BCG,
BUT OTHER CHEMOTHERAPIES ARE
ALSO USED, AND THERE'S A LOT OF
CLINICAL TRIALS CURRENTLY BEING
DEVELOPED IN ORDER TO FIND
BETTER TREATMENTS FOR PATIENTS
THAT ARE BCG REFRACTORY TO
PREVENT RECURRENCE AND
PROGRESSIVE DISEASE.
HERE AT THE NCI, WE HAVE TWO
UROLOGICAL ONCOLOGISTS
SPECIALIZING IN BLADDER CANCER
WHO ARE ALSO WORKING ON
DEVELOPING NEW THERAPIES FOR
LOCALIZED DISEASE.
SO NEXT I WANTED TO TALK ABOUT
MUSCLE INVASIVE BLADDER CANCER,
WHICH IS VERY AGGRESSIVE.
THE PRIMARY TREATMENT IS YOU
TAKE THE BLADDER OUT WITH A
RADICAL SI STEC CYST STECT ME, ABOUT
HALF OF THE TUMORS COME BACK
METASTATIC.
IN ORDER TO IMPROVE UPON THAT,
WE HAVE INCORPORATED NEOADJUVANT
TREATMENT AND EVEN ADJUVANT
TREATMENT, SONN AND THIS IS WHY IT'S
A MULTIDISCIPLINARY TUMOR AND WE
OFTEN DISCUSS THESE PATIENTS
WITH OUR UROLOGIC ONCOLOGY
COLLEAGUES AND SOMETIMES
RADIATION ONCOLOGY COLLEAGUES.
SO PRIMARY TREATMENT IS A
RADICAL CYSTECTOMY, NOT ONLY
REMOVAL OF THE BLATTER BLADDER, IT ALSO
INVOLVES REMOVING THE
REGIONAL -- THE SEMINAL VESICLES
AND THE PROXIMAL URETHRA.
IN WOMEN, YOU REMOVE THE
URETHRA, THE UTERUS, THE
FALLOPIAN TUBES AND ANTERIOR
VAGINAL WALL SO IT'S A VERY BIG
SURGERY.
THEN YOU RECONSTRUCT THE
BLADDER.
THERE'S A LOT OF DIRN WAY DIFFERENT WAYS
OF DOING THAT, URINARY
DIVERSIONS WE CALL THEM.
THE MOST COMMON IS THE ILEAL
CONDUIT, THE ILEAL CONDUIT, A
PIECE OF THE BOWEL IS RESECTED,
IS CUT OUT OF THE BOWEL AND THEN
THE BOWEL IS REANASTOMOSED, AND
THEN THE URETERS ARE ATTACHED TO
THIS PIECE OF BOWEL AND THEN IT
GETS ATTACHED TO THE ABDOMINAL
CAVITY, THEN A STOMA IS FORMED
AND AN OPENING RIGHT IN THE
ABDOMINAL AREA AND THEN A BLAG
IS PLACE -- ABAG IS PLACED THERE AND YOU H AVE
CONTINUOUS FLOW OF URINE COMING
FROM THE KIDNEYS INTO THE BAG.
A CUTANEOUS CONTINENT RESERVOIR,
SOMETIMES WE CALL THESE AN
INDIANA POUCH.
THESE ARE RESERVOIRS MADE FROM
BOWEL AND THE PATIENT CAN
CATHETERIZE THEMSELVES IN ORDER
TO GET THE URINE OUT.
AND THEN THERE'S A NEO BLADDER,
USUALLY THE MOST HIGHLY SOUGHT
BUT VERY HIGH MAINTENANCE IN
THAT THE BOWEL, THE BOWEL POUCH
IS ATTACHED TO THE NATIVE
URETHRA.
THIS CAN ONLY BE DONE IN
PATIENTS WHERE WE KNOW THERE
ISN'T ANY TUMOR IN THE URETHRA,
SO THERE HAS TO BE A FROZEN
SECTION DONE BY THE UROLOGIST
DURING THE SURGERY, AND THEN THE
BOWEL IS ATTACHED TO THE
URETHRA, AND THE PATIENT
URINATES AS IF THEY HAD A NATIVE
BLADDER THROUGH THEIR URETHRA.
SO WITH THAT BACKGROUND, I
WANTED TO MOVE ON TO TALK ABOUT
OUR NCI BLADDER CANCER PROGRAM,
AND WE HAVE A LOT OF STUDIES OF
BOTH PRE-CLINICAL, AND CLINICAL
AND I BROKE IT DOWN INTO THREE
RESEARCH AIMS JUST TO KIND OF
ORGANIZE IT AND FOCUS ON THE
PROGRAM THIS WAY.
SO THE FIRST AIM IS TO DEVELOP
TARGETED AND IMMUNE-BASED
THERAPIES AGAINST MUSCLE
INVASIVE AND METASTATIC
UROTHELIAL CARCINOMA WITH A
FOCUS ON TYROSINE KINASE
INHIBITORS AND COMBINATION
STRATEGIES.
THE SECOND AIM IS TO DEVELOP
PROGRESS MOSGNOSTIC BIOMARKERS RECEIVING
THESE THERAPIES, BOTH TARGETED
AND IMMUNE BASED THERAPIES.
AND THE THIRD IS TO IDENTIFY
EFFECTIVE THERAPIES FOR ADVANCED
METASTATIC RARE BLADDER TUMORS,
SUCH AS URACHAL/ADENOCARCINOMA
AND OTHER RARE G.U. TUMORS.
AND THE OVERARCHING HIGH
POTASSIUM THESE WITH THESE AIMS
IS THE DETAILED UNDERSTANDING OF
THE MAJOR DISEASE DRIVERS AND
IMMUNE MODULATION BY ACTIVE
THERAPEUTIC AGENTS WILL RESULT
IN THE IDENTIFICATION OF
EFFECTIVE TREATMENTS AND
BIOMARKER STRATEGIES FOR THESE
TUMORS.
SO WHEN I WAS A FELLOW AT
SLOANE-KETTERING, I DID A COUPLE
TRIALS WITH AGENTS AND WE WERE
SEEING SOME VERY NICE EFFICACY,
SO WHEN I CAME UP TO THE NIH
ABOUT 12, ALMOST 13 YEARS AGO, I
COLLABORATED WITH DR. DON
BOTTARO, WHO ALSO HAD AN
INTEREST IN SMALL MOLECULE
INHIBITORS OF MULTIPLE TYROSINE
KINASES, AND WE STUDIED MULTIPLE
DIFFERENT AGENT AND STARTED
STUDYING CABOZANTINIB WAS ONE OF
THEM.
LIKE I SAID I DID WORK WITH
OTHER TARGETED VEGF AGENTS AND
WE SAW SOME NICE ACTIVITY,
PRE-CLINICAL ACTIVITY AND WERE
WONDERING WHICH TARGET IS THE
MOST IMPORTANT AND DR. BOTTARO
HAS STRONG INTEREST IN MET, THAT
LEADS TO MULTIPLE CYTOKINE
ACTIVATIONS INVOLVE IN
TUMORIGENESIS.
SO IN COLLABORATION WITH
DR. BOTTARO, WE WORKED ON
SEVERAL PRE-CLINICAL STUDIES AND
FOUND WITHIN OUR BLADDER CANCER
CELL PROTEINS THAT MET PROTEIN
WAS HIGHER THAN THOSE DERIVED
FROM HIGHER STAGE AND CELL LINES
RESPONDED TO HGT FIM STIMULATION
WITH INCREASED ACTIVATION OF
DOWNSTREAM SIGNALING PATHWAYS,
PI3K AND MAPK AND THAT
CABOZANTINIB REVERSES
HGF/MET-MEDIATED ACTIVATION.
WE CONFIRMED THESE EXPERIMENTS
USING SPECIAL HGF KNOCK-IN SCID
MICE AND FOUND THAT CABOZANTINIB
DECREASED TUMOR GROWTH OF THE
BLADDER CANCER.
SO THIS WAS VERY EXCITING AND
THIS WAS OUR RATIONALE FOR
INITIATING A CLINICAL TRIAL FOR
PATIENTS WITH ADVANCED BLADDER
CANCER.
THIS WAS FOR PATIENTS THAT WERE
REFRACTORY TO CHEMOTHERAPY, I
INITIATED A PHASE 2 STUDY OF
MODEL THERAPY CABOZANTINIB IN
THESE PATIENTS.
I INCLUDED PATIENTS NOT ONLY
WITH METASTATIC BLADDER CANCER
THAT ALREADY RECEIVED
CHEMOTHERAPY, BUT ALSO PATIENTS
WITH BONE -- DISEASE.
YOU CAN'T MEASURE THEIR TUMORS,
WE DON'T HAVE GOOD IMAGING
MODALITY TO MEASURE THE QUANTITY
AND THE RESPONSE OF THE TUMORS
IN THE BONE.
SO I INCLUDED AN EXPLORATORY
COHORT OF BONE-ONLY DISEASE AND
ALSO AN EXPLORATORY COHORT OF
PATIENTS WITH RARE BLADDER
HISTOLOGIES BECAUSE WE HAVE A
HIGH REFERRAL PATTERN HERE AT
THE NIH AND WE WANTED TO LEARN
MORE ABOUT THESE THERAPIES IN
THESE RARE TUMORS.
IMOWN SO WE REPORTED THE RESULTS
OF THIS PHASE TWO STUDY OF
MONOTHERAPY CABOZANTINIB AND WE
FOUND AN OVERALL RESPONSE RATE
OF 19%, WHICH WAS PRETTY
EXCITING IN PATIENTS THAT WERE
REFRACTORY TO CHEMOTHERAPY.
AND WE ALSO SAW RESPONSES IN THE
BONE, AND THAT WAS VERY
EXCITING.
THESE ARE SODIUM CHLORIDE,
PATIENTS WITH BONE DISEASE AND
THE SPOTS THERE ARE TUMORS THAT
YOU SEE IN THE PATIENTS AND THEN
THERE'S THE PRE AND THE POST AND
THESE ARE THREE DIFFERENT
PATIENTS PRE-TREATMENT AND THEN
POST TREATMENT WITH
CABOZANTINIB, WE SEE IMPROVEMENT
IN THE SODIUM FLUORIDE IN THESE
PATIENTS.
AND WE DID THIS IN COLLABORATION
WITH THE MOLECULAR IMAGING
BRANCH, FOR THE PET SCAN STUDY.
IN CORRELATIVE STUDIES, I HAVE A
TERRIFIC COLLABORATION WITH JANE
TREPELL'S LAB, WE FOUND THAT
CABOZANTINIB MODULATED PRIF LAL
BLOOD-IMMUNE SUBSETS INCLUDING
DECREASING CLASSICAL MONOCYTES
WHICH ARE PRO TEUM ROWGENIC,
INCLUDES THOSE THAT HAVE
ANTITUMOR ACTIVITY WHILE
MAINTAINING THE RATIO OF
CT8 CELLS TO T REGS.
IN GENERAL, WE SAW CABOZANTINIB
HAS IMMUNOMODULATORY PROPERTIES
OF BOTH IMMUNOSTIMULATORY CELLS
AND IMMUNOSUPPRESSIVE CELLS.
AND THESE PROPERTY MAY, WE
HYPOTHESIZE, MAY INTERACT TUMOR
SUPPRESSION AND IT PROVIDED US A
RATIONALE FOR COMBINING
CABOZANTINIB WITH AN
IMMUNOTHERAPY SUCH AS A
CHECKPOINT INHIBITOR.
AT THE SAME TIME, I WAS RUNNING
PHASE ONE TRIALS WITH CHECKPOINT
INHIBITORS AND SAW REMARKABLE
ACTIVITY WITH CHECKPOINT
INHIBITORS AND IT JUST MADE
SENSE TO COMBINE THESE TWO
AGENTS AS THEY WERE BOTH ACTIVE.
SO I INITIATED A PHASE ONE TRIAL
OF CABOZANTINIB DOUBLET PLUS
NIVOLUMAB AND IPILIMUMAB SO WE
WERE LOOKING FOR A SAFE DOSE FOR
THE DUB LE DOUBLET AND THE TRIP LET.
WE LOOKED AT EIGHT DIFFERENT
ESCALATING DOSES AND WE
PUBLISHED THIS IN JCO AND THIS
WAS A VERY HETEROGENEOUS GROUP
OF PATIENTS.
IT INCLUDED PATIENTS WITH
BLADDER CANCER, KIDNEY CANCER,
PROSTATE CANCER, GERM CELL
TUMORS, AND RARE G.U. TUMORS,
AND PATIENTS WITH VERY ADVANCED
DISEASE, 80% OF THEM HAD
VISCERAL METASTASES INCLUDING
BONE, LIVER OR LUNG DISEASE.
THESE ARE THE RESULTS.
WE SAW SOME VERY NICE RESPONSES
WITH THE DOUBLET AND TRIPLET
THERAPY.
THIS IS THE WATERFALL PLOT, WE
SAW AN OVERALL RESPONSE RATE OF
31% IN THIS HETEROGENEOUS GROUP
OF PATIENTS.
SO THAT WAS VERY EXCITING, AND
ONE OF THE THINGS ABOUT IT IS
THESE RESPONSES WERE DURABLE.
THIS STUDY WAS INITIATED IN
EARLY 2015, AND I HAD PATIENTS
THAT ARE STILL COMING BACK TO
CLINIC NOW, SEVEN YEARS LATER,
IN FOLLOW-UP.
SO PATIENTS THAT RESPOND
ACTUALLY RESPOND REALLY WELL AND
THE RESPONSES ARE DURABLE FNLT
SO THIS WAS VERY EXCITING TO US.
AND WE EXPANDED THE PHASE ONE
BECAUSE WE SAW THE ACTIVITY IN
THE FIRST 54 PATIENTS, WE
EXPANDED IT INTO MULTIPLE
DIFFERENT COHORTS IN BLADDER
CANCER AND KIDNEY CAN SE WE
LOOKED AT ADENOCARCINOMA,
URECHAL, SQUAMOUS CARCINOMA OF
THE BLADDER, WE LOOKED AT PENILE
CANCER, AND WE ALSO HAD A SMALL
COHORT, ABOUT 30 PATIENTS THAT I
WANT TO HIGHLIGHT, THAT
PREVIOUSLY HAD CHECKPOINT
INHIBITOR AND HAD PROGRESSED.
AND WE SAW IN -- THIS IS 30
PATIENTS, WE SAW A RESPONSE RATE
IN FOUR OF THESE PATIENTS THAT
WERE PRETTY REMARKABLE.
SO THESE PATIENTS, AGAIN, HAD
ALREADY HAD CHECKPOINT AND THEY
RESPONDED, AND WE PUBLISHED
THIS, THIS IS MY FELLOW,
DR. GIRARDI, WHO PUBLISHED AS
FIRST AUTHOR THIS MANUSCRIPT,
AND THESE RESPONSES WERE VERY
DURABLE.
I MEAN, THEY LASTED FOR A VERY
LONG TIME.
HERE I HAVE A CAT SCAN OF A
PATIENT AT BAS BASELINE, YOU CAN SEE
THESE TUMORS THAT THE ARROW IS
POINTING AT, THOSE ARE LARGE 5,
6 CENTIMETER TUMORS IN THE LUNG,
THE PATIENT HAD TO HAVE NINE
MONTHS OF -- WE PUT HER ON THE
CABO AP NIVO COMBINATION AND SHE
JUST HAD A REMARKABLE RESPONSE,
VERY DURABLE FOR SEVERAL YEARS,
THE CANCER NEVER CAME BACK IN
THE LUNGS, ACTUALLY WHEN IT DID
COME BACK, IT CAME BACK --
RECENTLY IT CAME BACK IN THE
BRAIN.
WHICH IS A SANCTUARY SITE.
SO THE PATIENT DID PASS AWAY
RECENTLY WITH BRAIN METASTASES.
BUT THE CANCER NEVER CAME BACK
IN THE LUNG, WHICH WAS VERY
INTERESTING.
I WANTED TO HIGHLIGHT
DR. BERNADETTE RETT, SHE'S IN
THE CLINICAL CENTER IN THE
RADIOLOGY DEPARTMENT, AND SHE
HELPS US MEASURE THESE LESIONS
ON A WEEKLY BASIS ON PATIENTS
THAT ARE UNDERGOING TREATMENT
WITHIN THESE CLINICAL TRIALS AND
WE'RE VERY GRATEFUL TO HER AND
ALL HER HELP, AND ALSO OTHERS
WHO COME TO OUR
MULTIDISCIPLINARY CLINIC THAT IS
RUN WEEKLY, WHERE WE REVIEW
THESE SCANS, WE REVIEW PATHOLOGY
AND WE DISCUSS COMPLICATED
PATIENTS WITH IN THE
MULTIDISCIPLINARY APPROACH WITH
UROLOGISTS AND RADIATION
ONCOLOGISTS.
SO I'M VERY GRATEFUL TO THEM FOR
ALL THEIR HELP.
SO WE HAD MULTIPLE EXPANSION
COHORTS.
WE ENROLLED 150 PATIENTS TO THE
STUDY, AND I PRESENTED THE
RESULTS, SO WE ALREADY PUBLISHED
THE 30 PATIENTS THAT WERE
PREVIOUSLY TREATED.
I PRESENTED THE RESULTS OF THE
120 PATIENTS THAT WERE
IMMUNOTHERAPY-NAIVE AS AN ORAL
PRESENTATION AND THE RESPONSES
WERE JUST REMARKABLE.
WE SAW AN OVERALL RESPONSE RATE
OF 38% WITH 11% COMPLETE
RESPONSE IN THIS, AGAIN, VERY
HETEROGENEOUS GROUP OF PATIENTS
WITH G.U. TUMORS.
SO BLADDER, KIDNEY, PROSTATE,
GERM CELL, AND RARE GENE TUMORS.
AND WE BROKE IT DOWN BY TUMOR
TYPE.
SO WHEN WE LOOKED AT THE KIDNEY
TUMORS, WE SAW A RESPONSE RATE
OF 63%, WHICH WAS REALLY, REALLY
HIGH.
AND BASED ON THE KIDNEY CANCER
DATA, WE WENT ON TO A PHASE 3,
SO EXCITED BY THIS DATA THEY
LAUNCHED A PHASE III STUDY IN
KIDNEY CANCER BASED ON OUR PHASE
ONE STUDY, AND IN BLADDER
CANCER, WE SAW AN OVERALL
RESPONSE RATE OF 42% WITH HALF
OF THOSE PATIENTS, 21%, HAVING A
COMPLETE RESPONSE.
SO VERY, VERY IMPRESSIVE.
THE RESPONSE IN PROSTATE CANCER
WAS NOT AS HIGH, BUT IT WAS A
SMALL COHORT, AND WE ALSO SAW
RESPONSES IN RARE TUMORS, WHICH
IS REALLY IMPORTANT BECAUSE
THERE'S NO STANDARD OF CARE FOR
PATIENTS WITH RARE G.U. TUMORS,
AND THIS INCLUDED PATIENTS WITH
ADENOCARCINOMA, URECHAL,
PATIENTS WITH SQUAMOUS CELL
CARCINOMA OF THE BLADDER,
PATIENTS WITH SPLAWL CELL
CARCINOMA OF THE BLADDER,
PATIENTS WITH PENILE CANCER, WE
SAW SOME VERY NICE RESPONSES.
AND WE ALSO TREATED PATIENTS
WITH GERM CELL BUT DIDN'T SEE
MUCH RESPONSE IN GERM CELL
TUMORS.
HERE'S A PICTURE OF A PATIENT
WITH PENILE CANCER.
HE HAD A FUNGATING MASS AT THE
BEGINNING, AND THEN AFTER FOUR
CYCLES OF TREATMENT, THAT MASS
REGRESSED WITH A VERY NICE
RESPONSE TO THE DOUBLELET -- TO
THE TRIPLET.
WE ALSO HAD SMALL NUMBERS BUT WE
LOOKED AT ALSO PATIENTS WITH
RENO MEDULLARY CARCINOMA AND DID
SEE SOME RESPONSES.
AND BASED ON THIS DATA, I
INITIATED THE ICONIC SPH STUDY, A
COOPERATIVE GROUP STUDY, A LARGE
NATIONAL TRIAL THROUGH THE
COOPERATIVE GROUPS FOR RARE
TUMORS, AND THIS STUDY IS
ONGOING RIGHT NOW, AND IT HAS
MULTIPLE DIFFERENT COHORTS.
IT HAS SQUAMOUS CELL CARCINOMA
OF THE BLADDER, SMALL CELL
CARCINOMA OF THE BLADDER,
ADENOCARCARCINOMA, KIDNEY CANCER
SUBSETS, COLLECTING DUCT RENAL
CELL CARCINOMA, RENAL MEDULLARY
AND OF COURSE I HAVE A GROUP FOR
MISCELLANEOUS TUMORS, FOR THE
RARE, RARE, RARE TUMORS AND ALSO
BONE-ONLY DISEASE, BECAUSE
AGAIN, BONE-ONLY DISEASE IS NOT
ELIGIBLE FOR A TRIAL THAT US A USES
OVERALL RESPONSE RATE.
SO I WANTED TO TALK ABOUT THE
CHECKMATE 90R STUDY BECAUSE I
WAS INVOLVED IN THE DEVELOPMENT
OF THIS PHASE 3 TRIAL AGAIN BASE
OND OUON OUR PHASE 1 DATA THAT WE SAW
WITH THE DOUBLE CABOZANTINIB AND
NIVOLUMAB, SO THIS TRIAL
ENROLLED PATIENTS RANDOMIZED TO
NIVOLUMAB OR CABOZANTINIB
VERSUS -- FOR PATIENTS WITH
METASTATIC KIDNEY CANCER.
THE OUTCOMES OF THIS STUDY WERE
PRESENTED AS ESMOL 2020 AND IT
DOUBLED THE PROGRESSION-FREE
SURVIVAL FOR THE PATIENTS WITH A
HAZARD RATIO OF .51, SO
EXCELLENT RESULTS, IT ALSO
IMPROVED OVERALL SURVIVAL IN
PATIENTS RECEIVING THE DOUBLET
WITH A HAZARD RATIO OF .6, AND
THE OVERALL RESPONSE RATE FOR
KIDNEY CANCER PATIENTS WAS 56%.
SO VERY EXCITING RESULTS VERSUS
27% SEEN WITH STANDARD -- SO THE
FDA GRANTED APPROVAL FOR THE
COMBINATION OF CABOZANTINIB AND
NIVOLUMAB FOR THE FIRST LINE
TREATMENT OF PATIENTS WITH
METASTATIC RENAL CELL CARCINOMA.
I WANTED TO MENTION THE COSMIC
313 STUDY THAT WAS JUST
PRESENTED A MONTH AGO AT ESMO IN
PARIS AT THE ANNUAL MEETING AS A
PLENARY SESSION, SO THIS IS THE
TRIPLE COMBINATION OF
CABOZANTINIB, NIVOLUMAB, AND
IPIMIBULAB, AGAIN BASED ON OUR
PHASE ONE DATA THAT WAS COMPARED
TO -- THIS HAD A DIFFERENT
COMPARATOR, IT WAS COMPARED TO
IMMUNOTHERAPY NIVOLUMAB AND --
IT WAS A PLACEBO CONTROLLED
STUDY FOR THE CABOZANTINIB AND
THE OUTCOMES SHOWED THIS IS THE
PRELIMINARY OUTCOMES OF THE
PROGRESSION-FREE SURVIVAL SHOW
THAT THE TRIPLE THERAPY HAD A
BENEFIT TO IMMUNOTHERAPY BY
ITSELF.
SO THESE ARE VERY EXCITING
RESULTS.
ALSO BASED ON OUR PHASE ONE
DATA, MANY OTHER STUDIES HAVE
STEMMED OUT, INCLUDING THE
PEDIGREE STUDY, WHICH IS A STUDY
INSTEAD OF ASKING THE QUESTION
OF THE COMBINATION, WHAT ABOUT
THE SEQUENCE, WHAT IF WE GIVE
THE IMMUNOTHERAPY FIRST AND IF
YOU RESPOND, YOU STAY ON THE
IMMUNOTHERAPY BUT IF YOU DON'T
RESPOND U ADD THE CABOZANTINIB
AND ADD CABONIVO, SEQUENTIAL
THERAPY, THIS IS THROUGH THE
ALLIANCE COOPERATIVE GROUP.
AND THEN MANY PHASE TWO STUDIES
IN OTHER TUMORS SUCH AT BREAST
CANCER, CARCINOID HEPATOCELLULAR
CARCINOMA, ENDOMETRIAL AND
UTERINE CANCER.
SO I WANTED TO NEXT TALK ABOUT
MY RESEARCH AIM TWO, WHICH
HIGHLIGHTS SOME OF THE BIOMARKER
WORK THAT I DID WITHIN THESE
TRIALS OF MONOTHERAPY
CABOZANTINIB AND MONOTHERAPY --
AND COMBINATION CABOZANTINIB
PLUS NIVOLUMAB WITH OR WITHOUT
IPIMIBULAB, AND WE CAN START OUT
WITH CABOZANTINIB MODEL THERAPY,
AND YOU KNOW, I PRE VAST THIS BY
SAYING I KNOW CABOZANTINIB HAS A
LOT OF DIFFERENT TARGETS.
I MEAN, THIS IS THE KINOME OF
CABOZANTINIB AND THE IC50 VALUES
ON THE RIGHT, AND YOU CAN SEE
THAT THERE ARE MULTIPLE RECEPTOR
KINASES THAT ARE TARGETED BY
CABOZANTINIB.
BUT YOU KNOW, WE WERE TRYING TO
FIGURE OUT WHICH IS THE MOST
IMPORTANT.
IS IT THE VEGF PATHWAY, IS IT
THE MET PATHWAY, SO WE STAINED
TUMORS IN PATIENTS THAT ENROLLED
IN OUR CABOZANTINIB STUDY FOR
MET THROUGH
IMMUNOHISTOCHEMISTRY.
THIS WAS A TREMENDOUS EFFORT.
WE HAD 67 SPECIMENS AND 46
PATIENTS WITH BLADDER CANCER,
WITH SMALL CELL BLADDER CANCER,
SQUAMOUS CELL CANCER OF THE
BLADDER, SARCOMATOID AND
ADENOCARCINOMA, AND WE LOOKED AT
THE STAINING BOTH IN THE PRIMARY
TUMOR AND IN THE METASTASES, AND
THIS WAS A TREMENDOUS EFFORT RUN
BY DR. MARIA MARIE KNOW AND
DR. MARK RAFELT AND
UNFORTUNATELY WE DID NOT FIND A
CORRELATION WITH THE IHC
STAINING AND THE OUTCOMES OF HOW
THE PATIENT DID.
ACTUALLY THERE WAS ACTUALLY
INTRAPATIENT HETEROGENEITY, SO
IF I HAD TWO OR THREE SPECIMENS
FROM THE SAME PATIENT IN
DIFFERENT SITES, YOU CAN HAVE
DIFFERENT STAINING OF THE MET
PATHWAY.
SO IT JUST SHOWS THAT THE MET MET
PROTEIN EXPRESSION IS VERY
HETEROGENEOUS AND THERE'S MORE
TO IN TERMS OF THE ACTIVITY OF
CABOZANTINIB.
BUT YOU KNOW, WE LOOKED AT
MULTIPLE DIFFERENT MARKERS, WE
LOOKED AT OTHER TUMOR MARKERS,
WE LOOKED AT SEQUENCING, WE
LOOKED AT MET AND HGF IN PLASMA,
WE LOOKED AT MET AND HGF IN
URINE.
WE LOOKED AT CTCs, WE LOOKED
AT A LOT OF DIFFERENT BIOMARKERS
IN TERMS OF TRYING TO FIND A
CORRELATION AND WE DID NOT FIND
CORRELATION WITH OUTCOMES WITHIN
THESE BIOMARKERS.
BUT WE LOOKED, AND I THINK IT'S
IMPORTANT THAT WE REPORTED THIS
AND WE PUBLISHED THIS.
WE DID FIND PATIENTS WITH HIGH
LEVELS OF PLASMA IL-6 HAD WORSE
PROGRESSION-FREE AND OVERALL
SURVIVAL AND WE KNOW IL-6 IS PRO
INFLAMMATORY CYTOKINE THAT CAN
DIRECTLY STIMULATE TUMOR GROWTH
AND METASTASES AND TARGETING
IL-6 HAS BEEN LIMITED RIGHT NOW
TO REUM TOE LOGIC DISORDERS AND
OTHER CONDITIONS SUCH AS COVID.
SO MOVING ON TO BIOMARKERS,
CABOZANTINIB AND NIVOLUMAB, AND
BIOMARKERS IN THE DOUBLE AND THE
TRIP LET.
I WANTED TO HIGHLIGHT ONE
BIOMARKER LOOKING AT THE CTC
BURDEN IN PATIENTS TREATED WITH
CABONIVO AND CABO NIVOIPI.
SHE'S A UROLOGIST, SHE WAS A
FELLOW WITH THE UROLOGIC
ONCOLOGY BRANCH THAT WORKED WITH
ME AND REALLY HAD A LOT OF -- A
STRONG INTEREST IN LIQUID
BIOPSIES FOR PATIENTS WITH
BLADDER CANCER, AND WE USED THE
IP EMPLATFORM AND WE FOUND
CTCs PRESENT IN 75% OF OUR
CASES, AND THE CTC BURDEN WAS
ASSESSED AT THREE DIFFERENT TIME
POINTS AT BASELINE, CYCLE TWO,
CYCLE THREE, AND WE SAW A
DECLINE OF THE CTCs WITH
THERAPY.
SO AS WE WOULD HOPE TO SEE, AND
THAT THE CTC BURDEN AT BASELINE,
WE USE FOUR CTCs, MORE THAN
FOUR OR LESS THAN FOUR IF THE
PATIENTS HAD MORE THAN FOUR,
THOSE PATIENTS WERE ASSOCIATED
WITH WORSE OUT COME IN TERMS OF
PFS AND OS.
AND WE ACTUALLY ALSO LOOKED AT
THE CTCs THAT WERE
PDL1 POSITIVE, ALSO ASSOCIATED
WITH A POORER PROGNOSIS.
AND THIS IS WHAT WE SEE ALSO IN
TUMORS.
AND YOU KNOW, USING THE EPIC
PLATFORM, WE LOOKED AT
IMMUNOFLUORESCENT MICROSCOPY AND
COMPUTER VISION ALGORITHMS TO
ASSESS THE MORPHOLOGY.
WHAT DOES THE CDC ACTUALLY LOOK
LIKE?
WE LOOKED AT IT IN TERMS OF THE
NUCLEUS -- WAS THE CELL
ELONGATED, AND WE IDENTIFIED
FIVE MORPHOLOGIC SUBTYPES WITHIN
OUR CTCs, WE CATEGORIZED THEM
A, B, C, D AND E, AND WE FOUND
THAT WITHIN SUBTYPE B AND D,
THESE PATIENTS THAT HAD THESE
CTCs, EVEN HAVING ONE OF THESE
CTCs, THESE PATIENTS DID
WORSE.
AT BASELINE AND AT CYCLE 2.
NOW WE'RE ALSO TESTING THIS IN
PATIENTS THAT HAVE MUSCLE
INVASIVE BLADDER CANCER AND
WHETHER THEY HAVE ANY CTCs AND
HOW THE MORPHOLOGIES ARE
DETECTED, HOW DOES THAT
CORRELATE WITH OUTCOME.
SO WE APPLIED THIS EPIC SIGH INS SCIENCE
DETECTION PLATFORM TO ALSO
QUANTIFYING T-CELL POPULATIONS
AND FOUND THAT PATIENTS WITH LOW
BASELINE CD4 T-CELL POPULATIONS
HAD A WORSE PFS AND A WORSE
OVERALL SURVIVAL.
AND WE ALSO FOUND THAT PATIENTS
WITH LOW CD8 T-CELL POPULATIONS
ALSO HAD WORSE PFS AND WORSE
OVERALL SURVIVAL.
AND THEN WE LOOKED AT THE
CD4 AND THE CD8 BASED ON THE
RESPONSE RATE, SO YOU CAN SEE
THE LEFT IS COMPLETE RESPONSE,
PRESSURE RESPONSE, STABLE
DISEASE AND PROGRESSIVE DISEASE,
AND THE PATIENT THAT HAD THE
HIGHER CD4 AND CD8 LEVELS HAD
HIGHER RATES OF CR AND PR RATE.
SO WE SAW THAT CABOZANTINIB HAS
IMMUNOMODULATORY PROPERTIES OF
BOTH IMMUNOSTIMULATORY CELLS AND
IMMUNOSUPPRESSIVE CELLS BUT WHAT
ABOUT WHEN WE COMBINE CABONIVO
AND -- WE LOOKED AT SUPPRESSOR
CELLS, TREATED, AND WHEN YOU
TREATED THEM WITH THE TRIPLET
AND THE DOUBLET, SUPPRESSOR
CELLS DECREASE AND A LOWER
NUMBER WAS ASSOCIATED WITH
BETTER OUT COME FOR SURVIVAL.
MONOCYTES SIGNIFICANTLY
DECREASED BY TREATMENT OF BOTH
THE TRIPLET AND DOUBLET AND --
HIGHLY INCREASED AFTER TREATMENT
IN CYCLE 2 AND CYCLE 3 WITH THE
TRIPLET BUT ONLILY MILDLY
INCREASED WITH THE DOUBLET.
-- CORRELATED WITH SURVIVAL IN
THE DOUBLET BUT NOT IN THE
TRIPLET.
SO WE HAVE SOME HYPOTHESES ABOUT
THIS, PATIENTS TREATED WITH THE
DOUBLET VERSUS THE TRIPLET MAY
BE ADAPTING RESISTANCE TO
PROLONGED -- WE'RE ACTUALLY
DOING ADDITIONAL STUDIES TOO IN
TUMOR, USING MULTIPLEX IHC
ANALYSIS TO ASSESS THE QUANTITY
AND LOCATION OF THE IMMUNE
SUBSETS WITHIN THESE TUMORS.
SO ALONG WITH TUMOR AND
PERIPHERAL BLOOD BIOMARKERS, I
ALSO INCLUDE SEVERAL IMAGING
AIMS IN THE PHASE ONE STUDY, AND
WE CURRENTLY HAVE A DATABASE OF
OVER 400 PET SCANS DONE WITHIN
THESE STUDIES, BOTH FDG AND
SODIUM FLUORIDE OR COMBINED, AND
WE'RE ANALYZING THESE IN
COLLABORATION WITH
DR. LINDENBERG AND DR. AMENA NAT
ONLY WITH THE OUTCOMES BUT ALSO
WITH BIOMARKERS SUCH AS CTCs
AND CTBNA.
IT'S A VERY IMPORTANT STUDY,
THIS IS THE PHASE III TRIAL THAT
I RUN THROUGH THE COOPERATIVE
GROUP AND IT HAS COMPLETED
ACCRUAL OF 700 PATIENTS, AND
THIS IS FOR PATIENTS THAT HAVE
MUSCLE INVASIVE BLADDER CANCER.
THEY'RE RANDOMIZED TO RECEIVE
PEMBROLIZUMAB VERSUS
OBSERVATION, AND WITH THE
PRIMARY OUTCOME OF OVERALL
SURVIVAL AND DISEASE-FREE
SURVIVAL.
SO WITH THIS TRIAL COMES A LOT
OF CORRELATIVES AND THAT'S ONE
OF THE WONDERFUL THINGS ABOUT
DOING THESE LARGE PHASE
3 TRIALS, IS THE OPPORTUNITIES
TO COLLABORATE WITH MULTIPLE
NATIONAL INVESTIGATORS AT
MULTIPLE DIFFERENT INSTITUTES
AND WITHIN THE NCI, SO WE'RE
DOING IMMUNE GENE SIGNATURE, RNA
SUBTYPING, TUMOR TCR CLONALITY,
IMMUNE PROFILING PBMCs,
IMMUNOMODULATORY CYTOKINES,
DIRECT HLA SEQUENCING AND
NEOANTIGEN PREDICTION.
ONE CORRELATIVE I WANTED TO
HIGHLIGHT IS A CT DNA ASSAY
WE'RE ACTUALLY DOING BOTH WITH
NATERRA AND FOUNDATION MEDICINE.
WHY THIS IS IMPORTANT IS
BECAUSE -- SO THE PATIENT
UNDERGOES A RADICAL SURGERY, AND
THEY'RE SUPPOSEDLY NAD, THERE'S
NO CANCER THAT'S DETECTED ON
IMAGING, BUT LIKE I TOLD YOU
EARLIER, ABOUT MORE THAN HALF OF
THOSE PATIENTS WILL HAVE THEIR
CANCER COME BACK, AND IT USUALLY
COMES BACK METASTATIC, SO IT
MEANS THAT THERE'S CIRCULATING
TUMORS GOING ON IN THE BODY THAT
WE JUST CAN'T DETECT, WE JUST
CAN'T SEE ANYTHING ON IMAGING,
BUT THERE'S -- OBVIOUSLY THESE
PATIENTS HAVE ALREADY MICRO
METASTATIC DISEASE, SO THAT'S
WHAT THIS MARKER IS GOING TO
LOOK AT.
AND THIS IS A PERSONALIZED ASSAY
WHERE WE TAKE THE TUMOR, THE
TUMOR TISSUE AND THE GERMLINE
MATERIAL FROM THE PATIENTS AND
WE DO WHOLE EXOME SEQUENCING,
AND LOOK AT THE MUTATIONS, UP TO
16 MUTATIONS ARE SELECTED FOR
PCR, CTDNA ASSAY FOR EACH OF
THESE PATIENTS AND THEN WE TAKE
THE PLASMA SAMPLES, WE SEQUENCE
THAT, AND IF WE FIND AT LEAST
TWO OF THE MUTATIONS THAT WE
FOUND IN THE TUMOR IN THE
PLASMA, THEN WE CONSIDER THOSE
PATIENTS CT DNA POSITIVE.
AND THERE'S A LOT OF DIFFERENT
AIMS THAT WE'RE LOOKING AT WITH
THE CT DNA ASSAY.
NUMBER ONE IS, PROGNOSTICLY.
THE PATIENTS THAT ARE CTDNA
POSITIVE, HOW DO THEY COMPARE TO
PATIENTS THAT ARE CT DNA
NEGATIVE.
ALSO, CAN WE CORRELATE THE CT
DNA WITH THE RESPONSE WE SEE IN
THE PATIENTS THAT DO GET
TREATMENT WITH PEMBROLIZUMAB,
WITH THE CHECKPOINT INHIBITOR.
AND ALSO WHAT IS THE LEAD TIME
OF CT DNA POSITIVITY VERSUS WHAT
WE SEE ON IMAGING?
SO THERE'S A LOT OF DIFFERENT
AIMS, OTHER QUESTIONS THAT WE
HAVE IS WHEN THE PATIENTS GET
PEMBROLIZUMAB, DO THEY CLEAR IT.
DO THEY CLEAR THEIR CT DNA, AND
WHAT ABOUT IF WE COMBINE CT DNA
AND TUMOR MUTATION OF BURDEN OR
PDL1 STATUS AND USE IT AS A
MULTIMODAL BIOMARKER TO ASSESS
OUTCOMES IN THESE PATIENTS.
SO THERE'S A LOT OF QUESTIONS,
AND I'M VERY EXCITED ABOUT THIS
CORRELATIVE THAT WE'RE DOING.
ANOTHER STUDY THAT I WANTED TO
MENTION IS A STUDY WITH
AVELUMAB.
I WAS VERY FORTUNATE TO BE ASKED
TO RUN THE BLADDER CANCER
COHORT, AND WE DID THAT AND WE
SAW SOME VERY NICE RESPONSES,
18% RESPONSE, AND THESE ARE
THE -- THIS IS THE PHASE ONE
STUDY I WAS TELLING YOU ABOUT.
I WAS RUNNING THE CABOZANTINIB
AT THE SAME TIME AND I WAS
RUNNING THIS ONE, AND WE SAW
SOME VERY NICE RESPONSES IN
PATIENTS THAT WERE DURABLE.
SO 18% RESPONSE WITH DURABLE
RESPONSES.
AND BASED ON THIS FINDING, WE
EXPANDED THE BLADDER CANCER
COHORT TO 250 PATIENTS, AND
AGAIN CONSISTENTLY SAW 18%
RESPONSE RATE IN THESE PATIENTS
AND BASED ON THIS DATA IN 2017,
THE FDA GRANTED ACCELERATED
APPROVAL FOR AVELUMAB FOR THE
SECOND LINE TREATMENT OF
PATIENTS.
THIS WAS PRESENTED AT THE
PLENARY SESSION IN 2020.
AFTER CHEMOTHERAPY, USUALLY WE
DO NOTHING, BUT WHAT ABOUT
GIVING AVELUMAB AT THAT POINT
VERSUS GIVING NOTHING, AND 700
PATIENTS WERE RANDOMIZED WITH
THE PRIMARY OUTCOME OF OVERALL
SURVIVAL, AND THERE WAS A
SURVIVAL BENEFIT FOR PATIENTS
THAT RECEIVED AVELUMAB VERSUS
THE PATIENTS THAT RECEIVED BEST
SUPPORTIVE CARE.
BASED ON THIS DATA, AVELUMAB NOW
RECEIVED A SECOND APPROVAL IN
JUNE 2020, SO NOW IT HAS THE
APPROVAL FOR THE SECOND LINE
STUDY AND THAT ALSO HAS APPROVAL
FOR THE MAINTENANCE STUDY.
SO VERY PROUD OF THE DEVELOPMENT
AFTER MAN ALSO THROUGDEVELOPMENTAFTERDEVEL OPMENTOF DEVELOPMENT
OF AVELUMAB.
THIS STUDY, THIS MOLECULE
POTENTIALLY CAN OVER --
POTENTIALLY CAN OVERCOME
RESISTANCE IN PATIENTS RESISTANT
TO CHECKPOINT INHIBITORS.
WE HAVE A PHASE ONE TRIAL IN
COMBINATION WITH IL12 AND IN
COMBINATION WITH RADIATION AT
MULTIPLE DIFFERENT DOSES, SEEING
IF WE CAN ENHANCE THE EFFECT
THAT WE SAW ALREADY WITH
MONOTHERAPY AVELUMAB WITH THESE
COMBINATIONS.
I DON'T HAVE A LOT OF TIME BUT I
DID WANT TO MENTION MY THIRD
AIM, WHICH IS TO DEVELOP
EFFECTIVE THERAPIES FOR PATIENTS
WITH RARE TUMORS.
AND WE ALREADY TALKED ABOUT THE
CABONI.
NIVO IPI STUDY.
THIS IS FOR RARE TUMORS.
THE STUDY HAS ALREADY ACCRUED
163 PATIENTS, AND WE HAVE SEEN
SOME VERY NICE ACTIVITY AND ARE
PLANNING ON EXPANDING THESE
COHORTS.
AND BECAUSE WE SEE THESE RARE
TUMORS AT THE NCI, I HAVE A
NATURAL HISTORY STUDY THAT I
OPENED, SO WE CAN BETTER LEARN
ABOUT THE NATURAL HISTORY OF A
LOT OF THESE RARE TUMORS FROM
DIAGNOSIS TO DEFINITIVE THERAPY
TO SYSTEMIC THERAPY TO DEATH.
ALL OF THE STAGES IN BETWEEN
WHERE WE COLLECT TUMOR, PLASMA,
SALIVA, URINE, AND DO IMAGING TO
REALLY UNDERSTAND THE NATURAL
HISTORY OF THESE RARE G.U.
TUMORS.
WE HAD AN AUTOPSY PROGRAM HERE
AT THE NCI.
WE HAVE A RAPID AUTOPSY PROTOCOL
WE'RE A PART OF BUT MOST OF OUR
AUTOPSIES, WE'VE DONE ABOUT 35
AUTOPSIES ON OUR PATIENTS, MOST
OF THEM ARE NOT RAPID, AND I
REALLY WANT TO THANK DR. KLEINER
AND DR. THAN HUITT FOR REALLY HELPING
US WITH DOING THESE AUTOPSIES
AND THE EDUCATIONAL COMPONENT TO
OUR STUDENTS.
I WANT TO ALSO HIGHLIGHT TWO
OTHER STUDIES WITH ANTIBODY
CONJUGATES.
ONE IS AN ANTIBODY DRUG
CONJUGATE THAT TARGETS NECTIN-4.
THE LINGER RELEASES THE
CYTOTOXIC AGENT WHEN IT GETS TO
THE TARGET, HIGHLY EXPRESSED IN
BLADDER TUMORS AND NOW WE HAVE
150 SPECIMENS FOR RARE TUMORS
THAT WE'RE TESTING NECTIN-4 TO
SEE IF WE CAN POTENTIALLY USE
FOR THESE RARE TUMORS, AND
THERE'S ALREADY LITERATURE
SHOWING THAT NECTIN-4 IS
EXPRESSED IN SOME OF THESE RARE
TUMORS SO WE HAVE INITIATED A
PHASE 2 TRIAL WHERE WE TEST EV
IN PATIENTS AND THIS IS MY
FELLOW RIGHT NOW THAT'S HELPING
ME DEVELOP THIS, WHERE WE TEST
EV WITH OR WITHOUT IMMUNOTHERAPY
IN THESE RARE TUMORS.
ANOTHER ANTIBODY DRUG CONJUGATE
DIRECTED TOWARD TROP 2 WITH
SN-38, THE PARENT COMPOUND --
WE'VE SEEN ACTIVITY IN BLADDER
CANCER, SO I'M ALSO GOING TO
CONDUCT A TRIAL AND THIS WAS DR. KIDD, ONE OF MY FELLOWS
HELPED ME DEVELOP THIS CLINICAL
TRIAL TO TEST IN PATIENTS WITH
RARE TUMORS.
THIS IS IN DEVELOPMENT.
WE ALSO HAVE ANOTHER TRIAL IN
SMALL WEL CELL PATIENTS THAT OUR
FELLOW NOW ATTENDING DR. SIMON
HAS HELPED US DEVELOP IN
PATIENTS WITH SPLAWL CELL
BLADDER CANCERS.
THIS STUDY IS ALSO IN
DEVELOPMENT.
SO WHEN I JOINED THE NCI ALMOST
13 YEARS AGO, THERE WAS NO
BLADDER CANCER PROGRAM AND HI A
VISION OF INITIATING A
TRANSLATIONAL BLADDER CANCER
PROGRAM FOCUSING ON
SCIENCE-DRIVEN CLINICAL TRIALS
AT MULTIPLE STAGES OF DISEASE,
INCLUDING METASTATIC, FIRST
LINE, SECOND LINE AND BEYOND,
MUSCLE INVASIVE AND NON-MUSCLE
INVASIVE, AND WE HAVE CREATED A
LARGE BLADDER CANCER PROGRAM
WITH A LOT OF CLINICAL TRIAL
OPTIONS FOR OUR PATIENTS AT
MULTIPLE DIFFERENT STAGES.
SO THE PINK ARE TRIALS THAT HAVE
BEEN COMPLETED.
THE GREEN ARE TRIALS THAT ARE
OPEN AND ACCRUING RIGHT NOW, AND
THE PURPLE ARE TRIALS JUST ABOUT
TO OPEN THAT ARE IN DEVELOPMENT.
AND IT HAS BEEN REALLY THROUGH
HELP WITH OUR CLINICAL
COLLABORATORS TO HELP US RUN
THESE TRIALS IN THE UROLOGIC
ONCOLOGY BRANCH, WITH OUR
UROLOGISTS, OUR RADIATION
ONCOLOGISTS, OUR PATHOLOGISTS,
AND OUR INTERVENTIONAL
RADIOLOGIST.
BUT EVEN DOING THESE TRIALS, IT
IS REALLY THROUGH COLLABORATION
WITH OUR SCIENTIFIC
COLLABORATORS, OUR COLLEAGUES,
IMMUNOLOGISTS, MICRO BIOLOGISTS,
GENOMICS AND A PHARMACOLOGIST,
THAT WE CAN SPA UNDERSTAND THE
MECHANISMS OF THESE DRUGS, WHY
THEY WORK IN CERTAIN PATIENTS
AND NOT IN OTHERS THAT I HAVE
REALLY BEEN ABLE TO BUILD THIS
TRANSLATIONAL PROGRAM.
SO WITH THAT, I THANK YOU SO
MUCH FOR YOUR ATTENTION, AND I
WANT TO GIVE A SPECIAL THANK YOU
TO MY MENTORSHIP COMMITTEE.
I KNOW I'M TENURED, I BECAME
TENURED IN NOVEMBER, BUT THEY
HAVE HELPED ME OVER THE LAST 10
YEARS GET HERE.
MY WONDERFUL BLADDER CANCER
TEAM.
MILMY WONDERFUL RESEARCH NURSES.
OUR PATIENT CARE COORDINATOR,
OUR FANTASTIC PHARMACIST, AND
OUR VOLUNTEER WHO ALWAYS COMES
TO CLINIC.
OUR LAB COLLABORATORS, AND WE
HAVE A NEW LAB PERSON, A NEW
STAFF SCIENTIST THAT IS JUST
JOINING US, ALSO STARTING THE
GENOMICS STUDIES IN BLADDER
CANCER, SO VERY EXCITED TO HAVE
HIM, AND OUR LONG TERM
COLLABORATIONS, AND THANK YOU SO
MUCH, EVERYBODY, FOR YOUR
ATTENTION.
I REALLY APPRECIATE YOUR TIME.
>> WELL, THANK YOU SO MUCH FOR
THAT, ANDREA.
THAT WAS A TRULY ELEGANT
PRESENTATION.
WE CERTAINLY HAVE TIME FOR
QUESTIONS IF YOU WOULD PLEASE
SEND IN YOUR QUESTIONS.
I DO HAVE A COUPLE OF QUESTIONS
WHILE PEOPLE ARE WAITING TO SEND
IN THEIRS.
SO YOU STARTED OFF TALKING ABOUT
STANDARD OF CARE TREATMENT FOR
PATIENTS WITH BLADDER CANCER AND
THE SURGERIES INVOLVED FOR
MUSCLE INVASIVE BLADDER CANCER
WITH CYSTECTOMY AND THE
NEOBLADDER FORMATION AND THE
SIGNIFICANT MORBIDITY, REALLY,
THAT THAT DOES AFFORD PATIENTS.
I'M WONDERING, NOW THAT WE SAW
IN JUNE THE BEAUTIFUL PAPER,
JUST 12 PATIENTS EARLY ON WITH
MSI HIGH RECTAL CANCER SHOWING
THAT MAYBE WE DON'T NEED TO
IMMEDIATELY TREAT THESE PATIENTS
AND MAYBE WITH IMMUNOTHERAPY
APPROACHES BY THEMSELVES, WE CAN
SEE TUMORS THAT GO AWAY AND STAY
AWAY.
WHAT ARE THE OPPORTUNITIES HERE
IN BLADDER CANCER, AND HOW IS
THE FIELD CAPITALIZING ON SOME
OF THIS RESEARCH?
>> THANK YOU.
THANK YOU FOR ASKING ME THIS.
THIS IS SOMETHING THAT I HAVE
BEEN WORKING ON IN DEVELOPING
THROUGH THE COOPERATIVE GROUP.
AND WE HAVE A PROTOCOL IN
DEVELOPMENT RIGHT NOW TO SPARE
PATIENTS FROM UNDERGOING THESE
RADICAL SURGERIES, BUT ONLY FOR
PATIENTS THAT ARE MSI HIGH, OR
HAVE MISMATCHED REPAIR
DEFICIENCY, WHICH FOR BLADDER
CAN SE IT'S A SMALL PERCENTAGE,
IT'S 1 TO 2%, BUT FOR UPPER
TRACT TUMORS, IT'S ACTUALLY 8 TO
9%.
SO THE STUDY RIGHT NOW AS WE
HAVE IT PLANNED IS GOING TO
ENROLL ABOUT 800 TO 1,000
PATIENTS TO TREAT 50.
SO IT'S A BIG SCREENING EFFORT
IN ORDER TO FIND THOSE PATIENTS
THAT MAY BENEFIT FROM
IMMUNOTHERAPY WITHOUT UNDERGOING
THESE RADICAL SURGERIES.
SO THIS IS AN EFFORT THAT'S
ONGOING RIGHT NOW.
WE HAVE THE CONCEPT OF
PUT-THROUGH.
IT'S BEEN PRELIMINARILY APPROVED
BY THE COMPANY, AND WE HAVE A
MEETING NEXT WEEK WITH THE
ALLIANCE TO DISCUSS IT SOME
MORE.
BUT THAT'S FOR A REALLY SMALL
GROUP OF PATIENTS.
THAT'S FOR PATIENTS THAT HAVE
MISMATCH REPAIR DEFICIENCY,
WHICH IS A REALLY SPECIAL
PATIENT POPULATION.
THERE HAVE BEEN SO MANY EFFORTS
RIGHT NOW THAT ARE IN PLACE AND
ARE ONGOING LOOKING INTO ALL
BLADDER CANCERS.
WELL, WHAT ABOUT IF WE DO
RADIATION, WHAT ABOUT IF WE DO
CHEMO RADIATION, AND THEN NOT
TAKE THE BLADDER OUT AND HOW DO
THOSE PATIENTS DO, WE HAVE
SEVERAL TRIALS WITH TRI-MODALITY
THERAPY, WE CALL IT TRI-MODALITY
THERAPY, THAT HAVE SHOWN THAT
PATIENTS CAN HAVE A GOOD LIFE
WITH A RADIATED BLADDER, AND
HAVE GOOD FUNCTION AND KEEP
THEIR BLADDERS.
SO THERE'S A LOT OF INTEREST IN
IDENTIFYING WHO ARE THE BEST
PATIENTS, BECAUSE THERE'S THIS
RISK, RIGHT, THAT THEY'RE GOING
TO DEVELOP METASTATIC DISEASE,
SO WE HAVE THIS FEAR, CAN WE
SELECT THESE PATIENTS USING
BIOMARKERS, SO THERE'S A LOT OF
EFFORT IN THAT FIELD, AND THIS
IS SOMETHING THAT OUR UROLOGIC
ONCOLOGY COLLEAGUES AND OUR
RADIATION ONCOLOGY COLLEAGUES
ARE ALSO DISCUSSING ABOUT
DEVELOP AGO TRIAL HERE AING A TRIAL HERE A T THE
NCI TO A CYSTECTOMY-FREE STUDY
IN ORDER TO -- PATIENTS CAN KEEP
THEIR BLADDERS, WHICH IS REALLY
WHAT THEY WANT.
PATIENTS WANT TO KEAP THEIR KEEP THEIR
BLADDERS.
SO THERE ARE A LOT OF EFFORTS
ONGOING RIGHT NOW EVEN FOR
PATIENTS THAT DON'T HAVE DNA
REPAIR GENES, THAT DO NOT HAVE
MISMATCH REPAIR AND ARE NOT
MSI-HIGH.
>> RIGHT, AND I THINK THESE
EFFORTS WILL CONTINUE.
JUST ALSO FOR THE AUDIENCE WHO
MAY NOT BE AS FAMILIAR, JUST
GIVE US A LITTLE BIT ABOUT THE
UPPER TRACT DISEASE AND HOW THAT
TYPICALLY FAIRS COMPARED WITH
LOWER TRACT DISEASE.
>> THANK YOU FOR ASKING.
UPTRACT DISEASE, THERE WAS A --
IT WAS FOR A LONG TIME THOUGHT
IT WAS MORE AGGRESSIVE THAN
BLADDER TUMORS, BUT THEN THERE'S
ALSO THISH YO THE ISSUE OF DIAGNOSING
UPPER TRACT DISEASE.
IT CAN BE VERY DIFFICULT TO
DIAGNOSE THESE, BECAUSE YOU KNOW
HOW I SHOWED YOU THE UROLOGIST
GOES IN AND TAKES A LOOK AT THE
BLADDER, GOING UP THE URETER IS
SO NARROW AND THEN LOOKING AT
THE RENAL PELVIS, IT'S SO EASY
TO MISS A TUMOR THAT IS IN THE
UPPER TRACT, SO A LOT OF TIMES
YOU'LL HAVE SOMETHING LIKE A
POSITIVE CYTOLOGY, WHICH IS A
URINE TEST THAT LOOKS AT CELLS,
BUT YOU DON'T SEE ANYTHING.
SO WHAT ARE YOU SUPPOSED TO DO?
SO IT'S VERY FRUSTRATING, AND
SCARY BECAUSE YOU FOLLOW THESE
PATIENTS WITH IMAGING AND WE
HAVE A TERRIFIC IMAGING PROGRAM
HERE WITH A LOT OF RADIOLOGISTS
INTERESTED IN BLADDER CANCER, SO
WE'RE VERY LUCKY, AND WE'RE
TRYING TO DEVELOP PROTOCOLS IN
ORDER TO DO SPECIFIC IMAGING
TECHNIQUES TO FOLLOW THESE
PATIENTS, AND LOOKING AT THE
UPPER TRACK WITH DELAYED
CONTRAST IMAGING TO SEE IF WE
CAN SEE MASSES, BUT WE REALLY
STRUGGLING IN THE INITIAL
DIAGNOSIS AND EVEN IN THE
BIOPSY.
I TOLD YOU WHEN WE BIOPSIED
PATIENTS UNDERGOING -- WE LOOK
AT DEPTH OF INNOVATION.
YOU CAN'T REALLY DO THAT IN THE
URETER AND RENAL PELVIS.
GETTING MUSCLE IS, YOU KNOW,
SOMETIMES IMPOSSIBLE AND
SOMETIMES DANGEROUS.
SO YOU'RE GOING TO GET SOMETHING
LIKE HYDRATE BUT YOU DON'T
KNOW -- WHAT DO YOU DO WITH
THESE PATIENTS?
SO FOR MUSCLE INVASIVE T2, T3,
FOR MUSCLE INVASIVE UPPER TRACT
TUMORS, WE REALLY STRUGGLED WITH
HOW TO MANAGE THESE PATIENTS IN
TERMS OF DO WE GIVE THEM CHEMO,
DO WE GIVE JUST T # PATIENT1 PATIENTS
CHEMO.
I WROTE A TRIAL FOR UPPER TRACT
TUMORS AND IT JUST GOT PUBLISHED
IN JCO.
IT TOOK A LONG TIME TO ACCRUE
BECAUSE IT'S LESS COMMON, SO IT
ONLY OCCURS IN ABOUT 10%, UPPER
TRACT TUMORS VERSUS REGULAR
BLADDER CANCER, SO ACCRUING TO
THESE TRIALS ARE VERY DIFFICULT
AND ALSO THE ELIGIBILITY IS VERY
DIFFICULT, ARE YOU OVERTREATING
SOME PATIENTS, NOT CORRECTLY
DIAGNOSING OTHERS.
BUT WE DO SEE THAT GETTING
CHEMOTHERAPY AT THE STAGE WHEN
YOU INITIALLY DIAGNOSED THEM
WITH A HIGH GRADE TUMOR IS GOOD
TO DO BEFORE YOU DO THE NE FRECT
NEPHRECTOMY, THEN THEY ONLY HAVE
ONE KIDNEY, WE'RE GIVING THEM
SOMETHING VERY TOXIC TO THE
KIDNEY SO CAN WE DO IT BEFORE.
SO THIS ANSWERED THIS QUESTION,
CAN WE DO IT BEFORE.
BUT WHEN IT COMES TO METASTATIC
DISEASE, UPPER TRACT TUMORS HAVE
VERY SIMILAR OUTCOMES THAN
BLADDER PRIMARIES WHEN IT'S
METASTATIC, WHEN IT'S OUTSIDE IN
THE VISCERAL ORGANS.
AND WE TREAT IT THE SAME IN
TERMS OF THE SYSTEMIC THERAPIES
THAT WE HAVE AVAILABLE FOR THE
PATIENTS.
>> RIGHT.
JUST HIGHER LIKELIHOOD OF BEING
MSI-YOU HI.
LOOKS GOOD.
>-HIGH.
>> YES.
>> IT IS RARE WHEN A TENURE
TRACT DOES A FIRST IN HUMAN
STUDY THAT LEADS TO A PHASE III
STUDY THAT LEADS TO APPROVAL,
AND IT'S EVEN MORE RARE WHEN YOU
HAVE TWO DRUGS THAT YOU'VE BEEN
ASSOCIATED WITH, COMBINATIONS
YOU'VE BEEN ASSOCIATED WITH,
FIRST IN HUMAN COMBINATION OR
FIRST IN HUMAN -- LED TO FDA
APPROVAL, WHICH IS FANTASTIC.
I WANT TO ASK YOU A LITTLE BIT
ABOUT THE DATA THAT YOU HAD WITH
THE CABO-NS-NIBO.
YOU SAW ACTIVITY ACROSS A
SPECTRUM OF G.U. CANCERS, BUT
YOU SAW ACTIVITY IN RENAL AND IN
BLADDER, BUT NOT SO MUCH IN
PROSTATE.
AND I KNOW THERE'S FEW PATIENTS
THERE, BUT WHAT ARE YOUR
THOUGHTS THERE?
WERE THESE JUST SICKER PATIENTS
OR WAS IT A TUMOR MUTATION
BURDEN OR IS THERE SOMETHING
INTRINSIC IN PROSTATE CANCER
THAT DOESN'T LEND ITSELF TO THIS
APPROACH WHERE WE KNOW WITH
KIDNEY CANCER, FOR INSTANCE, WE
DO HAVE PEMBROLIZUMAB AND
AVELUMAB AND -- APPROVED FOR
KIDNEY CANCER, SO IT MAKES SENSE
THAT AN ANTIANGIOGENESIS AGENT
WITH IMMUNE CHECKPOINT INHIBITOR
MAY ALSO WORK WITH KIDNEY
CANCER, BUT WHAT ABOUT THESE
OTHER CANCERS?
>> I THINK THAT'S A GREAT
QUESTION, AND THE TRUTH IS, I
DON'T KNOW.
YOU KNOW, I THINK THAT THIS HAS
BEEN AN INTEREST OF MANY OF MY
COLLEAGUES, INCLUDING YOU AND
OTHER COLLEAGUES AT THE NCI
TRYING TO UNDERSTAND THE
MICROENVIRONMENT IN PROSTATE
CANCER TUMORS, AND HOW CAN WE
SIMULATE IT SO CHECKPOINT
INHIBITORS WORK, BECAUSE WHEN
THEY DO WORK, THEY WORK SO WELL.
ONE OTHER FACTOR, TOO, IN ALL
FAIRNESS IS PROSTATE TUMORS ARE
HARD TO MEASURE.
AND THE PATIENTS THAT I HAD
THERE IN THE WATERFALL PLOT HAD
LYMPH NODE DISEASE, AND IF IT'S
BONE-ONLY DISEASE, YOU CAN'T
REALLY DO THOSE WATERFALL PLOTS
BECAUSE YOU CAN'T MEASURE A
RESPONSE.
SO ASSESSING RESPONSE IN
PROSTATE CANCER PATIENTS HAS
BEEN A STRUGGLE, AND WE DO HAVE
PSA, WHICH IS GREAT, BUT REALLY
ASSESSING TUMOR BURDEN AND
RESPONSE TO THERAPY HAS BEEN
SOMETHING THAT I THINK HAS BEEN
ANOTHER AREA WHERE I THINK
IMAGING HAS TAKEN A VERY
IMPORTANT ROLE IN COMBINATION
WAYS WITH BIOMARKERS, PSA LEVELS
AND IMAGING TOGETHER IN ORDER TO
REALLY ASSESS WHETHER SOMEBODY
IS RESPONDING OR NOT.
BUT I DON'T KNOW WHY CERTAIN
TUMORS ARE MORE SUSCEPTIBLE TO
IMMUNOTHERAPY AND HOW CAN WE
MAKE CERTAIN TUMORS MORE
ACCESSIBLE TO IMMUNOTHERAPY, I
THINK THESE ARE ALL GREAT
RESEARCH QUESTIONS THAT ARE
ONGOING RIGHT NOW.
>> WELL, FANTASTIC.
I THINK WE'RE OUT OF TIME NOW.
WE'RE JUST EXACTLY AT 1:00.
THIS WAS JUST SUCH AN AMAZING
PRESENTATION, AND COP GRAT AND
CONGRATULATIONS ON YOUR TENURE.
>> THANK YOU SO MUCH.
>> MANY, MANY THANKS, ANDREA,
FOR A REAL TOUR DEFORCE, AND
THANKS, JAMES, FOR STARTING A
DISCUSSION THAT I THINK REALLY
ILLUMINATED SOME OF THE
IMPORTANT POINTS OF THE TALK.
I WANT TO THANK ALEX AND KENNY
AND KIM PUBLICLY FOR MAKING THIS
GO LIVE, AND ALL OF YOU WHO HAVE
TUNED IN, MANY THANKS FOR
LISTENING, AND I HOPE YOU'LL
JOIN US WITH FUTURE DIRECTOR
SEMINARS.
AND A SPECIAL THANKS AND HAPPY
BIRTHDAY TO DR. MICHAEL
GOTTESMAN.
THANKS FOR JOINING US,
EVERYBODY.
>> HAPPY BIRTHDAY, DR. GOTTESMAN