NCIMATCH EAY131 A phase II precision medicine cancer trial Codeveloped by the ECOGACRIN Cancer Research Group and the National Cancer Institute Version Date 06202018 On Behalf of the NCIMATCH Study Leadership ID: 731867
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Slide1
NCI-Molecular Analysis for Therapy Choice (NCI-MATCH / EAY131)
A phase II precision medicine cancer trial Co-developed by the ECOG-ACRIN Cancer Research Group and the National Cancer Institute
Version Date:
02/14/2019 Slide2
On Behalf of the NCI-MATCH Study Leadership
Keith T. Flaherty
1
, Alice P. Chen
2
, Peter J. O'Dwyer
3
, Barbara A. Conley
2
, Lyndsay N. Harris
2
, James V. Tricoli
2
, Stanley R. Hamilton
4
, Mickey Williams
5
, Robert J. Gray
6
, Shuli Li
6
, Lisa M.
McShane
2
,
Lawrence V. Rubinstein
2
, Susanna I. Lee
1
, Constantine A. Gatsonis
7
, Lalitha K. Shankar
8
, Paolo F. Caimi
9
, Shaji Kumar
10
, Edith P. Mitchell
11
, James A. Zwiebel
2
, A. John Iafrate
1
, Jeffrey Sklar
12
, Carlos L. Arteaga
13
1
Massachusetts General Hospital, Boston, MA
;
2
National Cancer Institute (NCI), Division of Cancer Treatment and Diagnosis, Bethesda, MD;
3
University of Pennsylvania, Philadelphia, PA;
4
MD Anderson Cancer Center, Houston, TX;
5
NCI Frederick National Laboratory for Cancer Research, Frederick, MD;
6
Dana-Farber Cancer Institute, Boston, MA;
7
Brown University, Providence, RI;
8
NCI Cancer Imaging Program, Rockville, MD;
9
Case Western Reserve University, Cleveland, OH;
10
Mayo Clinic, Rochester, MN;
11
Thomas Jefferson University, Philadelphia, PA;
12
Yale University, New Haven, CT;
13
UT Southwestern Medical Center, Dallas, TXSlide3
Trial DescriptionSlide4
What is NCI-MATCH?Slide5
Precision Medicine in Cancer TreatmentPrecision medicine is the tailoring of treatment for each individual based on molecular abnormalities found in tumors rather than the type of cancer
Example:BRAFV600E melanoma responds to BRAF inhibitors or BRAF inhibitors combined with MEK inhibitors but colorectal cancers with the same mutations appear not to respondWe need to know more about which tumors will respond to agents targeted to “driver” mutationsSlide6
NCI-MATCH Objective
To determine whether matching certain drugs or drug combinations in adults whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of the cancer type
This is a signal-finding trial; treatments that show promise can advance to larger, more definitive trialsSlide7
Design of NCI-MATCH
Master protocol with 35 subprotocols (treatment arms)Open and close independently Expanding to 39 arms by late summer 2019, pending approvalGenomic testing directs patients to molecularly-targeted treatmentsEach arm evaluates the activity of a treatment in tumors with relevant tumor gene abnormalitiesSlide8
NCI-MATCH Eligibility Overview
Adults ≥ 18 years of age
Solid tumor, lymphoma, or myeloma
Progressed
following at least one line of standard systemic therapy
AND no other standard systemic therapy for the patient’s disease that is known to prolong overall survival
OR a type of cancer for which no therapy exists that is known to prolong overall survival
Patients who cannot receive other standard therapy due to medical issues may be eligibleSlide9
NCI-MATCH Availability
Open in every
state, the
D
i
strict
of
C
olu
m
bia,
and
P
uerto
RicoThis trial is for eligible patients at about 1100 participating trial sitesTumor gene testing by a designated testing laboratory is the only pathway for patients at participating sites to enroll in the trialSlide10
Patient Referral ProcessSlide11
Genetic Testing Process for NCI-MATCH EligibilityTumor gene testing by a designated
testing laboratory is the only pathway for patients at participating sites to enroll in the trialLabs identify which patients at participating sites may be eligibleThrough routine tests ordered by physiciansReferring labs have approval from the National Cancer Institute for this trial This approach casts a wide net for patients
Labs perform tests for
many hospitals and clinicians across the
countrySlide12
Patient Pathway onto
NCI-MATCH via a Commercial Lab
Applies only to patients at ~1100 participating trial sitesSlide13
NCI-MATCH Treatment Arm Overall Design (Single-Arm Phase II)
Enroll in arm “x”
Complete response, partial response, stable disease
Progressive disease (PD)
PD
P
atients will be treated for
as long as their tumor shrinks or remains stableSlide14
Commercial Labs Referring Patients to NCI-MATCH
Caris Life Sciences® CellNetix Pathology and Laboratories
Foundation Medicine, Inc.
GenPath (BioReference
Laboratories, Inc.)
NeoGenomics Laboratories, Inc.
More
labs
to
come
Learn more:
ecog-acrin.org/
nci
-match
OmniSeq, Inc.
PathGroup
Strata
Oncology, Inc.
Tempus Labs, Inc.
The Jackson
LaboratorySlide15
Academic Labs Referring Patients to NCI-MATCH
Generally, cancer center labs test their own patient populationAugusta University
City of Hope
Cedars-Sinai
Medical Center
Columbia University
Johns Hopkins
University
Massachusetts General Hospital
Memorial Sloan Kettering Cancer Center
MD Anderson Cancer Center
More labs to come
Learn more:
ecog-acrin.org/
nci
-match
University of Chicago
University
of Colorado
University of Michigan
Weill Cornell Medicine
Yale
UniversitySlide16
Treatment ArmsSlide17
R
e
su
me with
2
4
arms
M
a
y
31
,
2016
Brief Timeline of
NCI-MATCH
Treatment Arms
Final 4 arms in development
39
total arms
by mid-2019
N
o
v
2015
-
M
a
y
2016
Pause for interim
analysis
and
L
ab
c
apac
i
ty
increase
Expand to
30
arms
Mar.
13, 2017
Open with
10
arms
Aug. 12, 2015
Expand to
35 armsJune 20, 2018Slide18
NCI-MATCH Treatment Arm Objectives
Primary:Estimate the proportion of patients with refractory solid tumor, lymphoma or myeloma who had an objective response (OR) If the OR rate is ≥ 5/31 (16%), agent worthy of further study Secondary:
Progression-free
survival (PFS)
PFS at 6 months (PFS6)
Time to progression/death
Toxicity
Potential predictive biomarkersSlide19
NCI-MATCH Outcomes Reporting on Individual ArmsAccrual goal per arm: 35
Early in the trial, some arms targeting more common gene variants were expanded to accommodate the higher numbers of patients with matches who came into the trial through central screening Reporting of primary and secondary endpoints will occur once there is complete response and toxicity data for at least 31 patients per armAccrue at least 35 to obtain at least 31 evaluable (10% ineligibility rate)
Need ~
8 months of follow-up after accrual is
completeSlide20
NCI-MATCH – Status of 39 Treatment ArmsSlide21
M
AP
k
i
n
as
e
PI
3
K
i
n
a
s
e
D
N
A
r
e
p
air
Im
m
u
n
o
-
o
nc
ce
ll
cy
c
l
e
F
G
FR
LO
XO
M
ET
M
A
P
Ki
n
a
s
e
:
E
G
FR
m
u
t:
r
a
r
e
a
n
d
T
790M
H
E
R
2
m
u
t
a
tion
a
n
d
HE
R
2
a
m
p
lALK, ROS translocationsRAF mutations, fusions NF2 loss, NF1 mutation NRAS mutationsSMO, PTCH1, KIT mutations
P13KPIK3CA mutations TSC1, 2 mutations MTOR mutations PTEN LOSSAKT mutations
MET exon 14 skipping MET amplification
FGFR ampl, mut, fusion
CCND1 AMP CDK4 OR 6 AMP
NTRK fusions
DDR2 BRCA 1, 2 mutations
MLH1, MSH2 LOSS
Treatment Arms in
NCI-MATCH by
Molecular PathwaySlide22
New NCI-MATCH Arms in Development
Tumor Gene Abnormality
Prevalence Rate %
Drug
Arm ID
Opens
(
Pending Approval)
AKT mutations
0.77
Ipatasertib
Z1K
Late
Spring 2019
Non-V600 BRAF mutations
0.80
Ulixertinib
(BVD-523)
Z1L
dMMR
status and
LAG-3 expression
1.51
Nivolumab +
relatlimab
(BMS-986016
)
Z1M
Late Summer
2019
TP53 mutations and MYC amplification
Not
available
AZD1775
Z1JSlide23
ResultsSlide24
NCI-MATCH Treatment Arms
with Results
Drug
Drug /
Variant
Arm
Primary
Result
(ORR Confirmed)
Publication / Presentation
Ado-trastuzumab emtansine
HER2 amplification
Q
8%
Jhaveri KL, ASCO 2018
(oral)
AZD4547
FGFR pathway aberrations
W
8%
Chae YK, ASCO 2018
(oral)
Taselisib
PIK3CA mutations
I
0%
Krop IE, ASCO 2018
(oral)
GSK2636771
PTEN expr or loss
by IHC
N & P
5% arm N (mut/del)
0% arm P
Janku FM,
ESMO 2018
(poster discussion)
Capivasertib
AKT mutations
Y
23%
Kalinsky KM,
EORTC-NCI-AACR 2018
(oral plenary)
Nivolumab
dMMR status
Z1D
Coming soon!
Afatinib
HER2 activating mutations
B
Palbociclib
CCND1, 2, and 3 amplifications and Rb protein expression by IHC
Z1B
ACD1775
BRCA1 or BRCA2 mutations
Z1ISlide25
Tissue SpecimensSlide26
Request for Tissue Specimens for NCI-MATCH
Trial leaders request that all patient referrals from the labs be confirmed on the NCI-MATCH assayBy the central lab at MD Anderson Cancer CenterUsing archived tissue - no new biopsy necessary Patient treatment will not be delayed for confirmationSlide27
What the Request for Tissue Specimens Means for Patients
For patients confirmed by the central lab, their data will be included in the primary outcome analysis Unless specifically required for treatment assignment (e.g. central IHC testing required to confirm eligibility)Those without confirmation will continue treatment and evaluation, but will not be included in the primary outcome analysisSlide28
DetailsSlide29
Level of Evidence
DefinitionLevel 1G
ene
v
ariant
credentialed
for
selection of
an
appro
v
ed
drug
Level 2
Variant is eligibility criterion for an
ongoing
clinical
trial
for
that
drug
O
R
v
ariant
has been
identified
in
an
N
of
one
res
pon
s
e
Level 3Variant has preclinical inferential dataModels
with variant respond; without variant
do notGain of function mu
tation demonstrated in preclini
c
al
m
odel
Lo
s
s
of
f
un
c
t
i
on
(
t
u
m
or
s
uppre
s
s
o
r
genes
or pathway inhibitor e.g. NF1); stop codon or demonstrated loss of function in pre
clinical modelCredentialing Tumor Gene Abnormalities for NCI-MATCHSlide30
Level of Evidence
DefinitionLevel 1F
D
A
-appro
v
ed
for
any
indication for
that
target
Level 2
A
gent
met a clinical endpoint (objective
res
pon
se,
PF
S
,
or
O
S
)
w
ith
e
v
iden
c
e
of
target
inhibition
Level 3
A
gent
de
m
on
strated evidence of clinical activity
with evidence of target inhibition at some level
Credentialing Drugs for NCI-MATCHSlide31
Rules for Assigning Patients to NCI-MATCH Treatment ArmsThree assay components are equal (SNV/indel; CNV; fusion)
If more than one actionable mutation of interest (aMOI):Level of evidence 1 > 2 > 3If aMOIs have same level of evidence:SNV/indels:If difference between VAF
≥ 15
%, choose greater
If difference < 15%, choose arm with fewer patients
If 1 aMOI is not an SNV, choose arm with fewer patientsSlide32
Request for Biopsy Submissions at Progression To aid future research, the NCI-MATCH trial requests that any patients who experience disease progression during the trial submit a biopsyThe study team encourages all participating sites and physicians to take this request into considerationSlide33
NCI-MATCH Reimbursement StatusThe NCI does not reimburse for the routine genomic testing performed by designated laboratoriesAssays done on the archived tissue blocks submitted for concordance purposes will be done free of charge
NCI will reimburse in the customary way for block submission and the reimbursement for patients entering the therapeutic armsNCI will reimburse optional progression biopsies at the end of MATCH treatment (master protocol Step 8)Slide34
Advocates were involved in trial design and are helping to oversee conductThere is widespread
participation across the NCI scientific communityAbout 120 treatment arm chairs and co-chairsNearly 1100 participating sites nationwide Over 150 individuals on 10 steering committees and working groups
NCI-MATCH AcknowledgementsSlide35
NCI-MATCH ResourcesMain Webpages:
ecog-acrin.org/nci-match-eay131 cancer.gov/nci-matchProtocol Documents: ctsu.org (password required)Spanish: cancer.gov/espanol/nci-matchEmail Inquiries: match@jimmy.harvard.edu
NCI Contact Center: 1-800-4-CANCER and
cancer.gov/contactSlide36
End of Primary Slides
Version Date: 02/14/2019 Slide37
Extra Content:
The First 6000 PatientsSlide38
Opened on August 12, 2015, with 10 treatment arms and a goal to have 3000 patients submit tumor samples for central testing
795 patients were screened in the first three monthsReached >100/week by the end of this periodFar surpassed the original estimate of 50 screens/month Paused enrollment of new patients in November 2015, for a planned interim analysis This resulted in a more accurate estimation of the prevalence rates for the targeted mutations
Brief History of Central Screening in NCI-MATCHSlide39
Resumed enrollment of new patients in May 2016, with 24 treatment arms and more laboratory capacity to handle rapid pace of enrollment
Increased central screening goal to 6000 patients in late 2016Added myeloma patients in late 2016Expanded to 30 treatment arms in March
2017
Completed screening of nearly 6k patients in July 2017
Central Screening Brief History (cont’d)Slide40
Central Screening Brief History (cont’d)NCI-MATCH
screened ~6000 patients in less than two years—a rate that far exceeded expectationsSlide41
NCI-MATCH Central Screening Results
Tumor gene sequencing was successful in 93% of patients with samples submitted, a rate well above the industry standard of ~80%
Goal
#
Registered for Screening
#
With Samples
Submitted
Successful Laboratory Testing
6000
6397
5962
93%
5560Slide42
FEWER than 8
>8 – <30
30 – 65
Doroshow
, NCI Community Oncology Research Program (NCORP) Annual Meeting, 08/29/2017
NCI-MATCH
6k Central
Screening
Enrollment Per One Million Population Slide43
NCI-MATCH Central Screening by Cancer Type
Less Common Disease Type
% of Total
Screened
(N=5560)
Ovarian
9.5
Uterine
6.2
Pancreas
6.1
Sarcoma
4.6
Head
and Neck
3.9
Neuroendocrine
3.3
Gastroesophageal
3.2
Cholangiocarcinoma
2.8
Liver
and Hepatobiliary other than Cholangio.
1.9
Central Nervous System
1.7
Bladder/Urinary
Tract
1.6
Cervical
1.6
Small Cell Lung
1.4
Melanoma
1.4
Kidney
1.2
Anal
0.8
Mesothelioma
0.8
Lymphoma
0.7
Myeloma
0
Other
9.7
Less Common Cancers
62.5%
Common Disease Type
% of Total
Screened
(N=5560)
Colorectal
15.3
Breast
12.4
Non-Small Cell
Lung
7.3
Prostate
2.5
Common Cancers
37.5%
Goal: 25%
Far exceededSlide44
NCI-MATCH Wait Times for Patients Tested Centrally
Processing Step
Median
Calendar Days
Tumor sample submission from sites to EA central lab
at MD Anderson Cancer Center
7
Completion of tumor testing by lab
network
and return
of results to site
16
Further eligibility evaluation
for patients assigned to a treatment arm
14Slide45
NCI-MATCH Important DiscoveryIn the 6000 patients tested, the tumor gene variants we are studying occurred less frequently than expected in this study population
, ranging from 3.47 percent to zeroSlide46
NCI-MATCH Central Screening ConclusionsRegistration for screening was rapidAssay turnaround time met (except for a few)
60% of screened patients with less common cancers far exceeded goal~50% of screened patients came from community-based sitesPatients screened in every state, the District of Columbia and Puerto RicoToxicity of biopsy was acceptableOverall, trial is feasible across the NCI-sponsored networksPublication of full results forthcomingSlide47
Changes to NCI-MATCH
How did reaching the 6000-patient central screening goal change the study?The trial laboratories stopped collecting and testing specimens centrally Patients no longer have biopsies specifically for this trialNCI ended reimbursement for these proceduresSlide48
Changes to NCI-MATCH (cont’d)
How did the discovery that gene abnormalities are rarer than expected change the study?It shed light on the fact that in order to fill the ‘rare variant’ arms, we need to look at tens of thousands of patientsIt required setting a new goal for the trialNew goal: broaden the base of screened patients to complete ongoing and upcoming treatment armsSlide49
Extra Content:Rare Variant Demonstration Project Slide50
NCI-MATCH Rare Variant Demonstration Project
Began in May 2017 To help trial ramp up to high volumes of patient referrals anticipated from designated labs Initially labs only reported on 19 treatment arms Rare abnormalities -- occurred in ≤1.5 percent of patients tested centrallyManual processing of patient cases until MATCHbox IT system fully automated
Successfully concluded in
mid
2018Slide51
Arm
Variant
Prevalence
Rate %
Arm
Variant
Prevalence
Rate %
Z1C
CDK4 or CDK6 1.36
L
mTOR 0.31
M
TSC1 or TSC2 1.11
S2
GNAQ/GNA11 0.16
Z1B
CCND1/2/3
0.84
E
EGFR T790M 0.11
R
BRAF fusions 0.80
V
cKIT 0.11
Y
AKT 0.77
Z1E
NTRK 0.10
H
BRAF V600 E/K
0.69
G
ROS1 0.05
U
NF2 loss 0.69
A
EGFR activating 0.05
C2
MET exon
14 sk
0.61
F
ALK 0.03
C1
MET amplif. 0.51
X
DDR2 0.00
T
SMO/PTCH1 0.42
19 Treatment Arms in NCI-MATCH Rare Variant Demonstration Project, By Gene Abnormality Prevalence Rate %