NCI-COG Pediatric MATCH Study
(Molecular Analysis for Therapy Choice)
Peter C. Adamson, MD
D. Will Parsons, MD, PhD
Nita Seibel, MD
Pediatric MATCH
Target/Agent Prioritization
• Is there a clearly defined target or biomarker?
• Can the target/biomarker be detected with the
proposed testing platform?
• What is the frequency of target alterations in
pediatric solid tumors and lymphomas?
• What is the evidence linking the target to activity
of the agent? (clinical vs. pre-clinical)
• What are the specific agents in the drug class?
• Are trials of the agents already planned in
biomarker-defined patient populations?
Target/Agent Prioritization
• Level 1: FDA approved; evidence of target
inhibition, or proof of mechanism; demonstration
that patient selection with CDx are more likely to
respond
• Level 2: Agent met a clinical endpoint (objective
response, PFS, or OS); with evidence of target
inhibition; plausible evidence of a predictive or
selection assay/analyte
• Level 3: Agent demonstrated evidence of clinical
activity with evidence of target inhibition; some
evidence of a predictive or selection assay
Target/Agent Prioritization
Agent classes initially reviewed
ALK inhibitor
MEK inhibitor
BET bromodomain inhibitor
PARP inhibitor
BRAF inhibitor
PDGFRA/B inhibitor
CDK 4/6 inhibitor
PI3K/AKT/mTOR inhibitor
EGFR inhibitor
ROS1 inhibitors
ERK inhibitor
SMO inhibitor
FGFR inhibitor
TRK inhibitor
IDH inhibitor
Target/Agent Prioritization
Agent classes not initially reviewed
MDM2 inhibitors
Target (MDM2 amplification) uncommon
ERBB inhibitors
Target uncommon
Met inhibitor
Target (met amplification) uncommon
Src/Syk inhibitor
Target uncommon
c-Kit inhibitor
Target uncommon
Anti-angiogenic (VEGF and Ang/Tie)
Not sufficiently targeted to define biomarker
Pan-tyrosine kinase inhibitors
Not sufficiently targeted to define biomarker
Aurora kinase inhibitors
Target/Biomarker not known
Base excision repair inhibitor (TRC102)
Target/Biomarker not known
ATR kinase inhibitor (VX-970)
Target/Biomarker not known
FAK inhibitor
Target/Biomarker not known
CK2 inhibitors
Target/Biomarker not defined by genomic alteration
IGF1R inhibitors
Target/Biomarker not defined by genomic alteration
Pediatric Match Subprotocols
(Subprotocols in development – subject to change)
Clinical Sequencing
• FFPE tumor samples
• Oncomine DNA/RNA mutation panel (Life
Technologies/ Thermo Fisher Scientific)
• >140 genes
• >4000 mutations of interest
• defined set of SNVs, indels, CNVs, gene fusions
• Analytic pipeline adapted for pediatric study
• Sequencing to be initially be performed at two
existing MATCH laboratories
• Plan to perform germline sequencing in parallel
Levels of Evidence: Variants
• Level 1: Gene variant approved for selection of an approved
drug (BRAF V600E and vermurafenib). The variant will be
Level 1 in all tissues open to treatment with the approved drug .
• Level 2a: Gene variant is an eligibility criteria for an ongoing
clinical trial for that treatment
• Level 2b: Gene variant has been identified in an N of 1
responses (TSC1 and everolimus) for that treatment
• Level 3: Preclinical inferential data (in vivo and in vitro models)
that provide biological evidence sufficient to support the use of
a variant for treatment selection
Tumor and Germline Mutations
• Genomic evaluation of tumors can reveal both
tumor and germline cancer mutations
• Need plan for interpretation and return of germline
results detectable by the study mutation panel
NCI-COG Pediatric MATCH Study
Study committees
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Study design and logistics:
Target/agent prioritization:
Sequencing platform/analysis:
Germline result reporting:
Biospecimens:
Informatics:
Stacey Berg, Beth Fox
Katie Janeway, Jae Cho
Will Parsons, Jim Tricoli
Sharon Plon, Steven Joffe
Julie Gastier-Foster
Hema Chaudhary, David Patton
COG leadership and staff
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Peter Adamson, Catalina Martinez, Rita Tawdros, Todd Alonzo, Thalia Beeles,
Heather Day…
NCI/CTEP leadership and staff
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Nita Seibel (NCI study PI), Malcolm Smith, adult NCI-MATCH leadership (Conley,
Chen, Williams, Patton…)
FDA leadership
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Martha Donoghue, Greg Reaman
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
Mutational Burden
Lawrence MS, et al. Nature 2013:499(7457):214-218
NCI-MATCH Testing and Enrollment as of 1/29/17
4094 patients with tumor samples (N=6000)
3516 patients had received their test results
642 had a gene abnormality matching an available
treatment
And proceeded to be further evaluated for the specific eligibility for
the arm to which they matched
429 patients had enrolled for treatment
NOTE: These are strictly numbers reflecting a point in
time and cannot be used to calculate overall rates;
some are assigned and still in evaluation for eligibility
for an arm; estimated 72% of those assigned will enroll
NCI-MATCH Expanded to 24 Arms May 31, 2016
(8-10 additional arms in review/in development)
Arm / Target
A EGFR mut
B HER2 mut
C1 MET amp
C2 MET ex 14 sk
E EGFR T790M
F ALK transloc
G ROS1 transloc
H BRAF V600
I PIK3CA mut
N PTEN mut
P PTEN loss
Q HER 2 amp
Drugs(s)
Afatinib
Afatinib
Crizotinib
Crizotinib
AZD9291
Crizotinib
Crizotinib
Dabrafenib+trametinib
Taselisib
GSK2636771
GSK2636771
Ado-trastuzumab
emtansine
Arm / Target
Drug(s)
R BRAF nonV600 Trametinib
S1 NF1 mut
Trametinib
S2 GNAQ/GNA11 Trametinib
T
SMO/PTCH1
Vismodegib
U NF2 loss
Defactinib
V cKIT mut
Sunitinib
W FGFR1/2/3
AZD 4547
X
DDR2 mut
Dasatinib
Y
AKT1 mut
AZD 5363
Z1A NRAS mut
Binimetinib
Z1B CCND1,2,3 amp Palbociclib
Z1D dMMR
Nivolumab
Red = accrued 35 patients;
Green = nearing 35 patient
Arms to be added: Feb 2017
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EAY131-J: Herceptin + Perjeta/HER2 Amp (to follow Arm Q).
EAY131-L: MLN0128/mTOR Mutations (New target)
EAY131-M: MLN0128/TSC1/TSC2 Mutations (New target)
EAY131-Z1C: Palbociclib/CDK4/CDK6 Amplification (New target)
EAY131-Z1E: Loxo 101/NTRK Fusions (New target)
EAY131-Z1I: AZD1775/BRCA1, BRCA2 mutations (New target)