View
1
Download
0
Category
Preview:
Citation preview
NCI-COG Pediatric MATCH Study
(Molecular Analysis for Therapy Choice)
Peter C. Adamson, MDD. Will Parsons, MD, PhDNita Seibel, MD
Pediatric MATCH
• 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 reviewedMDM2 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
Target/Agent Prioritization
Pediatric Match Subprotocols
(Subprotocols in development – subject to change)
• 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
Clinical Sequencing
• 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
Levels of Evidence: Variants
• 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
Tumor and Germline Mutations
NCI-COG Pediatric MATCH Study
Study committees• Study design and logistics: Stacey Berg, Beth Fox
• Target/agent prioritization: Katie Janeway, Jae Cho
• Sequencing platform/analysis: Will Parsons, Jim Tricoli
• Germline result reporting: Sharon Plon, Steven Joffe
• Biospecimens: Julie Gastier-Foster
• Informatics: Hema Chaudhary, David Patton
COG leadership and staff• Peter Adamson, Catalina Martinez, Rita Tawdros, Todd Alonzo, Thalia Beeles,
Heather Day…
NCI/CTEP leadership and staff• Nita Seibel (NCI study PI), Malcolm Smith, adult NCI-MATCH leadership (Conley,
Chen, Williams, Patton…)
FDA leadership• 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
Arm / Target Drugs(s)
A EGFR mut Afatinib
B HER2 mut Afatinib
C1 MET amp Crizotinib
C2 MET ex 14 sk Crizotinib
E EGFR T790M AZD9291
F ALK transloc Crizotinib
G ROS1 transloc Crizotinib
H BRAF V600 Dabrafenib+trametinib
I PIK3CA mut Taselisib
N PTEN mut GSK2636771
P PTEN loss GSK2636771
Q HER 2 amp 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
(8-10 additional arms in review/in development)
Red = accrued 35 patients; Green = nearing 35 patient
Arms to be added: Feb 2017
• 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)
Recommended