NCI-Molecular Analysis for Therapy Choice

(NCI-MATCH or EAY131)

A phase II precision medicine cancer trial

Co-developed by the ECOG-ACRIN Cancer Research Group

and the National Cancer Institute

Version Date: 09/29/2015

NCI-MATCH Hypotheses

Primary:

Tumors that share common somatic genetic alterations in oncogenes will be variably responsive to therapies targeting the oncogenic pathway based on lineage specific factors. 

Secondary:

Concomitant somatic genetic alterations will predict responsiveness or resistance.

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Matching patients to therapy on the basis of genetic features in lung cancer: erlotinib in EGFR mutant NSCLC and crizotinib in ALK translocated NSCLC

Rizvi N et al. CCR 2011 Camidge R et al. Lancet Oncol 2012

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BRAF inhibitor therapy markedly more effective for V600EBRAF melanoma compared to colon cancer

Kopetz, ASCO 2010

melanoma colorectal

Sosman J et al. NEJM 2012

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Decoding the cancer genome: ERBB2 (HER2)

Breast cancerGastric cancerBladder cancerUterine cancer

Prostate cancerChromophobe kidney cancerLiver cancer

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Mutation Frequency in TCGA

Gene Bladder Breast Cervix Colo-rectal GBM Glioma

Head and

Neck

Lung (Adeno)

Lung (Squam) Melanoma Ovarian Pancreas Prostate Stomach Thyroid Uterine

AKT 0 2.4 0 0.9 0.4 0 0.7 0.9 0.6 1.4 0 3.5 0.4 1.4 0.7 1.6BRAF 0.8 0.6 2.6 9.9 2.1 1 1.4 9.6 4.5 50.2 0.6 1.8 2.4 4.1 61.3 2.8EGFR 1.5 0.8 2.6 4.5 26.1 5.9 4.7 14.3 3.9 6.5 2.2 1.8 1.2 5 0 3.2FGFR1 3.1 0.3 0 1.3 1.1 0 0.4 1.3 1.7 3.6 0 0 0 4.5 0 3.2FGFR2 2.3 1.1 0 1.3 1.1 0.3 0.7 3.1 3.9 9.3 0 1.8 1.2 3.6 0.2 12.5FGFR3 14.6 0.4 0 0.9 1.1 0 2.2 0.9 2.3 2.9 0.3 1.8 0.4 1.4 0 2HRAS 4.6 0.2 0 0 0 0 3.9 0.4 2.8 1.1 0 1.8 0.8 0 3.5 0.4IDH1 3.6 0.4 0 1.3 4.9 76.1 0.7 1.3 1.1 5.7 0 1.8 1.6 0.5 0 1.6IDH2 0 0 0 3.1 0 4.2 0 0.9 0.6 0.4 0 1.8 0 0.5 0 1.6KIT 2.3 1 0 2.7 1.1 0.7 1.3 2.2 3.9 3.9 2.2 1.8 0 4.1 0 6.9KRAS 0 0.8 2.6 43 1.1 0.3 0.4 32.6 1.1 1.4 0.6 57.9 0 11.4 1 21.4NF1 9.2 2.8 7.7 3.6 14.3 6.6 2.9 11.8 11.9 13.3 4.4 1.8 0.4 5.9 0.5 8.1NF2 3.6 0.4 5.1 1.3 0 0.3 1.4 0.9 1.1 1.1 0.3 1.8 0.8 1.4 0.2 2.4NRAS 0 3.6 0 9 1.1 0.3 0.4 1.7 0.6 30.8 0.6 0 0 0.9 8.5 3.6PIK3CA 20 35.1 23.1 20.1 10.6 0 20.9 6.5 15.7 3.6 0.6 1.8 3.2 21.8 0.5 53.2PIK3R1 3.6 2.6 2.6 4 11.3 4.5 2 1.3 1.1 0.7 0.3 1.8 0.8 3.6 0.2 33.1PTCH 7.1 1.2 2.6 4 1.1 0.3 3.6 4.8 2.8 2.5 1.9 1.8 0.8 5 0.5 7.7PTEN 3.1 3.6 7.7 3.6 31.9 4.5 2 3.1 7.9 8.2 0.6 1.8 5.2 6.4 0.5 64.9SMO 3.6 0.5 0 0.4 0.4 0 0.3 2.6 0.6 3.6 0 3.5 0 4.1 0 2TSC1 10.7 0.6 2.6 2.2 1.1 0.3 0.7 2.6 3.4 3.2 0.9 1.8 0 1.4 0 4TSC2 2.3 0.6 2.6 0.9 2.2 0.7 1.1 2.2 3.4 3.9 0.6 2 0.8 3.2 0 4.8

Compiled by MD Anderson Investigators

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Amplification Frequency in TCGA

Gene Bladder Breast Cervix Colo-rectal GBM Glioma

Head and

Neck

Lung (Adeno)

Lung (Squam) Melanoma Ovarian pancreas Prostate Stomach Thyroid Uterine

HER2 6.3 12.9 2.3 3.1 2.6 2.6 2.2 0.6 2.6 13 0.6 5.5FGFR1 9.4 12 1.2 3.6 0.4 8.5 3.5 16.9 0.3 3.5 4 2 1 2.5FGFR2 0.5 1.8 0.3 0.6 0.7 0.9 3.5 5.1 FGFR3 5.5 0.5 0.4 1.8 0.8 0.7 1.3 0.6 1.5 7.9 2 0.8 0.7 0.2 2.2MET 0.5 0.8 1.8 0.4 8.9 0.8 0.7 3.5 1.1 3.9 6.3 1.2 4.1 0.3PIK3CA 5.5 4.9 19.3 2.9 1.1 21.1 2.2 38.2 28.8 4 2.8 5.5 14.3

Compiled by MD Anderson Investigators

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OncomineTM Focus Assay Gene List

52 unique genes

269 amplicons in DNA panel 272 amplicons in RNA panel

DNA Panel

RNA Panel

Hotspot genes, n=35

Fusion drivers, n=23

Copy number variants, n=19

AKT1 ALKAR BRAF CDK4CTNNB1 DDR2 EGFR ERBB2 ERBB3 ERBB4 ESR1 FGFR2 FGFR3 GNA11 GNAQ HRAS IDH1

IDH2 JAK1 JAK2 JAK3 KIT KRAS MAP2K1 MAP2K2 MET MTOR NRAS PDGFRA PIK3CA RAF1 RET ROS1 SMO

FGFR3 FGFR4 KITKRAS MET MYC MYCN PDGFRA PIK3CA

ALK AR BRAF CCND1 CDK4 CDK6 EGFR ERBB2 FGFR1 FGFR2

ABL1 AKT3 ALK AXL BRAFERBB2 EGFR ERG ETV1 ETV4 ETV5 FGFR1

FGFR2 FGFR3 METNTRK1 NTRK2 NTRK3PDGFRA PPARGRAF1 RET ROS1

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NCI-MATCH Rationale

Molecularly targeted therapy has improved outcomes

– Within individual tumor types• imatinib in CML (bcr-abl)

• imatinib in GIST (CKIT & PDGFRα)

• erlotinib in NSCLC (EGFR)

• crizotinib in NSCLC (EML4-ALK)

– And across tumor types• trastuzumab in breast & gastric (HER2)

• vemurafenib in melanoma, thyroid & NSCLC, but not colon cancer (BRAF)

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NCI-MATCH Objective

To understand the relative efficacy of the same therapy applied to oncogene-defined subsets across different tumor histologies, we propose to initiate a broad-based genomic prescreening study to assign patients whose tumors harbor specific molecular abnormalities to relevant targeted treatments, regardless of tumor histology type

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NCI-MATCH Design Features

• Test many patients to find widely distributed genetic alterations

– 3,000 to find 1,000

• Biopsies needed at time of study entry (cost covered by NCI)

• Response rate (tumor regression) will be primary efficacy measure

• Across 22 approved/in-development arms PIs drawn from:

– 37% ECOG-ACRIN, 30% Alliance, 16% SWOG, 16% NRG

• More than 150 NCI and NCTN members of 10 subcommittees

• Advocates involved in trial design and help oversee conduct

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NCI MATCH Eligibility Defined Molecularly

• Initial tumor biopsy to identify mutations/amplifications/ translocations

• Patients can be screened with local NGS but results must be confirmed on NCI-MATCH assay

• Patient assignment to relevant agent(s)/subprotocol

• Perform tumor biopsies and sequencing at progression to illuminate resistance mechanisms

– Submit de-identified samples to central labs

– Conduct whole-exome, mRNA sequencing (research purposes)

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NCI-MATCH Schema

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NCI-MATCH Eligibility

• Patients with solid tumors or lymphomas whose disease has progressed following at least one line of standard systemic therapy – or with tumors that do not have standard therapy

– Exclude histologies that had been approved by the FDA or had shown lack of efficacy with an agent

• Tumor accessible to biopsy and patient willing to undergo biopsy

• Adults ≥ 18 year of age

• ECOG performance status ≥ 1

• Adequate organ function

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NCI-MATCH Patient Population Considerations

• Target: at least 25% of total enrollment to be patients who have “rare” tumors

• “Common” defined as breast, NSCLC, colon, prostate

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Statistical Considerations for Each Molecularly-Defined Arm

• Primary Endpoint: Overall Response Rate 5% vs 25%

• Secondary Endpoints:

– Progression Free Survival (PFS) 6 months 15% (median PFS 2.2 m) vs 35% (median PFS 4 m)

– TTP

– Toxicity

– Biomarker

• One stage design with

– 35 evaluable patients per arm09/29/2015 16

Rules for Treatment Selection in NCI-MATCH

• Three assay components are equal (SNV/indel; CNV; fusion)

• Select actionable mutation of interest (aMOI) winner in each component

– Level of evidence 1,2 > 3

– If > 1 LOE 2,3, assign to arm with fewer patients

– SNV/indels: LOI 1,2 > 3; IF > 1 LOE 1,2

• If difference between VAF > 15%, choose greater

• If difference < 15%, choose arm with fewer patients

• If 2 or more aMOI meet LOE 1,2, choose arm with fewer patients

• Compare winner of each component

– LOE 1,2 > 3

– If > 1 LOE 1,2 select arm with fewer patients

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aMOIs in NCI MATCH and Estimated Prevalence

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Molecular Target Estimated % Prevalence

Agent(s) for Molecular Target Subprotocol ID

EGFR activating mutations 1 - 4 Afatinib EAY131-A

HER2 activating mutations 2 - 5 Afatinib EAY131-B

EGFR T790M mutations and rare activating mutations of EGFR 1 - 2 AZD9291 EAY131-E

ALK translocations 4 Crizotinib EAY131-F

ROS1 translocations 5 Crizotinib EAY131-G

BRAF V600E or V600K mutations 7 Dabrafenib and trametinib EAY131-H

HER2 amplification 5 Ado-trastuzumab emtansine EAY131-Q

BRAF fusions, or non-V600E, non-600K BRAF mutations 2.8 Trametinib EAY131-R

NF2 loss 2 Defactinib EAY131-U

cKIT mutations 4 Sunitinib EAY131-V

NCI-MATCH Subprotocols - Activated August 2015

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Molecular Target Estimated % Prevalence

Agent for Molecular Target Subprotocol ID

PIK3CA mutations or amplifications, but without RAS mutations or PTEN loss 17-18 Taselisib EAY131-I

mTOR mutations 5 MLN0128 EAY131-L

TSC1 or TSC2 mutations 2.6-3.5 MLN0128 EAY131-M

PTEN mutations or deletions, with PTEN expression on IHC 11 GSK2636771 EAY131-N

PTEN loss by IHC 11 GSK2636771 EAY131-P

NF1 mutations 7.7 Trametinib EAY131-S1

GNAQ or GNA11 mutations 2 and 1.6 Trametinib EAY131-S2

Smoothened (SMO) or patched 1 (PTCH1) mutations 2.6 - 3.8 Vismodegib EAY131-T

DDR2 mutations 2 Dasatinib EAY131-X

NCI-MATCH Subprotocols – Expected December 2015

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Molecular Target Estimated % Prevalence

Agent for Molecular Target Subprotocol ID

MET amplifications 4 Crizotinib EAY131-CAberrations in FGFR pathway 5 AZD4547 EAY131-WAKT mutations 1 - 10 AZD5363 EAY131-Y

NCI-MATCH Subprotocols – Expected April 2016

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Levels of Evidence for Drugs in NCI-MATCH

• Level 1: FDA approved for any indication for that target

• Level 2: Agent met a clinical endpoint (objective response, PFS, or OS) with

evidence of target inhibition

• Level 3: Agent demonstrated evidence of clinical activity with evidence of

target inhibition at some level

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Levels of Evidence for Target Selection in NCI-MATCH

• Level 1: Gene variant credentialed for selection of an approved drug

• Level 2a: Variant is eligibility criteria for an ongoing clinical trial for that drug

• Level 2b: Variant identified in an N of 1 response(s)

• Level 3: Preclinical inferential data

– Models with variant respond; without variant do not

– Gain of function mutation demonstrated in preclinical model

– Loss of function (tumor suppressor genes or pathway inhibitor e.g. NF1); stop

codon or demonstrated loss of function in pre-clinical model

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Requirements for New NCI-MATCH Subprotocol Proposals

• Rationale: Why proposed treatment should be effective in a particular molecular subgroup – NEED evidence in patients

• Preliminary data: Levels of Evidence for drug(s) AND target

• At least 2% estimated prevalence of aMOI across refractory solid tumors, lymphomas

• Proposal for measurement of the molecular eligibility criterion(a)

• Recommended phase 2 dose

• Willingness of company

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Genetic Platform and Laboratory Network in NCI-MATCH

• Ion Personal Genome Machine® (PGMTM) System and Ion TorrentTM Server

• Ion AmpliseqTM custom DNA panel

– About 200 genes

– SNV, indel, CNV, targeted translocations

• Selected IHC, FISH

• Network of 4 CLIA-approved molecular diagnostics laboratories provides capacity

– NCI Molecular Characterization Laboratory (Dr. Mickey Williams)

– Plus competitively chosen lab sites: MD Anderson (Dr. Stanley Hamilton), Massachusetts General (Dr. John Iafrate), Yale (Dr. Jeffrey Sklar)

• Validation within and across all four labs: same SOP

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Tumor Biopsy in NCI-MATCH

• Upon entry to initial screening (Step 0) a biopsy (4 cores) FFPE, shipped to

MDACC

• Adjacent section H&E stained, examined by pathologist for tumor content, %

necrosis, inflammation, and scanned into high resolution image database

• RNA and DNA extracted from the same tissue section

• Planned research assays:

– If sufficient DNA available, whole-exome sequencing performed for research

– RNA will be used for research grade gene expression profiling by either whole-

transcriptome or miRNA microarray analysis

• Biopsy and sequencing on progression

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NCI-MATCH Assay Workflow: 10-14 Day Turn-Around Time

Tissue FixationPath Review

Nucleic Acid Extraction

Library/Template Prep

Sequencing , QC Checks

Clinical Laboratory aMOI Verification

Biopsy Received

1 DAY

1 DAY

1 DAY

1 DAY

3 DAYS

10-14 days Rules Engine Treatment Selection

Tumor content >70%

DNA/RNA yields > 20 ng

Library yield > 20 pMTest fragmentsTotal readReads per BCCoverageNTC, Positive, Negative Controls

Centralized Data Analysis aMOIs identified

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NCI-MATCH Logistics

• Master protocol with multiple ph 2 subprotocols with molecularly defined eligibility

• Activated on CTSU on August 12, 2015 with 10 subprotocols

– Expected to expand to 19 by December 2015 and to 22 by April 2016

• IND for protocol template

– Subprotocols can be opened or closed without affecting others

• Single agents or combinations - recommended phase II dose is known

• FDA approved (for a different indication) or investigational agents/combinations

• Central IRB required as the IRB of record

• US-based sites across NCTN and NCORPs

• CLIA lab network: Validated assay

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Team Approach to NCI-MATCH

• NCI-MATCH Steering Committee

– Agent & Gene Selection Committee

• Vetting of actionable genetic alterations and most robust agents

– Informatics Committee

– Imaging Committee

– Specimen/Assay Committee

• Developed and validated next-generation sequencing platform

• Additional IHC or other assays developed at ECOG-ACRIN Central

Biorepository and Pathology Facility at MDACC09/29/2015 29

NCI-MATCH Steering Committee

• Clinical Study Chairs: Drs. Alice Chen, Keith Flaherty, Peter O'Dwyer

• Scientific Chairs: Drs. Barbara Conley, Stanley Hamilton, Mickey

Williams, Carlos Arteaga

• Statistical Chairs: Drs. Robert Gray, Shuli Li, Lisa McShane, Larry

Rubenstein

• Safety Chairs: Drs. Edith Mitchell, James Zwiebel

• Informatics Chairs: Warren Kibbe, Jose Galvez, Susan Lemont,

Mark Routbot

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Additional Expertise for NCI-MATCH

• Leadership for each individual subprotocol

– From all NCTN groups

– From outside NCTN groups

– Young to mid career investigators

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NCI-MATCH Overview

• NCI-MATCH is a signal-finding trial

• Largest, most rigorous precision oncology trial in history

• Conducted by ECOG-ACRIN but has PIs on subprotocols from across NCTN

• Target selection based on levels of evidence

• Coordinated sample collection/pre-analytics

• Validated, standardized gene sequencing through MATCH Box

• Using NCI-MATCH to inform other trials

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Resources for NCI-MATCH

• Main Webpages: cancer.gov/nci-match

ecog-acrin.org/nci-match-eay131

• Protocol Documents: ctsu.org (password required)

• Spanish: cancer.gov/espanol/nci-match

• Email Inquiries: match@jimmy.harvard.edu

• Patient Brochure: EA website (above)

• Site Process Brochure: Coming soon

• NCI’s Cancer Information Service: 1-800-4-CANCER and cancer/gov/contact

This slide presentation is updated regularly. For the latest version, visit ecog-acrin.org.

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Questions?

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