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: 11/17/2015

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 11/17/20152

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 /17/20153

BRAF inhibitor therapy markedly more effective for V600E BRAF melanoma compared to colon cancer Kopetz, ASCO 2010 melanomacolorectal Sosman J et al. NEJM /17/20154

Decoding the cancer genome: ERBB2 (HER2) Breast cancer Gastric cancer Bladder cancer Uterine cancer Prostate cancer Chromophobe kidney cancer Liver cancer 11/17/20155

Mutation Frequency in TCGA Gene Bladder Breast Cervix Colo- rectal GBM Glioma Head and Neck Lung (Adeno) Lung ( Squam) Melanoma OvarianPancreasProstateStomachThyroid Uterine AKT BRAF EGFR FGFR FGFR FGFR HRAS IDH IDH KIT KRAS NF NF NRAS PIK3CA PIK3R PTCH PTEN SMO TSC TSC Compiled by MD Anderson Investigators 11/17/20156

Amplification Frequency in TCGA Gene Bladder Breast Cervix Colo- rectal GBM Glioma Head and Neck Lung (Adeno) Lung ( Squam ) Melanoma Ovarianpancreas Prostate StomachThyroid Uterine HER FGFR FGFR FGFR MET PIK3CA Compiled by MD Anderson Investigators 11/17/20157

Oncomine Comprehensive Assay Gene List 811/17/2015 ALK RET ROS1 NTRK1 NTRK3 FGFR1 FGFR2 FGFR3 BRAF RAF1 ERG ETV1 ETV4 ETV5 ABL1 AKT3 AXL EGFR ERBB2 PDGFRA PPARG ABL1 AKT1 ALK AR ARAF BRAF BTK CBL CDK4 CHEK2 CSF1R CTNNB1 DDR2 DNMT3A EGFR ERBB2 ERBB3 ERBB4 ESR1 EZH2 FGFR1 FGFR2 FGFR3 FLT3 FOXL2 GATA2 GNA11 GNAQ GNAS HNF1A HRAS IDH1 IDH2 IFITM1 IFITM3 JAK1 JAK2 JAK3 KDR KIT KNSTRN KRAS MAGOH MAP2K1 MAP2K2 MAPK1 MAX MED12 MET MLH1 MPL MTOR MYD88 NFE2L2 NPM1 NRAS PAX5 PDGFRA PIK3CA PPP2R1A PTPN11 RAC1 RAF1 RET RHEB RHOA SF3B1 SMO SPOP SRC STAT3 U2AF1 XPO1 ACVRL1 AKT1 APEX1 AR ATP11B BCL2L1 BCL9 BIRC2 BIRC3 CCND1 CCNE1 CD274 CD44 CDK4 CDK6 CSNK2A1 DCUN1D1 EGFR ERBB2 FGFR1 FGFR2 FGFR3 FGFR4 FLT3 GAS6 IGF1R IL6 KIT KRAS MCL1 MDM2 MDM4 MET MYC MYCL MYCN MYO18A NKX2-1 NKX2-8 PDCD1LG2 PDGFRA PIK3CA PNP PPARG RPS6KB1 SOX2 TERT TIAF1 ZNF217 APC ATM BAP1 BRCA1 BRCA2 CDH1 CDKN2A FBXW7 GATA3 MSH2 NF1 NF2 NOTCH1 PIK3R1 PTCH1 PTEN RB1 SMAD4 SMARCB1 STK11 TET2 TP53 TSC1 TSC2 VHL WT1 Hotspot genes, n=73 Copy Number Variants, n=49 Fusion drivers, n=22 Full-gene coverage, n= unique genes 2530 amplicons in DNA panel 207 amplicons in RNA panel

Reporting and Actionable Mutations by NCI-MATCH Assay Total genes: 143 Mutations of interest (MOI) reported by assay: 4066 pre-defined hotspot 3259 SNVs 114 Small indels 435 Large indels (gap >=4bp) 75 CNVs 183 Gene fusions Deleterious mutations in 26 tumor suppressor gene EGFR exon 19 inframe deletions and insertions ERBB2 exon 20 inframe insertions KIT exons 9 and 11 inframe deletions/ insertions Actionable MOI (aMOI): Subset of MOIs with level of evidence 911/17/2015

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) 11/17/201510

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 11/17/201511

NCI-MATCH Design Features Test many patients to find widely distributed genetic alterations Biopsies needed at time of study entry (cost covered by NCI) Response rate (tumor regression) will be primary efficacy measure Across initial 22 arms, PIs drawn from: –37% ECOG-ACRIN, 30% Alliance, 16% SWOG, 16% NRG 150+ NCI and NCTN members of 10 subcommittees Advocates involved in trial design and help oversee conduct 11/17/201512

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) 11/17/201513

NCI-MATCH Schema 11/17/201514

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 11/17/201515

NCI-MATCH Patient Population Considerations Target: at least 25% of total enrollment to be patients who have “rare” tumors “Common” cancers defined as –Breast –Non-small cell lung –Colon –Prostate 11/17/201516

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 arm 11/17/201517

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 11/17/201518

aMOIs in NCI-MATCH and Estimated Prevalence 1911/17/2015

NCI-MATCH Subprotocols - Activated August /17/201520

NCI-MATCH Subprotocols – Expected January /17/201521

NCI-MATCH Subprotocols – Expected April /17/201522

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 11/17/201523

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 11/17/201524

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 II dose Willingness of company 2511/17/2015

Genetic Platform and Laboratory Network in NCI-MATCH Ion Personal Genome Machine ® (PGM TM ) System and Ion Torrent TM Server Ion Ampliseq TM 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 11/17/201526

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 11/17/201527

NCI-MATCH Assay Workflow 2811/17/2015

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 17 in January 2016 and to 22 or more in 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 11/17/201529

Pause of New Accrual to Screening Step 0 Protocol design has built-in review after 500 patients enrolled for screening Pause effective November 4, 2015 Accrual will resume upon completion of interim analysis, likely in January 2016 No change for the following patients: –With informed consents signed prior to Nov 4 th –Registered to Step 0 by November 11, 2015 –Being treated on one of the subprotocols Physicians referring new patients for enrollment should discuss other options Sites activating the study should continue with the process No change in adding new subprotocols 11/17/201530

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 MDACC 11/17/201531

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 11/17/201532

Additional Expertise for NCI-MATCH Leadership for each individual subprotocol –From all NCTN groups –From outside NCTN groups –Young to mid career investigators 11/17/201533

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 11/17/201534

Resources for NCI-MATCH Main Webpages:cancer.gov/nci-matchcancer.gov/nci-match ecog-acrin.org/nci-match-eay131 Protocol Documents:ctsu.org (password required)ctsu.org Spanish:cancer.gov/espanol/nci-matchcancer.gov/espanol/nci-match Patient Brochure:EA website (above) Site Process Brochure:EA website (above) NCI’s Cancer Information Service: CANCER and cancer/gov/contactcancer/gov/contact This slide presentation is updated regularly. For the latest version, visit ecog-acrin.org. 11/17/201535

Questions? 11/17/201536