Pl I enary Tr T anslational Medicine April 30, 2015

Transcription

1 Plenary I Translational Medicine April 30, 2015

2 NCI MATCH and the Future of Genomic-Driven Trials Funded by CTEP/NCI Jeffrey Abrams, MD Director, Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis National Cancer Institute SWOG Spring Meeting 2015

3 Opening Statement No conflicts of interest I will discuss investigational agents but only in the context of clinical trials Confidential information: ASCO embargo - press conference on June 1, 2015 NCI National Clinical Trials Network 3

4 NCTN as a Network in the Era of Precision Medicine LAPS NCI National Clinical Trials Network 4

5 Vision for NCTN Innovative Science Answer questions the private sector might not address Reach special populations (minorities, iti rare tumors, uncommon subsets of common tumors) Community practice Integrated Systems Maximize collaboration and make data available to broader community Share expertise across the network Greater timeliness Activate, conduct and complete trials in a timely fashion Bring research findings into clinical practice faster Increased Efficiencies Reduce duplication of efforts (e.g., CIRB, MediData Rave, CTSU) NCI National Clinical Trials Network 5

6 Developing a National Strategy for Precision Medicine Advance molecular profiling from research use to the clinic Select patients based on molecular alterations - Develop pportfolio of trials across spectrum from prevention and screening to early stage and advanced disease - Screen for molecular features that may predict response to a screening test or to a drug with a given mechanism of action - Analyze tumor specimens at relapse to define mechanisms of resistance and develop preclinical models that reflect human cancer - Develop public database that t links clinical i l outcomes with molecular tumor characteristics NCI National Clinical Trials Network 6

7 Precision medicine trials the first wave Activated: Lung-MAP (S1400) led by SWOG ALCHEMIST (A151216) led by Alliance and E-A Exceptional Responders (9671) open in NCTN and beyond In development: NCI MATCH ALK Master Protocol Pediatric MATCH It takes a network NCI National Clinical Trials Network 7

8 Exceptional Responders Initiative: Phenotype to Genotype 1-10% of patients respond well to drugs that do not go on to receive FDA approval for that indication Molecular mutations or changes in gene expression may explain these exceptional responses Inactive drugs are sometimes active in a subset of patients Could lead to development of predictive assays Improve biologic understanding for better therapeutics/diagnostic development NCI National Clinical Trials Network 8

9 Response to everolimus MSKCC protocol year old with metastatic bladder cancer. Complete response to everolimus (mtorc1 inhibitor) on MSKCC protocol The patient remains on drug with no evidence of disease 24 months after starting treatment. This patient was one of only 2 who responded to drug (of 45 patients). The drug did not achieve it s pre-trial statistical endpoint (>70% of patients progression free at 2 months). Pre Treatment 3 month interval 6 month interval 18 month interval Why did this patient respond so dramatically? NCI National Clinical Trials Network Iyer/Berger/Taylor/Solit

10 TSC1 mutation correlates with response to mtor inhibition in metastatic bladder cancer NCI National Clinical Trials Network Iyer/Berger/Taylor/Solit

11 Exceptional Responders Broad Solicitation for Tissue Samples and Clinical Data - Cooperative Groups - Cancer Centers - Letters to CTEP investigators for identified ER cases - Pharma Sites will be reimbursed for effort ENROLL: NCI National Clinical Trials Network 11

12 MOLECULAR ANALYSIS FOR THERAPY CHOICE NCI MATCH A Joint ECOG-ACRIN/NCI Clinical Trial NCI National Clinical Trials Network

13 Overview NCI MATCH is a signal finding trial NCI MATCH will be conducted by ECOG-ACRIN but has PIs on sub-protocols from across NCTN Levels of evidence Coordinating sample collection/pre-analytics Assay platforms Logistics Using MATCH to inform other (basket, umbrella) trials. NCI National Clinical Trials Network 13

14 Team Approach MATCH Steering Committee Agent & Gene Selection Committee: vetting actionable genetic alterations and most robust agents Informatics Committee Imaging Committee Specimen/Assay Committee: Genetic (NGS) platform developed and validated; Additional IHC or other assays developed at ECOG-ACRIN PCO (MDACC) Public Relations Committee Site Education Committee NCI National Clinical Trials Network 14

15 MATCH Steering Committee Scientific Chairs: Barbara Conley, Stanley Hamilton, Mickey Williams, Carlos Arteaga Clinical Study Chairs: Alice Chen, Keith Flaherty, Peter O'Dwyer Statistical Chairs: Robert Gray, Shuli Li, Lisa McShane, Larry Rubenstein Safety Chairs: Edith Mitchell, James Zwiebel Informatics Chairs: Warren Kibbe, Jose Galvez, Susan Lemont and Mark Routbot t NCI National Clinical Trials Network 15

16 NCI MATCH Eligibility molecularly defined; Identify mutations/amplifications/translocations in patient tumor sample Assign patient to relevant agent/regimen Need to sequence large numbers of tumors and need to have large numbers of targeted treatments Tumor biopsies i & sequencing at progression to illuminate resistance mechanisms - De-identified samples submitted to central labs - Whole-exome, mrna sequencing (research purposes) NCI National Clinical Trials Network 16

17 SCHEMA Genetic sequencing PTEN IHC Actionable mutation detected Study agent Stable Disease, Complete or partial response (CR+PR) 1 Continue on study agent until progression PD Repeat biopsy and sequencing Progressive disease (PD) 1 Check for additional actionable mutations 2 Yes No No additional actionable mutations, or withdraw consent 1 CR, PR, SD, and PD as defined by RECIST 2 Rebiopsy; if patient had CR or PR or SD for greater than 6 months or had 2 rounds of treatment after a biopsy on MATCH Off study NCI National Clinical Trials Network 17

18 Statistical Considerations: Each sub-protocol Primary Endpoint: Overall Response Rate 5% vs. 25% Secondary Endpoints Progression Free Survival 6 months 15% (median PFS 2.2 m) vs 35% (median PFS 4 m) TTP Toxicity Biomarker One stage design: 31 evaluable patients per arm NCI National Clinical Trials Network 18

19 Levels of Evidence: Drugs Level 1: FDA approved for any indication for that target; evidence of target inhibition, or proof of mechanism; demonstration that patient selection with Companion Dx are more likely to respond Level el 2: Agent met a clinical endpoint (objective e 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 it with evidence of target t inhibition at some level; some evidence of a predictive or selection assay/analyte NCI National Clinical Trials Network 19

20 Frequency of Actionable Mutations BRAF fustions or mutatiuons (non V600E or V600K) (2.79%) ALK fusions/translocations (4%) Pending Agreements 18% 3% 4% Agreements in Place 5% ROS1 transolcations (5%) BRAF V600E or V600K (1 12%) mtor mutations (5%) TSC1 or TSC2 mutations ( %) 7% T790M mutations (1 2%) NF1 mutations (7.7%) 5% 5% GNAQ (2%) GNA11 (1.6%) 3% 5% 11% 2% 4% 4% 3% 4% 3% 8% 2% 2% 2% ckit (4%) EGFR activating mutations (1 4%) HER Activating Mutations (2 5%) MET amplifications (4%) NF2 loss (2%) PTEN (mutations and loss) (11%) SMO or PTCH1 mutations (2.63 and 3.76%) HER amplifications (5%) FGFR amplifications or FGFR mutations (5%) PIK3CA mutations (17 18%) NCI National Clinical Trials Network 20

21 Current arms Crizotinib for ROS1 translocations Crizotinib for ALK translocations Dabrafenib and Trametinib for BRAF V600E mutations Trametinib for BRAF activating mutations and BRAF fusions NCI National Clinical Trials Network 21

22 Current arms Afatinib in patients with EGFR del 19 or L858R mutations (non-nsclc) Afatinib in patients with HER2neu kinase mutations TDM1 in patients with HER2 amplifcation (non-breast cancer) AMG337 in patients with MET amplification VS6063 in patients with NF2 mutations Trametinib in patients with NF1, GNAQ, GNA11 mutations Sunitinib in patients with KIT mutations (non GIST) NCI National Clinical Trials Network 22

23 Concepts/protocols in development FGFR inhibitor in patients with FGFR mutations and FGFR fusions Dasatinib in patients with DDR2 mutations AKT inhibitor for AKT mutations PIK3CA inhibitor TORC1/2 inhibitor SMO inhibitor PI3K beta inhibitor for PTEN loss NCI National Clinical Trials Network 23

24 Rules of Evidence for Target Selection Level 1: Gene variant credentialed for selection of an approved drug Level 2a: Variant is eligibility criteria for ongoing clinical trial for that drug Level 2b: Variant identified in 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 (TSG or Pathway inhibitor eg NF1; stop codon or demonstrated LOF in preclinical model NCI National Clinical Trials Network 24

25 Rules for Treatment Selection Four assay components are equal (SNV/indel; CNV; fusion) point mutations/indels, amplifications, translocations, IHC Select actionable mutation of interest (amoi) winner in each component - Level of evidence for target selection 1,2 > 3 - If more than 1 LOE 1,2, assign arm with fewer pts - If > 1 SNV/indels: LOE 1,2 > 3; IF more than 1 LOE 1,2 If difference between VAF > 15%, choose greater If difference < 15%, choose arm with fewer pts Compare winner of each component - LOE 1,2 > 3 - If > 1 LOE 1,2 select arm with fewer pts (or randomize if equal) Rules rigorously validated in MATCHBOX NCI National Clinical Trials Network 25

26 MATCH Assay System Components Clinical site: 5 core needle biopsies Overnight ship in formalin to MD Anderson (Core resource) - Centralized pre-analytics - Purified nucleic acids shipped frozen to 1 of 4 clinical laboratories Standardized analytically validated targeted NGS assay performed - Molecular Characterization Laboratory FNLCR - MD Anderson Cancer Center - Massachusetts General Hospital - Yale University Central data analysis server; actionable variants called and sent to clinical lab for verification Rules engine selects treatment options Treatment selection to Clinical Site NCI National Clinical Trials Network 26

27 Logistics Single IND for Master protocol - Arms could be added or deleted without affecting other arms Central IRB Fresh biopsy CLIA lab network: analytically validated targeted NGS assay 2400 NCTN sites Locked treatment assignment rules (not a tumor board) Presubmission meeting with CDRH no IDE New York State regulation NCI National Clinical Trials Network 27

28 Other issues Discovery of germ line mutations Even if sequencing tumor only, there can be mutations that could also be germline Most germline mutations have been documented by obtaining family history and then obtaining a test for a relevant mutation With sequencing of many variants at one time, and smaller, mobile families, there is the possibility for description of previously unacknowledged germline mutations How to advise? Followup sequencing? Research on this needed NCI National Clinical Trials Network 28

29 Status MATCH master protocol approved by CTEP with 4 subprotocols CIRB approval expected late April IND submitted to FDA mid April Preactivation late May 2015 Open to enrollment: June - July 2015 Amendments? - add histology-specific patients on particular arms - add ancillary protocols for PDX models NCI National Clinical Trials Network 29

30 Basket and Umbrella Trials Tumor X Drug A Basket or Bucket trials Single drug targeting a single mutation Variety of tumors carrying genetic aberration X Molecular profile X DrugA X Drug A Same tumor type X Drug A Umbrella trials Y Drug B Multiple drugs targeting multiple mutations Variety of tumors carrying a variety of genetic aberrations X, Y, & Z randomized or nonrandomnized rules based treatment assignment or per patient based on review of individual profile data Molecular profile Z Variety of tumor types Y Drug C Drug B Z Drug C Kummar et al., JNCI, 2015 X Drug A

31 ALK MASTER PROTOCOL In Advanced Lung Adenocarcinoma Master Protocol with single control arm to test second generation ALK inhibitors A Joint NRG/NCI Clinical Trial PIs: Alice Shaw, M.D., Shakun Malik, M.D. NCI National Clinical Trials Network

32 ALK 2 nd gen Inhibitors in clinical trials Ariad- AP26113 Ignyta- RXDX-101 Novartis - Ceritinib (Zykadia) Pfizer- PF Roche/Chugai - Alectinib Tesaro - TSR-011 Xcovery-x-396 NCI National Clinical Trials Network 32

33 2 nd generation ALK inhibitor To develop a Master protocol with a single shared control arm (Crizotinib) Eligibility Criteria: Metastatic ALK positive NSCLC No prior therapy with ALK inhibitor NCI National Clinical Trials Network 33

34 Proposed Trial Design Control Arm Crizotinib Crizotinib to A Crizotinib to B ALK positive NSCLC Treatment Naïve patients Drug A Drug B PD Cross Over A to B A To Crizotinib PD Central Confirmation ALK NGS Archived tissue NGS New Biopsy B to A B To Crizotinib NGS New Biopsy NCI National Clinical Trials Network 34

35 ALK-MP structure Led by NRG/NCI, in partnership with Friends of Cancer Research, FNIH Advice and consultation from FDA Still needs approval from Thoracic Malignancy Steering Committee All groups will participate via NCTN or NCORP Available nationwide on the Cancer Trials Support Unit (CTSU) to any site in the Network. If approved, projected to open Winter 2015 NCI National Clinical Trials Network 35

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37 Plenary I Translational Medicine April 30, 2015