1. 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

2. 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.
09/29/2015

3. 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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4. BRAF inhibitor therapy markedly more effective for V600EBRAF melanoma compared to colon cancer
Sosman J et al. NEJM 2012
Kopetz, ASCO 2010
melanoma
colorectal
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5. Decoding the cancer genome: ERBB2 (HER2)
Breast cancer
Prostate cancer
Gastric cancer
Chromophobe kidney cancer
Bladder cancer
Liver cancer
Uterine cancer
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6. 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
2.4
0.9
0.4
0.7
0.6
1.4
3.5
1.6
BRAF
0.8
2.6
9.9
2.1 1
9.6
4.5
50.2
1.8
4.1
61.3
2.8
EGFR
1.5
26.1
5.9
4.7
14.3
3.9
6.5
2.2
1.2 5
3.2
FGFR1
3.1
0.3
1.3
1.1
1.7
3.6
FGFR2
2.3
9.3
0.2
12.5
FGFR3
14.6
2.9 2
HRAS
4.6
IDH1
4.9
76.1
5.7
0.5
IDH2
4.2
KIT
2.7
6.9
KRAS 43
32.6
57.9
11.4
21.4
NF1
9.2
7.7
6.6
11.8
11.9
13.3
4.4
8.1
NF2
5.1
NRAS 9
30.8
8.5
PIK3CA 20
35.1
23.1
20.1
10.6
20.9
15.7
21.8
53.2
PIK3R1 4
11.3
33.1
PTCH
7.1
4.8
2.5
1.9
PTEN
31.9
7.9
8.2
5.2
6.4
64.9
SMO
TSC1
10.7
3.4
TSC2
Compiled by MD Anderson Investigators
09/29/2015

7. 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
2.2
0.6 13
5.5
FGFR1
9.4 12
1.2
3.6
0.4
8.5
3.5
16.9
0.3 4 2 1
2.5
FGFR2
0.5
1.8
0.7
0.9
5.1
FGFR3
0.8
1.3
1.5
7.9
0.2
MET
8.9
1.1
3.9
4.1
PIK3CA
4.9
19.3
2.9
21.1
38.2
28.8
2.8
14.3
Compiled by MD Anderson Investigators
09/29/2015

8. OncomineTM Focus Assay Gene List
Hotspot genes, n=35
Copy number variants, n=19
Fusion drivers, n=23
AKT1 ALK AR
BRAF CDK4
CTNNB
1 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 KIT
KRAS MET MYC MYCN PDGFRA PIK3CA
ALK
AR BRAF CCND1 CDK4 CDK6 EGFR ERBB2 FGFR1 FGFR2
ABL1
AKT3
ALK
AXL
BRAF
ERBB2
EGFR
ERG
ETV1
ETV4
ETV5
FGFR1
FGFR2 FGFR3
MET
NTRK1 NTRK2 NTRK3
PDGFRA PPARG
RAF1
RET
ROS1
RNA Panel
52 unique genes
DNA Panel
269 amplicons in DNA panel
272 amplicons in RNA panel
09/29/2015

9. 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)
09/29/2015

10. 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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11. 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
09/29/2015

12. 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)
09/29/2015

13. NCI-MATCH Schema
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14. 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
09/29/2015

15. 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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16. 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
09/29/2015

17. 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
09/29/2015

18. aMOIs in NCI MATCH and Estimated Prevalence
09/29/2015

19. NCI-MATCH Subprotocols - Activated August 2015
Molecular Target
Estimated % Prevalence
Agent(s) for
Subprotocol ID
EGFR activating mutations
1 - 4
Afatinib
EAY131-A
HER2 activating mutations
2 - 5
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
EAY131-G
BRAF V600E or V600K mutations 7
Dabrafenib and trametinib
EAY131-H
HER2 amplification
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
Sunitinib
EAY131-V
09/29/2015

20. NCI-MATCH Subprotocols – Expected December 2015
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
EAY131-M
PTEN mutations or deletions, with PTEN expression on IHC 11
GSK
EAY131-N
PTEN loss by IHC
EAY131-P
NF1 mutations
7.7
Trametinib
EAY131-S1
GNAQ or GNA11 mutations
2 and 1.6
EAY131-S2
Smoothened (SMO) or patched 1 (PTCH1) mutations
Vismodegib
EAY131-T
DDR2 mutations 2
Dasatinib
EAY131-X
09/29/2015

21. NCI-MATCH Subprotocols – Expected April 2016
Molecular Target
Estimated % Prevalence
Agent for Molecular Target
Subprotocol ID
MET amplifications 4
Crizotinib
EAY131-C
Aberrations in FGFR pathway 5
AZD4547
EAY131-W
AKT mutations
1 - 10
AZD5363
EAY131-Y
09/29/2015

22. 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
09/29/2015

23. 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
09/29/2015

24. 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
09/29/2015

25. 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
09/29/2015

26. 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
09/29/2015

27. NCI-MATCH Assay Workflow: 10-14 Day Turn-Around Time
Biopsy Received
Tissue Fixation
Path Review
Tumor content >70%
1 DAY
Nucleic Acid
Extraction
DNA/RNA yields > 20 ng
1 DAY
Library/Template Prep
Library yield > 20 pM
Test fragments
Total read
Reads per BC
Coverage
NTC, Positive, Negative Controls
1 DAY
Sequencing , QC Checks
Centralized Data Analysis
1 DAY
aMOIs identified
3 DAYS
Clinical Laboratory aMOI Verification
10-14 days
Rules Engine Treatment Selection
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28. 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
09/29/2015

29. 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
09/29/2015

30. 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
09/29/2015

31. 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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32. 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
09/29/2015

33. 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
Inquiries:
Patient Brochure: EA website (above)
Site Process Brochure: Coming soon
NCI’s Cancer Information Service: CANCER and cancer/gov/contact
This slide presentation is updated regularly. For the latest version, visit ecog-acrin.org.
09/29/2015

34. Questions?
09/29/2015