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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 Version Date: 08/03/2018
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On Behalf of the NCI-MATCH Study Leadership
Keith T. Flaherty1, Alice P. Chen2, Peter J. O'Dwyer3, Barbara A. Conley2, Lyndsay N. Harris2, James V. Tricoli2, Stanley R. Hamilton4, Mickey Williams5, Robert J. Gray6, Shuli Li6, Lisa M. McShane2, Lawrence V. Rubinstein2, Susanna I. Lee1, Constantine A. Gatsonis7, Lalitha K. Shankar8, Paolo F. Caimi9, Shaji Kumar10, Edith P. Mitchell11, James A. Zwiebel2, A. John Iafrate1, Jeffrey Sklar12, Carlos L. Arteaga13 1Massachusetts General Hospital, Boston, MA; 2National Cancer Institute (NCI), Division of Cancer Treatment and Diagnosis, Bethesda, MD; 3University of Pennsylvania, Philadelphia, PA; 4MD Anderson Cancer Center, Houston, TX; 5 NCI Frederick National Laboratory for Cancer Research, Frederick, MD; 6Dana-Farber Cancer Institute, Boston, MA; 7Brown University, Providence, RI; 8NCI Cancer Imaging Program, Rockville, MD; 9Case Western Reserve University, Cleveland, OH; 10Mayo Clinic, Rochester, MN; 11Thomas Jefferson University, Philadelphia, PA; 12Yale University, New Haven, CT; 13UT Southwestern Medical Center, Dallas, TX
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Trial Description
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What is NCI-MATCH?
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Precision Medicine in Cancer Treatment
Precision medicine is the tailoring of treatment for each individual based on molecular abnormalities found in tumors rather than the type of cancer Example: BRAFV600E melanoma responds to BRAF inhibitors or BRAF inhibitors combined with MEK inhibitors but colorectal cancers with the same mutations appear not to respond We need to know more about which tumors will respond to agents targeted to “driver” mutations
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NCI-MATCH Objective To determine whether matching certain drugs or drug combinations in adults whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of the cancer type This is a signal-finding trial; treatments that show promise can advance to larger, more definitive trials
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Design of NCI-MATCH Master protocol with individual arms that open and close independently 39 treatment arms Including 4 new arms planned to open in late 2018 Genomic testing directs patients to molecularly-targeted treatments Each arm evaluates the activity of a treatment in tumors with relevant actionable mutations in refractory malignancies Goal to include at least 25% less common or rare cancers Other than breast, colon, lung, prostate
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NCI-MATCH Brings Genomics to the Community
Availability at over sites reflects the broad community interest in the promise of genomics Open in every state, the District of Columbia, and Puerto Rico
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NCI-MATCH Laboratory Network
ECOG-ACRIN Central Biorepository and Pathology Facility at MD Anderson Cancer Center Stan Hamilton, MD Massachusetts General, Center for Integrated Diagnostics John Iafrate, MD, PhD MD Anderson Molecular Diagnostics NGS Laboratory Stan Hamilton, MD NCI Molecular Characterization Laboratory Mickey Williams, PhD Yale University, Clinical Molecular Pathology Jeffrey Sklar, MD, PhD
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NCI-MATCH’s Customized Thermo Fisher OncomineTM Assay
Copy Number Variants, N=49 Full-Gene Coverage, N=26 Fusion Drivers, N=22 Hotspot Genes, N=73 143 genes amplicons in DNA panel 207 amplicons in RNA panel 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 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 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 ALK RET ROS1 NTRK1 NTRK3 FGFR1 FGFR2 FGFR3 BRAF RAF1 ERG ETV1 ETV4 ETV5 ABL1 AKT3 AXL EGFR ERBB2 PDGFRA PPARG
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Assay Reproduced with Accuracy by Laboratory Network
“…the assay tailored for this trial is highly sensitive for detecting genetic mutations from a variety of tumor tissue and, for the first time, has been reproduced with accuracy by multiple clinical laboratories, laying the groundwork for future clinical utility.” Chih-Jian Lih et al, The Journal of Molecular Diagnostics, Vol 19, Issue 2, March 2017
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Treatment Arms
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Brief Timeline of NCI-MATCH Treatment Arms
Open 10 arms Aug. 12, 2015 Resume 24 arms May 31, 2016 Expand 30 arms Mar. 13, 2017 Late 2018 Expand 39 arms Expand 35 arms June 20, 2018 Nov 2015-May 2016 Pause Interim analysis Lab capacity increase
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NCI-MATCH Treatment Arm Overall Design (Single-Arm Phase II)
Screening (Step 0) results in treatment assignment to arm “x” Complete response, partial response, stable disease Check eligibility for arm “x” PD Offer arm “x”; enroll Check for additional matching aberrations Progressive disease (PD)
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NCI-MATCH Treatment Arm Objectives
Primary: Estimate the proportion of patients with refractory solid tumor, lymphoma or myeloma who had an objective response (OR) Secondary: Progression-free survival (PFS) PFS at 6 months (PFS6) Time to progression/death Toxicity Potential predictive biomarkers
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NCI-MATCH Treatment Arms Open and Enrolling
Tumor Gene Abnormality Prevalence Rate % Drug(s) Arm ID Accrual as of 06/24/18) ALK 0.03 Crizotinib F 2 BRCA1 or BRCA2 Enrollment suspended 2.79 AZD1775 Z1I 33 CDK4 or CDK6 1.36 Palbociclib Z1C 21 cKIT 0.11 Sunitinib malate V 9 EGFR activating 0.05 Afatinib A 1 EGFR T790M AZD9291 E 5 FGFR amplification 1.86 Erdafitinib K1 FGFR mutations or fusions 1.00 K2 GNAQ/GNA11 0.16 Trametinib S2 3 HER2 amplification 1.49 Trastuzumab + pertuzumab J 11
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NCI-MATCH Treatment Arms Open and Enrolling, cont’d
Tumor Gene Abnormality Prevalence Rate % Drug Arm ID Accrual (as of 06/24/18) MET amplification Enrollment suspended 0.51 Crizotinib C1 35 MET exon 14 deletion 0.61 C2 16 mTOR 0.31 TAK-228 L 10 NTRK 0.10 Larotrectinib Z1E 3 PIK3CA 3.47 Copanlisib Z1F PTEN loss by IHC (without PIK3CA) 1.93 Z1G PTEN mutation and expression by IHC 1.75 Z1H ROS1 0.05 G SMO/PTCH1 0.42 Vismodegib T 21 TSC1 or TSC2 1.11 M 22
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NCI-MATCH Outcomes Reporting on Individual Arms
Accrual goal per arm: 35 Some arms targeting more common gene variants were expanded to accommodate the higher numbers of patients with matches who came into the trial through central screening Reporting of primary and secondary endpoints will occur once there is complete response and toxicity data for at least 31 patients per arm Accrue at least 35 to obtain at least 31 evaluable (10% ineligibility rate) Need ~8 months of follow-up after accrual is complete If the OR is ≥ 5/31 (16%), agent worthy of further study Secondary analyses will examine response by a variety of factors
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NCI-MATCH Treatment Arms Completed or Closed to Enrollment
Variant Prevalence Rate % Drug(s) Arm Final Accrual Publication Status AKT 0.77 AZD5363 Y 35 Abstract in development BRAF fusions 0.80 Trametinib R In follow-up BRAF V600 E/K 0.69 Dabrafenib + trametinib H CCND1/2/3 0.84 Palbociclib Z1B 40 DDR2 0.00 Dasatinib X TBD dMMR status 1.51 Nivolumab Z1D 47 Results: Azad JITC 2017, 5(Suppl 3):89 FGFR 2.86 AZD4547 W 52 Results at ASCO 2018 HER2 activating 1.04 Afatinib B HER2 amplif. 1.49 Ado-trastuzumab emtansine Q 38 NF1 1.77 S1 50 NF2 loss Defactinib U NRAS 1.90 Binimetinib Z1A 53 Manuscript in development PIK3CA 3.47 Taselisib I 70 Results at ASCO 2018 PTEN 1.75 GSK N 24 Results submitted (N closed early for administrative reasons; its results will combine with Arm P) PTEN loss 1.93 P
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New NCI-MATCH Arms in Development
Tumor Gene Abnormality Prevalence Rate % Drug Arm ID Opening (Pending Approval) AKT mutations 0.77 Ipatasertib Z1K Late 2018 dMMR status 1.51 Nivolumab + BMS (a LAG-3 inhibitor) Z1M Early 2019 Non-V600 BRAF mutations 0.80 Ulixertinib (BVD-523) Z1L TP53 mutations and MYC amplification Not available AZ1775 Z1J
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NCI-MATCH Enrollment Status Per Arm is Publicly Available in a Searchable Spreadsheet
Green – open to patient enrollment Red – closed to enrollment Yellow – suspended Dark Yellow - open, but not for referrals from designated labs Grey – in development
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Treatment Arms in NCI-MATCH by Molecular Pathway
DDR2 BRCA 1, 2 mutations MLH1, MSH2 LOSS NTRK fusions MAP Kinase: EGFR mut: rare and T790M HER2 mutation and HER2 ampl ALK, ROS translocations RAF mutations, fusions NF2 loss, NF1 mutation NRAS mutations SMO, PTCH1, KIT mutations CCND1 AMP CDK4 OR 6 AMP FGFR ampl, mut, fusion MET exon 14 skipping MET amplification P13K PIK3CA mutations TSC1, 2 mutations MTOR mutations PTEN LOSS AKT mutations MAP kinase PI3Kinase DNA repair Immuno-onc cell cycle FGFR LOXO MET
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Credentialing Tumor Gene Abnormalities for NCI-MATCH
Level of Evidence Definition Level 1 Gene variant credentialed for selection of an approved drug Level 2 Variant is eligibility criterion for an ongoing clinical trial for that drug OR variant has been identified in an N of one response Level 3 Variant has 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 preclinical model
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Credentialing Drugs for NCI-MATCH
Level of Evidence Definition 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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Rules for Assigning Patients to NCI-MATCH Treatment Arms
Three assay components are equal (SNV/indel; CNV; fusion) If more than one actionable mutation of interest (aMOI): Level of evidence 1 > 2 > 3 If aMOIs have same level of evidence: SNV/indels: If difference between VAF > 15%, choose greater If difference < 15%, choose arm with fewer patients If 1 aMOI is not an SNV, choose arm with fewer patients
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Patient Referral Process
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Screened through trial’s central laboratory network
NCI-MATCH Brief History of Patient Screening (Step 0) Applies only to patients at ~1100 participating trial sites Screened through trial’s central laboratory network Tumor gene testing by a designated laboratory is the only pathway for new patients to enroll, effective May 11, 2017 First 6000 patients All additional patients
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Verification centrally Lab sends written referral to physician
Patient Pathway onto NCI-MATCH via a Commercial Lab Applies only to patients at ~1100 participating trial sites Physician orders routine genomic test to guide patient’s care – not looking specifically for NCI-MATCH Lab runs its standard test; sends results to physician Verification centrally Lab flags case – patient has tumor gene abnormality and disease characteristics that possibly qualify them for arm “x” Lab sends written referral to physician Patient and physician decide to pursue NCI-MATCH; patient enrolls onto trial for screening (Step 0)
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Designated Commercial Labs Referring Patients to NCI-MATCH
GenPath (BioReference Laboratories, Inc.) Caris Life Sciences® Foundation Medicine, Inc. NeoGenomics Laboratories, Inc. OmniSeq, Inc. Tempus Labs, Inc. Strata Oncology, Inc. Learn more at ecog-acrin.org/nci-match-eay131-designated-labs More laboratories to come, pending NCI approval
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Designated Academic Labs Referring Patients to NCI-MATCH
Massachusetts General Hospital Columbia University Memorial Sloan Kettering Cancer Center MD Anderson Cancer Center Weill Cornell Medicine Yale University Generally, the cancer center labs test their own patient population Learn more at ecog-acrin.org/nci-match-eay131-designated-labs More labs to come, pending NCI approval
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Effect on Patients of Laboratory Referrals
Referrals will be confirmed on the NCI-MATCH assay, by the central lab Using archived tissue - no fresh biopsy necessary Both the participating trial site AND the designated lab are possible sources for the archived samples Patient treatment will not be delayed for confirmation Patients confirmed by NCI-MATCH assay will be included in the primary outcome analysis Those without confirmation will continue treatment and evaluation, but will not be included in the primary outcome analysis
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Request for Biopsy Submissions at Progression
To aid future research, the NCI-MATCH trial requests that any patients who experience disease progression during the trial submit a biopsy The study team encourages all participating sites and physicians to take this request into consideration
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NCI-MATCH Reimbursement Status
The NCI does not reimburse for the routine genomic testing performed by designated laboratories Assays done on the archived tissue blocks submitted for concordance purposes will be done free of charge NCI will reimburse in the customary way for block submission and the reimbursement for patients entering the therapeutic arms
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NCI-MATCH Acknowledgements
Advocates were involved in trial design and are helping to oversee conduct There is widespread participation across the NCI scientific community About 120 treatment arm chairs and co-chairs Nearly 1100 participating sites nationwide Over 150 individuals on 10 steering committees and working groups
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NCI-MATCH Resources Main Webpages: ecog-acrin.org/nci-match-eay131 cancer.gov/nci-match Protocol Documents: ctsu.org (password required) Spanish: cancer.gov/espanol/nci-match Inquiries: NCI Contact Center: CANCER and cancer.gov/contact
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Extra Content: The First 6000 Patients
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Brief History of Central Screening in NCI-MATCH
Opened on August 12, 2015, with 10 treatment arms and a goal to have patients submit tumor samples for central testing 795 patients were screened in the first three months Reached >100/week by the end of this period Far surpassed the original estimate of 50 screens/month Paused enrollment of new patients in November 2015, for a planned interim analysis This resulted in a more accurate estimation of the prevalence rates for the targeted mutations
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Central Screening Brief History (cont’d)
Resumed enrollment of new patients in May 2016, with 24 treatment arms and more laboratory capacity to handle rapid pace of enrollment Increased central screening goal to 6000 patients in late 2016 Added myeloma patients in late 2016 Expanded to 30 treatment arms in March 2017 Completed screening of nearly 6k patients in July 2017
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Central Screening Brief History (cont’d)
NCI-MATCH screened ~6000 patients in less than two years—a rate that far exceeded expectations
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NCI-MATCH Central Screening Results
Tumor gene sequencing was successful in 93% of patients with samples submitted, a rate well above the industry standard of ~80% Goal # Registered for Screening # With Samples Submitted Successful Laboratory Testing 6000 6397 5962 93% 5560
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NCI-MATCH 6k Central Screening Enrollment Per One Million Population
FEWER than 8 >8 – <30 30 – 65 JH Doroshow, NCI Community Oncology Research Program (NCORP) Annual Meeting, 08/29/2017
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NCI-MATCH Central Screening Rates
Overall match rate: 18% Patients with a tumor gene abnormality that matched to one of the 30 treatment arms (992/5560 with testing completed) Enrollment rate: 69% Patients with a treatment assignment who enrolled (689/992)
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NCI-MATCH Central Screening by Cancer Type
Less Common Disease Type % of Total Screened (N=5560) Ovarian 9.5 Uterine 6.2 Pancreas 6.1 Sarcoma 4.6 Head and Neck 3.9 Neuroendocrine 3.3 Gastroesophageal 3.2 Cholangiocarcinoma 2.8 Liver and Hepatobiliary other than Cholangio. 1.9 Central Nervous System 1.7 Bladder/Urinary Tract 1.6 Cervical Small Cell Lung 1.4 Melanoma Kidney 1.2 Anal 0.8 Mesothelioma Lymphoma 0.7 Myeloma Other 9.7 Less Common Cancers 62.5% Common Disease Type % of Total Screened (N=5560) Colorectal 15.3 Breast 12.4 Non-Small Cell Lung 7.3 Prostate 2.5 Common Cancers 37.5% Goal: 25% Far exceeded
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NCI-MATCH Wait Times for Patients Tested Centrally
Processing Step Median Calendar Days Tumor sample submission from sites to EA central lab at MD Anderson Cancer Center 7 Completion of tumor testing by lab network and return of results to site 16 Further eligibility evaluation for patients assigned to a treatment arm 14
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NCI-MATCH Important Discovery
In the 6000 patients tested, the tumor gene variants we are studying occurred less frequently than expected in this study population, ranging from 3.47 percent to zero
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NCI-MATCH Central Screening Conclusions
Registration for screening was rapid Assay turnaround time met (except for a few) 60% of screened patients with less common cancers far exceeded goal ~50% of screened patients came from community-based sites At least one patient screened in every state, the District of Columbia and Puerto Rico Toxicity of biopsy was acceptable Overall, trial is feasible across the NCI-sponsored networks Publication of full results forthcoming
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Changes to NCI-MATCH How did reaching the 6000-patient central screening goal change the study? The trial laboratories stopped collecting and testing specimens centrally Patients no longer have biopsies specifically for this trial NCI ended reimbursement for these procedures
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Changes to NCI-MATCH (cont’d)
How did the discovery that gene abnormalities are rarer than expected change the study? It shed light on the fact that in order to fill the ‘rare variant’ arms, we need to look at tens of thousands of patients It required setting a new goal for the trial New goal: broaden the base of screened patients to complete ongoing and upcoming treatment arms
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Extra Content: Rare Variant Demonstration Project
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NCI-MATCH Demonstration Project
Began in May 2017 to help trial ramp up to high volumes of patient referrals anticipated from designated labs Initially only report on 19 treatment arms – rare gene abnormalities that occurred in 1.5 percent or fewer patients tested centrally Manual processing of patient cases until MATCHbox IT system fully automated Staging of laboratory involvement Now, with ramp-up successfully concluding in mid 2018: Anticipate more labs will start referring patients All open treatment arms will be available to patients
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19 Treatment Arms in NCI-MATCH Rare Variant Demonstration Project, By Gene Abnormality Prevalence Rate % Arm Variant Prevalence Rate % Variant Prevalence Rate % Z1C CDK4 or CDK L mTOR M TSC1 or TSC S2 GNAQ/GNA Z1B CCND1/2/ E EGFR T790M R BRAF fusions V cKIT Y AKT Z1E NTRK H BRAF V600 E/K G ROS U NF2 loss A EGFR activating C2 MET exon 14 sk F ALK C1 MET amplif X DDR T SMO/PTCH Still enrolling patients Closed to enrollment
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