The Molecular Analysis for Therapy Choice (NCI-MATCH) Trial: Lessons for Genomic Trial Design

Keith T Flaherty, Robert Gray, Alice Chen, Shuli Li, David Patton, Stanley R Hamilton, Paul M Williams, Edith P Mitchell, A John Iafrate, Jeffrey Sklar, Lyndsay N Harris, Lisa M McShane, Larry V Rubinstein, David J Sims, Mark Routbort, Brent Coffey, Tony Fu, James A Zwiebel, Richard F Little, Donna Marinucci, Robert Catalano, Rick Magnan, Warren Kibbe, Carol Weil, James V Tricoli, Brian Alexander, Shaji Kumar, Gary K Schwartz, Funda Meric-Bernstam, Chih-Jian Lih, Worta McCaskill-Stevens, Paolo Caimi, Naoko Takebe, Vivekananda Datta, Carlos L Arteaga, Jeffrey S Abrams, Robert Comis, Peter J O'Dwyer, Barbara A Conley, NCI-MATCH Team, Keith T Flaherty, Robert Gray, Alice Chen, Shuli Li, David Patton, Stanley R Hamilton, Paul M Williams, Edith P Mitchell, A John Iafrate, Jeffrey Sklar, Lyndsay N Harris, Lisa M McShane, Larry V Rubinstein, David J Sims, Mark Routbort, Brent Coffey, Tony Fu, James A Zwiebel, Richard F Little, Donna Marinucci, Robert Catalano, Rick Magnan, Warren Kibbe, Carol Weil, James V Tricoli, Brian Alexander, Shaji Kumar, Gary K Schwartz, Funda Meric-Bernstam, Chih-Jian Lih, Worta McCaskill-Stevens, Paolo Caimi, Naoko Takebe, Vivekananda Datta, Carlos L Arteaga, Jeffrey S Abrams, Robert Comis, Peter J O'Dwyer, Barbara A Conley, NCI-MATCH Team

Abstract

Background: The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology.

Methods: Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA-targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial.

Results: At interim analysis, accrual was robust, tumor biopsies were safe (<1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround).

Conclusions: The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.

© The Author(s) 2019. Published by Oxford University Press.

Figures

Figure 1.
Figure 1.
National Cancer Institute (NCI)-MATCH design and patient entry procedures. A) NCI -MATCH design (a type of platform trial with features of both umbrella and basket design). B) NCI -MATCH procedures for trial entry. IHC = immunohistochemistry; PD = progressive disease.
Figure 2.
Figure 2.
Subprotocol activation timeline for National Cancer Institute (NCI)-MATCH. EGFR = epidermal growth factor receptor; HER2 = human epidermal growth factor receptor 2; ALK = anaplastic lymphoma kinase; ROS = proto-oncogene tyrosine-protein kinase ROS; BRAF = B-Raf proto-oncogene, serine/threonine kinase; NF2 = neurofibromatosis type 2; KIT = KIT proto-oncogene, receptor tyrosine kinase; PIK3CA = phosphatidylinositol 3-kinase catalytic subunit; PTEN = Phosphatase and tensin homolog; NF1 = neurofibromatosis type 1; GNAQ = G protein subunit alpha q; GNA11 = Guanine nucleotide-binding protein subunit alpha-11; PTCH1 = Patched1; SMO = Smoothened; DDR2 = DNA damage response 2; NRAS = Rat sarcoma virus GTPase, neuroblastoma; CCN = cyclin; MLH1 = mutL homolog 1; MSH2 = mutS homolog 2; MET = Mesenchymal Epithelial Transition, receptor tyrosine kinase; FGFR = Fibroblast Growth Factor Receptor; AKT = V-Akt Murine Thymoma Viral Oncogene Homolog.

References

    1. Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH.. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. 2010;28(1):92–98.
    1. Cortesi L, De Matteis E, Cirilli C, Marcheselli L, Proietto M, Federico M.. Outcome evaluation in pre-trastuzumab era between different breast cancer phenotypes: a population-based study on Italian women. Tumori. 2012;98(6):743–750.
    1. Slamon DJ, Leyland-Jones B, Shak S, et al.. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–792.
    1. Pao W, Miller V, Zakowski M, et al.. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101(36):13306–13311.
    1. Paez JG, Janne PA, Lee JC, et al.. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–1500.
    1. Kwak EL, Bang YJ, Camidge R, et al.. Anaplatic lymphoma kinase inhibition in non-small cell lung cancer. N Engl J Med. 2010;363(18):1693–1703.
    1. Wu Y-L, Yang JC-H, Kim D-W, et al.. Phase II study of crizotinib in East Asian patients with ROS1 positive advanced non-small cell lung cancer. J Clin Oncol. 2018;36(14):1405–1411.
    1. Druker BJ.Imatinib as a paradigm of targeted therapies. Adv Cancer Res. 2004;91:1–30.
    1. Tefferi A, Pardanani A.. Imatinib therapy in clonal eosinophilic disorders, including systemic mastocytosis. Int J Hematol. 2004;79(5):441–447.
    1. Duffaud F, Le Cesne A.. Imatinib in the treatment of solid tumours. Targ Oncol. 2009;4(1):45–56.
    1. Le DT, Durham JN, Smith KN, et al.. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–413.
    1. US Food and Drug Administration. FDA approves larotrectinib for solid tumors with NTRK gene fusions. . Published December 14, 2018. Accessed January 14, 2019.
    1. Hyman DM, Puzanov I, Subbiah V, et al.. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373(8):726–736.
    1. Prahallad A, Sun C, Huang S, et al.. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483(7387):100–103.
    1. Lih CJ, Harrington RD, Sims DJ, et al.. Analytical validation of the next-generation sequencing assay for a nationwide signal-finding clinical trial: molecular analysis for therapy choice clinical trial. J Mol Diagn. 2017;19(2):313–327.
    1. Khoury JD, Wang W-L, Prieto VG, et al.. Validation of immunohistochemical assays for integral biomarkers in the NCI-MATCH EAY131 clinical trial. Clin Cancer Res. 2018;24(3):521–531.
    1. Eisenhauer EA, Therasse P, Bogaerts J, et al.. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–247.
    1. Cheson BD, Fisher RI, Barrington SF, et al.. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–3068.
    1. Wen PY, Macdonald DR, Reardon DA, et al.. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28(11):1963–1972.
    1. Kumar S, Paiva B, Anderson KC, et al.. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328–e346.
    1. Le Tourneau C, Delord JP, Goncalves A, et al.. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 2015;16(13):1324–1334.
    1. Stockley TL, Oza AM, Berman HK, et al.. Molecular profiling of advanced solid tumors and patient outcomes with genotype-matched clinical trials: the Princess Margaret IMPACT/COMPACT trial. Genome Med. 2016;8(1):109.
    1. TsimberIdou A-M, Hong DS, Ye Y, et al.. Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): an MD Anderson Precision Medicine Study. J Clin Oncol Precis Oncol. 2017;(1):1–18.
    1. Zehir A, Benayed R, Shah RK, et al.. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703–713.

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