Nivolumab Is Effective in Mismatch Repair-Deficient Noncolorectal Cancers: Results From Arm Z1D-A Subprotocol of the NCI-MATCH (EAY131) Study

Nilofer S. Azad, Robert J. Gray, Michael J. Overman, Jonathan D. Schoenfeld, Edith P. Mitchell, James A. Zwiebel, Elad Sharon, Howard Streicher, Shuli Li, Lisa M. McShane, Larry Rubinstein, David R. Patton, P. Mickey Williams, Brent Coffey, Stanley R. Hamilton, Nathan Bahary, J. Marie Suga, Hassan Hatoum, Jeffrey S. Abrams, Barbara A. ConleyCarlos L. Arteaga, Lyndsay Harris, Peter J. O'Dwyer, Alice P. Chen, Keith T. Flaherty

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

PURPOSE: The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, the largest national precision oncology study to date (> 1,100 sites) of patients with relapsed or refractory malignancies, assigned patients to targeted therapy in parallel phase II studies based on tumor molecular alterations. The anti-programmed death receptor 1 inhibitor nivolumab previously showed activity in mismatch repair (MMR)-deficient colon cancer. We hypothesized that nivolumab would have activity in patients with MMR-deficient, noncolorectal tumors. PATIENTS AND METHODS: Eligible patients with relapsed or refractory tumors, good end-organ function, and Eastern Cooperative Oncology Group performance status of ≤ 1 underwent tumor biopsy for centralized screening of molecular alterations. MMR deficiency was defined by complete loss of nuclear expression of MLH1 or MSH2 MMR gene products by immunohistochemistry (IHC). Patients with MMR-deficient colorectal cancer were excluded. Nivolumab, 3 mg/kg every 2 weeks (28-day cycles) and 480 mg every 4 weeks after cycle 4, was administered intravenously. Disease reassessment was performed every 2 cycles. The primary end point was RECIST 1.1 objective response rate (ORR). RESULTS: Two percent of 4,902 screened patients had an MMR-deficient cancer by IHC. Forty-two evaluable patients were enrolled, with a median age of 60 years and a median of 3 prior therapies. The most common histologies were endometrioid endometrial adenocarcinoma (n = 13), prostate adenocarcinoma (n = 5), and uterine carcinosarcoma (n = 4). ORR was 36% (15 of 42 patients). An additional 21% of patients had stable disease. The estimated 6-, 12-, and 18-month progression-free survival rates were 51.3% (90% CI, 38.2% to 64.5%), 46.2% (90% CI, 33.1% to 59.3%), and 31.4% (90% CI, 18.7% to 44.2%), respectively. Median overall survival was 17.3 months. Toxicity was predominantly low grade. CONCLUSION: A variety of refractory cancers (2.0% of those screened) had MMR deficiency as defined in NCI-MATCH. Nivolumab has promising activity in MMR-deficient noncolorectal cancers of a wide variety of histopathologic types.

Original languageEnglish (US)
Pages (from-to)214-222
Number of pages9
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume38
Issue number3
DOIs
StatePublished - Jan 20 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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