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

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.

Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study

“…Nivolumab and Pembrolizumab, two anti PD1 immune checkpoint inhibitors, demonstrated therapeutic efficacy in solid tumors with MMRd [ 2 , 9 , 10 , 11 , 12 ]. Based on these results, the US Food and Drug Administration (FDA) approved pembrolizumab for the treatment of MMR-deficient solid tumors.…”

PD-L1 Expression Is Associated with Deficient Mismatch Repair and Poor Prognosis in Middle Eastern Colorectal Cancers

“…Recent evidence suggests that MMR deficient tumors could provide a robust marker for anti-PD-1/PD-L1 response [16,41,42]. A strong association between PD-L1 tumor expression and MMR deficiency has been documented in endometrial and colorectal carcinoma [43,44] and the efficacy of anti-PD-1/PD-L1 therapy has been shown to increase in MMR deficient tumors [16,45,46]. MMR deficiency allows for rapid accumulation of neoantigens [47], which could explain the positive relationship between PD-L1 expression and better immunotherapeutic response in dMMR tumors.…”

ARID1A genomic alterations driving microsatellite instability through somatic MLH1 methylation with response to immunotherapy in metastatic lung adenocarcinoma: a case report

“…In deficient MMR cancers across 12 different histologies, overall response rate (ORR) of 53% (48/86) (95% CI 42–64) and complete response (CR) in 21% of patients, with a 2-year overall survival (OS) rate of 64%, were observed with anti-PD-1 antibody pembrolizumab [ 5 ]. Anti-PD-1 inhibitor nivolumab has shown an ORR of 36% (7% CR) in 42 patients with pretreated deficient MMR tumors [ 6 ]. However, no patients with non-small cell lung cancer (NSCLC) were included in these studies.…”