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Ref Type Journal Article
PMID (31765263)
Authors Azad NS, Gray RJ, Overman MJ, Schoenfeld JD, Mitchell EP, Zwiebel JA, Sharon E, Streicher H, Li S, McShane LM, Rubinstein L, Patton DR, Williams PM, Coffey B, Hamilton SR, Bahary N, Suga JM, Hatoum H, Abrams JS, Conley BA, Arteaga CL, Harris L, O'Dwyer PJ, Chen AP, Flaherty KT
Title Nivolumab Is Effective in Mismatch Repair-Deficient Noncolorectal Cancers: Results From Arm Z1D-A Subprotocol of the NCI-MATCH (EAY131) Study.
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Abstract Text 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.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).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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MLH1 negative Advanced Solid Tumor predicted - sensitive Nivolumab Phase II Actionable In a Phase II trial (NCI-MATCH), Opdivo (nivolumab) treatment demonstrated preliminary efficacy in advanced solid tumor patients (excluding colorectal cancer) with deficient mismatch repair (defined by the loss of MLH1 or MSH2 expression by IHC), resulting in an objective response rate of 36% (15/42, 3 complete and 12 partial responses), a median progression-free survival (PFS) of 6.3 mo, a 6-month PFS rate of 51.3%, and a median overall survival of 17.3 months (PMID: 31765263; NCT02465060). 31765263
MLH1 negative cholangiocarcinoma predicted - sensitive Nivolumab Case Reports/Case Series Actionable In a Phase II trial (NCI-MATCH), Opdivo (nivolumab) treatment demonstrated preliminary efficacy in advanced solid tumor patients (excluding colorectal cancer) with deficient mismatch repair (defined by the loss of MLH1 or MSH2 expression by IHC), resulting in an objective response rate of 36% (15/42, 3 complete and 12 partial responses), including 1 complete response and 1 stable disease in two patients with cholangiocarcinoma (PMID: 31765263; NCT02465060). 31765263
MLH1 negative endometrial adenocarcinoma predicted - sensitive Nivolumab Case Reports/Case Series Actionable In a Phase II trial (NCI-MATCH), Opdivo (nivolumab) treatment demonstrated preliminary efficacy in advanced solid tumor patients (excluding colorectal cancer) with deficient mismatch repair (defined by the loss of MLH1 or MSH2 expression by IHC), resulting in an objective response rate of 36% (15/42, 3 complete and 12 partial responses), including 2 complete responses and 2 partial responses in patients with endometrioid endometrial adenocarcinoma (n=13) (PMID: 31765263; NCT02465060). 31765263