Arm Z1D of NCI-MATCH Shows Promise for Nivolumab Beyond Colorectal Cancer

Final results from Arm Z1D, a subprotocol of the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH or EAY131) trial, showed promise for the use of nivolumab (Opdivo) beyond just colorectal cancer in treating DNA mismatch repair (MMR)-deficient tumors that had complete loss of the tumor suppressor proteins MLH1 or MSH2. 

“In Arm Z1D, we confirmed that testing for complete loss of either the MLH1 or MSH2 tumor suppressing proteins is a useful biomarker for selecting single-agent nivolumab immunotherapy beyond colon cancer,” Nilofer S. Azad, MD, the lead researcher and medical oncologist from Johns Hopkins Medicine in Baltimore, said in a press release.

In this cohort of 42 patients across 18 different types of cancer, the confirmed overall response rate for nivolumab in tumors with DNA mismatch repair deficiencies was 36%, with an additional 21% who had stable disease. Under predefined criteria, an overall response rate in a given arm larger than 16% signals that the therapy warrants further study. 

Median overall survival for the immune checkpoint inhibitor was 17.3 months. The estimated 6-month, 12-month, and 18-month progression-free survival rates were 51.3%, 46.2% and 31.4%, respectively.

“The silencing of the proteins MLH1 or MSH2 is the most common cause of DNA repair defects due to mismatch repair deficiency, and, a little less commonly, MSH6 or PMS2. This can happen through DNA mutation, as well as promoter methylation,” Azad explained.

Cancer types studied included endometrioid endometrial adenocarcinoma, prostate adenocarcinoma, uterine carcinosarcoma, adenocarcinoma of esophagus/esophagogastric junction, cholangiocarcinoma, ductal carcinoma of breast, and pancreatic neuroendocrine carcinoma. The cancers were mostly rare, and none were colorectal given that nivolumab had already previously shown activity in MMR-deficient colon cancer.

“Overall, the NCI-MATCH trial is providing insight into tumor types that might benefit from targeted therapies,” Lyndsay Harris, MD, Associate Director for the Cancer Diagnosis Program at NCI and co-principal investigator of the NCI-MATCH trial, said in a press release. “The results of NCI-MATCH subprotocols, if confirmed, will help inform physicians’ decisions of whether to provide these treatments to most or all tumor types, using genomic testing.” 

The primary objective of each arm of NCI-MATCH is to determine the proportion of patients who have an objective response. Each treatment arm is intended to provide information on responsive vs unresponsive tumor types, especially in rare cancers where there is currently little or no data available. More than 1,100 trial sites are participating in the study.

The FDA has already granted accelerated approval for nivolumab alone or in combination with ipilimumab (Yervoy) for the treatment of microsatellite instability-high or MMR-deficient metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan (Onivyde and Camptosar). Continued approval may be dependent upon verification and description of clinical benefit in confirmatory trials. 

Pembrolizumab, another drug for pretreated MMR-deficient cancer, is approved for use by the FDA regardless of cancer type.

Reference:

NCI-MATCH: promising signal for nivolumab beyond colorectal cancer [news release]. Philadelphia, Pennsylvania. Published December 19, 2019. ecog-acrin.org/news-and-info/press-releases/nci-match-z1d-promising-signal-for-nivolumab-beyond-colorectal-cancer-dmmr-dna-mis-match-repair-deficiencies. Accessed December 20, 2019.