Accelerated Approval for Nivolumab for DNA Repair—Deficient Advanced CRC

The approval follows a review of phase 2 results from CheckMate-142.

Pediatric and adult patients with microsatellite instability—high (MSI-H) or mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine and oxaliplatin or irinotecan, have an additional treatment option: the programmed death-1 inhibitor, nivolumab (Opdivo). The FDA requires the drug’s manufacturer, Bristol-Myers Squibb, to conduct confirmatory trials to ensure clinical benefit for continued approval of this indication.

The clinical data submitted for review included phase 2 results from CheckMate-142, a multicenter (31 sites across 8 nations), single-arm study that evaluated nivolumab in 74 patients with dMMR or MSI-H mCRC who had progressed on or after fluoropyrimidine-oxaliplatin or irinotecan-based chemotherapy. The study also included patients who were intolerant to any of these treatments. Seventy-four patients were administered 3 mg/kg nivolumab every 2 weeks, a much higher dose than the recommended 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks.

The study noted an objective response rate of 28% with nivolumab (95% CI, 17-42) in patients who had received prior treatment with a fluoropyrimidine, oxaliplatin, or irinotecan—this included a 1.9% complete response rate and a 26% partial response rate. In the entire patient cohort, 32% responded to nivolumab (95% CI, 22-44), which included a 2.7% complete response rate and a 30% partial response rate. Median duration of response was not reached in the overall population or in the pretreated subgroup.

All responders were alive, and 8 had responses lasting 12 months or longer (event rate 86%, 95% CI, 62—95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (6 [8%]) and amylase (2 [3%]). Twenty-three patients (31%) died during the study, but none of these deaths were deemed to be treatment related by the investigator.

“Patients with metastatic colorectal cancer who have dMMR or MSI-H tumors are less likely to respond to conventional chemotherapy,” said Heinz-Josef Lenz, MD, FACP, University of Southern California. “While the challenges of treating these patients have been significant, tumors characterized by these biomarkers are immunogenic. Therefore, advances in immunotherapy research are encouraging in presenting new treatment options for appropriate patients with MSI-H metastatic colorectal cancer.”

MMR or MSI testing is a recommendation in the National Comprehensive Cancer Network Guidelines for patients with a personal history of colon or rectal cancer. Nivolumab has been included as a category 2A treatment option in patients with dMMR or MSI-H CRC as second-line or third-line treatment.