Nivolumab (3 mg/kg) plus low-dose ipilimumab (1 mg/kg) (injections for IV use) received approval from the FDA for the treatment of adult and pediatric patients 12 years and older with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Approval for this indication has been granted under Accelerated Approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
This approved indication was based on data from the ongoing phase II CheckMat-142 study evaluating the nivolumab plus ipilimumab combination in patients with MSI-H or dMMR mCRC previously treated with a fluoropyrimidine-, oxaliplatin- or irinotecan-based chemotherapy. The application was granted Priority Review and Breakthrough Therapy Designation by the FDA.
The nivolumab + ipilimumab cohort of the CheckMate-142 trial enrolled MSI-H/dMMR mCRC patients who had received at least one prior line of therapy for metastatic disease, and efficacy was analyzed for both patients who had received prior treatment with a fluoropyrimidine, oxaliplatin and irinotecan (82 of the total 119 patients) as well as for all enrolled patients.
Among the 82 patients who received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, 46 percent (95% CI: 35-58; n=38/82) responded to treatment with nivolumab + ipilimumab as assessed by Independent Radiographic Review Committee (IRRC). The percentage of these patients with a complete response was 3.7 percent (n = 3/82), and the percentage of patients with a partial response was 43 percent (n = 35/82). Among these 38 responders, the median DOR was not reached (range: 1.9-23.2+ months); 89 percent of those patients had responses of 6 months or longer, and 21 percent had responses of 12 months or longer. This trial is ongoing.
Among all enrolled patients, 49 percent (95% CI: 39-58; n = 58/119) responded to treatment with nivolumab + ipilimumab; 4.2 percent (n = 5/119) experienced a complete response, while 45 percent (n = 53/119) experienced a partial response. Among these 58 responders, the median DOR was not reached (range: 1.9-23.2+ months); 83 percent of those patients had responses of 6 months or longer, and 19 percent had responses of 12 months or longer. In the combination cohort, 51 of 58 responders were ongoing at the time of database lock; 78 percent of these ongoing responders had not reached 12 months of follow-up from the date of onset of response.
The recommended dosing schedule includes the nivolumab + low-dose ipilimumab combination nivolumab (3 mg/kg), administered as an IV infusion over 30 minutes, followed by ipilimumab (1 mg/kg), administered as an IV infusion over 30 minutes, on the same day, every 3 weeks for four doses), followed by nivolumab maintenance therapy (240 mg, administered as an IV infusion over 30 minutes, every 2 weeks) after completion of four doses of the combination until disease progression or unacceptable toxicity.
In the nivolumab + ipilimumab cohort of CheckMate-142, 86 percent of patients received all four doses of nivolumab + ipilimumab. Nivolumab was discontinued in 13 percent of patients and delayed in 45 percent of patients due to an adverse reaction. Serious adverse reactions occurred in 47 percent of patients.
"Metastatic colorectal cancers with dMMR or MSI-H biomarkers can be difficult to treat and some patients may need additional options," said Heinz-Josef Lenz, MD, FACP, L. Terrence Lanni Chair in Gastrointestinal Cancer Research, Keck School of Medicine of University of Southern California and principal investigator of the study at USC Norris Comprehensive Cancer Center. "The FDA's approval of an I-O/I-O combination provides us with an encouraging approach to address this challenging disease in patients who have progressed following treatment with three standard chemotherapy options."