FDA Grants Nivolumab/Ipilimumab Priority Review for MSI-H/dMMR Colorectal Cancer

The FDA has granted a priority review to a supplemental biologics license application (sBLA) for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of adult patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

The sBLA is based on results from a cohort of 119 patients treated with the combination in the phase II CheckMate-142 study. At a median follow-up of 13.4 months, the investigator-assessed overall response rate (ORR) in the cohort was 55% (95% CI, 45.2-63.8), with 31% of patients having stable disease. The disease control rate (DCR) for ≥12 weeks was 80%. Three-fourths (78%) of 115 evaluable patients had a reduction in tumor burden from baseline.

By comparison, patients treated with nivolumab in the monotherapy cohort of CheckMate-142 had a 31% ORR and a 69% DCR at 13 months’ follow-up.

“The FDA acceptance of this application with priority review reinforces our belief in the potential of the Opdivo plus Yervoy combination to treat patients with previously treated metastatic colorectal cancer defined by MSI-H or dMMR biomarkers, and is a result of our longstanding commitment to the exploration of I-O/I-O combinations for patient populations with high unmet need,” Ian M. Waxman, MD, development lead, Gastrointestinal Cancers, BMS, said in a statement. “We look forward to working with the FDA with the goal of bringing this combination to these colorectal cancer patients.”

The 119 patients in the combination cohort were treated with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab at 3 mg/kg every 2 weeks. The median patient age was 58 (range, 21-88), 59% of patients were male, and 92% were white. Forty-five percent of patients had an ECOG performance status of 0, with the remaining 55% having a status of 1.

At diagnosis, the disease stages were II (12%), III (44%), and IV (45%). Fifty-five percent had a tumor in the right colon and 25% had a tumor in the left and sigmoid colon. Mutational status included BRAF/KRAS wild-type (26%), BRAF-positive (24%), KRAS-positive (37%), and unknown (13%).

Of the 119 treated patients, 76% had ≥2 prior lines of therapy. The most common prior chemotherapies were fluoropyrimidine (99%), oxaliplatin (93%), and irinotecan (73%). Sixty-three percent continue on treatment; disease progression (19%) was the main reason for discontinuation, followed by toxicity related to a study drug (13%). At baseline, 22% of patients had a PD-L1 expression level ≥1%, 55% had a level <1%, and the level was unknown for 24%. Twenty-nine percent of patients had a known clinical history of Lynch syndrome.

The 55% ORR rate included 4 (3%) complete responses and 61 (51%) partial responses. Thirty-seven patients had stable disease and 14 had progressive disease. The best overall response had not yet been determined at the cutoff for 3 patients. The median time to response in those treated with combination therapy was 2.8 months and the responses were durable; the median duration of response was not reached and 94% of responders had ongoing responses at data cutoff.

Responses were observed irrespective of PD-L1 expression or BRAF/KRAS mutation status. Among patients with PD-L1 levels ≥1, the ORR was 54%, compared to 52% in patients with levels <1. For BRAF-positive, KRAS-positive, and BRAF/KRAS-wild type patients, the ORRs were 55%, 57%, and 55%, respectively. Patients with a clinical history of Lynch syndrome had an ORR of 71%, compared to 48% among patients with no such history.

The 9- and 12-month rates of progression-free survival with combination immune checkpoint inhibitor therapy were 76% and 71%, respectively. In the nivolumab monotherapy cohort, these rates were 54% and 50%. Overall survival at 9 and 12 months was 87% and 85%, respectively, in patients treated with the combination, which was also superior relative to nivolumab monotherapy (78% and 73%, respectively).

Forty-one percent of patients experienced a treatment-related adverse event (TRAE). The most common grade 1/2 TRAEs were diarrhea (20%), fatigue (16%), pruritus (15%), pyrexia (15%), hypothyroidism (13%), nausea (12%), rash (9%), hyperthyroidism (11%), increased AST (7%), and increased ALT (5%).

Grade 3/4 TRAEs occurred in 32% of patients. Grade 3 TRAEs specifically included increased AST (8%), increased ALT (7%), diarrhea (2%), fatigue (2%), pruritus (2%), rash (2%), hypothyroidism (1%), and nausea (1%).

Patients (13%) who discontinued treatment because of TRAEs had an ORR (63%) consistent with that of the overall population.

Quality of life (QOL) was assessed by the EORTC QLQ-C30 global health status/QoL and the EQ-5D visual analog scale. Statistically significant and clinically meaningful improvements were achieved in key QOL measures, and improvements were maintained for extended periods. No new safety signals or treatment-related deaths were observed.

In August 2017, the FDA granted an accelerated approval to single-agent nivolumab for the treatment of adult and pediatric patients with MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773-779. doi: 10.1200/JCO.2017.76.9901.

The combination, both drugs of which are manufactured by Bristol-Myers Squibb (BMS), previously received a breakthrough designation in this setting. Under the Prescription Drug User Fee Act, the FDA is scheduled to make its final decision by July 10, 2018.