FDA Approves Nivolumab/Ipilimumab for MSI-H/dMMR Colorectal Cancer

The FDA granted an accelerated approval to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) 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) following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

The approval is based on results from a cohort of 119 patients with MSI-H or dMMR mCRC treated with the combination in the phase II CheckMate-142 study. In this cohort, 82 patients received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, and the overall response rate (ORR) was 46% (95% CI, 35-58) among these patients.¹ Among the 38 responders, there were 3 complete responses (CRs) and 35 partial responses (PRs). The median duration of response (DOR) was not reached (range, 1.9-23.2+ months). Eighty-nine percent of the responders had a response of ≥6 months, with 21% having a response ≥12 months.

Among all 119 patients, the ORR was 49% (95% CI, 39-58). Among the 58 responders, there were 5 CRs and 53 PRs. The median DOR was not reached (range, 1.9-23.2+ months), with 83% of responders having a response ≥6 months and 19% having a response ≥12 months. Fifty-one of the 58 responses were ongoing at the data cutoff.

“Metastatic colorectal cancers with dMMR or MSI-H biomarkers can be difficult to treat and some patients may need additional options,” Heinz-Josef Lenz, MD, 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, said in a statement.

“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,” added Lenz.

Data from the trial were published in the Journal of Clinical Oncology in March 2018.² 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.

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%).

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.

The accelerated approval of nivolumab/ipilimumab in this setting is contingent upon results from a confirmatory trial.

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.

References

1. Bristol-Myers Squibb’s Opdivo ® (nivolumab) + Low-Dose Yervoy ® (ipilimumab) is the First Immuno-Oncology Combination Approved for MSI-H/dMMR mCRC Patients Who Progressed Following Treatment with a Fluoropyrimidine, Oxaliplatin and Irinotecan. Published July 11, 2018. Access July 11, 2018. https://bit.ly/2uaofBD.
2. 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.