FDA Approves Nivolumab Plus Ipilimumab for Unresectable/Metastatic MSI-H/dMMR CRC

Median PFS was not reached for either combination therapy arm.

The FDA has approved the use of nivolumab (Opdivo) with ipilimumab (Yervoy) in adult and pediatric patients age 12 or older with unresectable/metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC), per an announcement from the agency.

With this announcement, the FDA has also stated that the accelerated approval of nivolumab monotherapy for adult and pediatric patients of at least 12 years of age with MSI-H or dMMR metastatic CRC who have progressed after fluoropyrimidine, oxaliplatin, and irinotecan, has been converted to regular approval.

The efficacy and safety of nivolumab/ipilimumab and single-agent nivolumab for the approved indication was investigated in the randomized, three-arm, open label CHECKMATE-8HW trial (NCT04008030).

Efficacy Data

In this trial, patients were randomized to receive either 240 mg of nivolumab every 3 weeks and 1 mg/kg of ipilimumab every 3 weeks for a maximum of 4 doses followed by 480 mg of nivolumab every 4 weeks, 240 mg of nivolumab every 2 weeks for 6 doses followed by 480 mg of nivolumab every 4 weeks, or investigator’s choice of chemotherapy.

The primary end point was progression-free survival (PFS), assessed by blinded independent central review (BICR) using RECIST v1.1. in patients with centrally confirmed MSI-H or dMMR status.

Nivolumab/ipilimumab vs chemotherapy was evaluated in the frontline setting (n = 255), and the combination therapy was compared to nivolumab monotherapy in all lines (n = 582).

In the first-line, median PFS was not reached (NR) (95% CI, 38.4-not estimable [NE]) for patients in the nivolumab/ipilimumab arm and 5.8 months (95% CI, 4.4-7.8) for those in the chemotherapy arm (hazard ratio [HR], 0.21; 95% CI, 0.14-0.32; P < .0001). Data on objective response rates (ORR) and overall survival (OS) were not available at the time of interim PFS analysis.

Comparison of nivolumab/ipilimumab with nivolumab in all lines of therapy yielded a median PFS of NR (95% CI, 53.8-NE) and 39.3 months (95% CI, 22.1-NE) in the combination and monotherapy arms, respectively (HR, 0.62; 95% CI, 0.48-0.81; P = .0003).

ORR was 71% (95% CI, 65-76) in those on combination therapy and 58% (95% CI, 52-63) in those on monotherapy (P = .0011). OS results for this data set were also immature at the interim analysis of PFS.

Safey Indications

The most commonly reported adverse events (AEs), which were reported in at least 20% of those treated with nivolumab/ipilimumab, were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea.

Likewise, the most common AEs for those on nivolumab monotherapy, were fatigue, diarrhea, abdominal pain, pruritic, and musculoskeletal pain.

Reference

1. FDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancer. FDA. April 8, 2025. Accessed April 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancer