On April 8, the U.S. Food and Drug Administration (FDA) approved the PD-1 inhibitor nivolumab (Opdivo) with the CTLA-4 inhibitor ipilimumab (Yervoy) for adult and pediatric patients aged 12 years and older with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) colorectal cancer (CRC). The FDA also converted the accelerated approval to regular approval for single-agent nivolumab for adult and pediatric patients aged 12 years and older with MSI-H or dMMR metastatic CRC that has progressed after treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
CheckMate 8HW
Efficacy of nivolumab with ipilimumab was evaluated in CheckMate 8HW (ClinicalTrials.gov identifier NCT04008030), a randomized, three-arm, open-label trial in immunotherapy-naive patients with unresectable or metastatic CRC with known MSI-H or dMMR status. Patients were randomly assigned to receive one of the following treatments:
- Nivolumab at 240 mg every 3 weeks and ipilimumab at 1 mg/kg every 3 weeks for a maximum of four doses, then nivolumab at 480 mg every 4 weeks
- Nivolumab at 240 mg every 2 weeks for six doses, then nivolumab 480 mg every 4 weeks
- Investigator’s choice chemotherapy.
The major efficacy outcome measure of the trial was progression-free survival assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1 in patients with centrally confirmed MSI-H/dMMR status in the following prespecified settings:
- First-line setting: nivolumab plus ipilimumab vs chemotherapy
- All lines: nivolumab plus ipilimumab vs nivolumab alone.
The analysis of nivolumab plus ipilimumab vs chemotherapy in the first-line setting was conducted in 255 patients with centrally confirmed MSI-H/dMMR status of 303 patients based on local testing. Median progression-free survival was not reached (95% confidence interval [CI] = 38.4 months to not estimable) in the nivolumab-plus-ipilimumab arm and 5.8 months (95% CI = 4.4–7.8 months) in the chemotherapy arm (hazard ratio [HR] = 0.21, 95% CI = 0.14–0.32, P < .0001). Comparative results of overall response rate and overall survival between arms were not available at the time of the interim progression-free survival analysis because of a statistical testing strategy.
The analysis of nivolumab plus ipilimumab vs nivolumab (all lines) was conducted in 582 patients with centrally confirmed MSI-H/dMMR status of 707 patients based on local testing. Median progression-free survival was not reached (95% CI = 53.8 months to not evaluable) in the nivolumab-plus-ipilimumab arm and 39.3 months (95% CI = 22.1 months to not evaluable) in the nivolumab arm (HR = 0.62, 95% CI = 0.48–0.81; P = .0003). Overall response rate was 71% (95% CI = 65%–76%) with nivolumab plus ipilimumab and 58% (95% CI = 52%–63%) with nivolumab alone (P = .0011). The comparative results of overall survival between arms were not available at the interim progression-free survival analysis because of a statistical testing strategy.
The most common adverse reactions reported in at least 20% of patients treated with nivolumab with ipilimumab were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. The most common adverse reactions reported in at least 20% of patients treated with nivolumab as a single agent were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain.
Expedited Programs
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence, which provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Brazilian Health Regulatory Agency, the Israel Ministry of Health, and Health Canada; the application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 10 weeks ahead of the FDA goal date.
This application was granted Priority Review, Breakthrough Therapy designation, and Orphan Drug designation.
