FDA Grants Accelerated Approval to Nivolumab, Ipilimumab Combination

The Food and Drug Administration (FDA) granted accelerated approval to the combination of nivolumab and ipilimumab (OPDIVO and YERVOY, Bristol-Myers Squibb Co.) for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Efficacy of the combination was investigated in Cohort 4 of CHECKMATE-040, (NCT01658878) a multicenter, multiple cohort, open-label trial conducted in patients with HCC who progressed on or were intolerant to sorafenib. A total of 49 patients received nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg every 3 weeks for four doses, followed by single-agent nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity.

The main efficacy outcome measures were overall response rate and duration of response as determined by blinded independent central review (BICR) using RECIST v1.1. ORR was 33% (n=16; 95% CI: 20, 48), with 4 complete responses and 12 partial responses. Response duration ranged from 4.6 to 30.5+ months, with 31% of responses lasting at least 24 months.

The most common adverse reactions (³20%) with nivolumab in combination with ipilimumab are: fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, decreased weight, and dizziness.

For HCC, the recommended doses are nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

FDA had previously granted Breakthrough Therapy Designation for this indication and the application received priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

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