U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab

Abstract

On December 22, 2014, the FDA granted accelerated approval to nivolumab (OPDIVO; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on a clinically meaningful, durable objective response rate (ORR) in a non-comparative analysis of 120 patients who received 3 mg/kg of nivolumab intravenously every 2 weeks with at least 6-month follow-up in an ongoing, randomized, open-label, active-controlled clinical trial. The ORR as assessed by a blinded independent review committee per RECIST v1.1 was 31.7% (95% confidence interval, 23.5-40.8). Ongoing responses were observed in 87% of responding patients, ranging from 2.6+ to 10+ months. In 13 patients, the response duration was 6 months or longer. The risks of nivolumab, including clinically significant immune-mediated adverse reactions (imARs), were assessed in 268 patients who received at least one dose of nivolumab. The FDA review considered whether the ORR and durations of responses were reasonably likely to predict clinical benefit, the adequacy of the safety database, and systematic approaches to the identification, description, and patient management for imARs in product labeling. .

Population Pharmacokinetics of Durvalumab in Cancer Patients and Association With Longitudinal Biomarkers of Disease Status

“…found in a complementary analysis that the maximum decrease in nivolumab clearance was statistically associated with baseline disease status and hinted that posttreatment disease status may also play a role in nivolumab exposure. None of the covariates were found clinically relevant and the same conclusion was reached in the analysis described in the approval summary . While this analysis focused on the 3 mg/kg q2w (every 2 weeks) dosing regimen, a subsequent study supported the use of 240 mg q2w …”

Challenges and Opportunities in Adapting Clinical Trial Design for Immunotherapies

“…One approach relies on single-arm or small non-comparative phase II trials (e.g. (12)); others transition seamlessly from phase I trial to multi-cohort expansion phase or basket trial in specific histologies. These studies seek accelerated approval by meeting the US Food and Drug Administration (FDA) criteria for unmet medical need based on a surrogate endpoint, such as objective response rate (ORR).…”

The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta‐analysis of efficacy and safety

“…Cancer immunotherapy has become a focus of investigation, including research into immune checkpoint inhibitors (ICIs). Programmed death (PD) 1 inhibitors such as nivolumab or the cytotoxic T‐lymphocyte‐associated antigen (CTLA) 4 inhibitors such as ipilimumab have been approved by the US Food and Drug Administration (FDA) . Several phase III randomized controlled trials (RCTs) have concluded that monotherapy with these agents can exert robust antitumor effects.…”