FDA Expands Nivolumab's Frontline Melanoma Approval to Include BRAF-Mutant Patients

Jedd D. Wolchok, MD, PhD

The FDA has expanded the frontline melanoma indications for nivolumab (Opdivo) as a single agent and in combination with ipilimumab (Yervoy) to include patients with BRAF V600 mutations, based on data from the phase III CheckMate-067 trial.

Nivolumab was previously approved in advanced melanoma as a monotherapy and in combination with ipilimumab for BRAF V600 wild-type patients, as well as for patients with unresectable or metastatic melanoma following treatment with ipilimumab or a BRAF inhibitor. The new indications for patients with BRAF mutations are both accelerated approvals that are contingent on results from confirmatory trials.

In the three-arm CheckMate-067 study, the combination of nivolumab and ipilimumab reduced the risk of progression by 58% compared with ipilimumab alone (HR, 0.42; P <.0001) in patients with advanced melanoma. Single-agent nivolumab reduced the risk of progression by 43% versus ipilimumab (HR, 0.57; P <.0001). Outcomes were similar regardless of BRAF mutation status.

“The combination of two Immuno-Oncology treatments, nivolumab and ipilimumab, has been shown to provide these patients with a much needed improvement in progression-free survival and response rates,” CheckMate-067 lead investigator Jedd D. Wolchok, MD, PhD, Chief, Melanoma and Immunotherapeutics Service, Department of Medicine and Ludwig Center at Memorial Sloan Kettering Cancer Center, said in a statement. “This expanded approval for the nivolumab and ipilimumab regimen provides more advanced melanoma patients with an Immuno-Oncology combination treatment, and the potential for improved outcomes.”

CheckMate-067 randomized 945 patients with untreated unresectable or metastatic melanoma to receive nivolumab (n = 316), ipilimumab (n = 315), or nivolumab plus ipilimumab followed by nivolumab (n = 314). In the monotherapy arms, nivolumab was administered at 3 mg/kg every 2 weeks and ipilimumab was administered at 3 mg/kg every 3 weeks. In the combination arm, nivolumab at 1 mg/kg was administered with 3 mg/kg of ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg of nivolumab every 2 weeks.

Patients were stratified by M-stage, PD-L1 status, and BRAF mutation status. Approximately one-third of patients were BRAF mutation positive. The coprimary endpoints were progression-free survival (PFS) and overall survival (OS), with objective response rate (ORR), safety, and other measures as secondary endpoints.

At greater than 9 months of follow-up, the median PFS was 11.5 months for the combination, 6.9 months for nivolumab monotherapy, and 2.9 months for single-agent ipilimumab.

In PD-L1—positive patients, the ligand was not found to be a biomarker for outcomes, with a PFS of 14 months in both nivolumab arms versus 3.9 months with ipilimumab. In PD-L1–negative patients, the combination was more effective compared with single-agent therapy, with a PFS of 11.2 months versus 5.3 and 2.8 months in the single-agent nivolumab and ipilimumab arms, respectively.

The ORR was 50.0% with the combination compared with 40.0% and 14% for single-agent nivolumab and ipilimumab, respectively. In the combination arm, the complete response rate was 8.9% versus 8.5% and 1.9% with single-agent nivolumab and ipilimumab.

The benefit with the nivolumab regiments was consistent, regardless of BRAF mutation status. For those with BRAF-mutant melanoma treated with the combination of nivolumab and ipilimumab (n = 102), the median PFS was 11.7 months, representing a 53% reduction in the risk of progression versus ipilimumab (HR, 0.47; 95% CI, 0.32-0.68). For patients with BRAF wild-type disease (n = 212), the median PFS with the combination was 11.2 months (HR versus ipilimumab, 0.41; 95% CI, 0.32-0.53).

For those with BRAF mutations treated with single-agent nivolumab (n = 98), the median PFS was 5.6 months compared with 4.0 months with single-agent ipilimumab (n = 100; HR, 0.77; 95% CI, 0.54-1.09). In those with wild-type BRAF melanoma treated with nivolumab (n = 218), the median PFS was 7.9 months versus 2.8 months with ipilimumab (HR, 0.50; 95% CI, 0.39-0.63).

The safety data were consistent with outcomes previously reported for the drugs. All grade adverse-events (AEs) were 95.5%, 82.1%, and 86.2%, in the combination, nivolumab, and ipilimumab arms, respectively. Rates of treatment-related discontinuations with the combination and single-agent nivolumab and ipilimumab arms were 36.4%, 7.7%, and 14.8%, respectively.

The most common any-grade AEs in the combination arm versus the nivolumab and ipilimumab arms were diarrhea (44.1%, 19.2%, 33.1%), rash (40.3%, 25.9%, 32.8%), fatigue (35.1%, 34.2%, 28.0%), pruritus (33.2%, 18.8%, 35.4%), and nausea (25.9%, 13.1%, 16.1%).

Grade 3/4 AEs were reported in 55%, 16.3%, and 27.3% of the combination, nivolumab, and ipilimumab groups, respectively. The most frequent grade 3/4 toxicities reported in the ipilimumab/nivolumab arm compared with nivolumab and ipilimumab were diarrhea (9.3%, 2.2%, 6.1%) colitis (7.7%, 0.6%, 8.7%), increased lipase (8.6%, 3.5%, 3.9%), increased ALT levels (8.3%, 1.3%, and 1.6%) and increased AST levels (6.1%, 1.0%, 1.6%).

Assessment of the CheckMate-067 study remains ongoing for the coprimary endpoint of OS, which is expected to reach maturity at an approximate median follow-up of 22 months.

“We are incredibly proud of today’s approval to expand the use of the Opdivo plus Yervoy Regimen to include patients with BRAF mutation-positive unresectable or metastatic melanoma. CheckMate-067 is the first phase III study to observe the efficacy and safety of both Opdivo as a single-agent as well as in combination with Yervoy versus Yervoy alone,” said Chris Boerner, head of US Commercial at Bristol-Myers Squibb, the manufacturer of nivolumab and ipilimumab.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.