FDA Expands Frontline Melanoma Indications for Nivolumab to Include BRAF V600 Mutations

FDA Expands Frontline Melanoma Indications for Nivolumab

Jedd D. Wolchok, MD, PhD

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

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

In the three-arm phase III CheckMate-067 study, the nivolumab plus ipilimumab combination reduced the risk of progression by 58% compared to 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.

&ldquo;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,&rdquo; 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. &ldquo;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.&rdquo;

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&ndash;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.

&ldquo;We are incredibly proud of today&rsquo;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,&rdquo; said Chris Boerner, head of US Commercial at Bristol-Myers Squibb, the manufacturer of nivolumab and ipilimumab.

References

1. 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.