The approval was based on data from the phase 3 CheckMate-067 trial.
The FDA has expanded the frontline melanoma indications for Opdivo (nivolumab) as a single agent and in combination with Yervoy (ipilimumab) to include patients with BRAF V600 mutations. The approval was based on data from the phase 3 CheckMate-067 trial.
Opdivo was previously approved in advanced melanoma as a monotherapy and in combination with Yervoy for BRAF V600 wild-type patients, as well as for patients with unresectable or metastatic melanoma following treatment with Yervoy 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 Opdivo and Yervoy reduced the risk of progression by 58 percent compared with Yervoy alone in patients with advanced melanoma. Single-agent Opdivo reduced the risk of progression by 43 percent versus Yervoy. Outcomes were similar regardless of BRAF mutation status.
“The combination of two immuno-oncology treatments, [Opdivo] and [Yervoy], 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, 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 [Opdivo] and [Yervoy] 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 Opdivo (316 patients), Yervoy (315 patients), or Opdivo plus Yervoy followed by Opdivo (314 patients). In the monotherapy arms, Opdivo was administered at 3 mg/kg every two weeks and Yervoy was administered at 3 mg/kg every three weeks. In the combination arm, Opdivo at 1 mg/kg was administered with 3 mg/kg of Yervoy every three weeks for four doses followed by 3 mg/kg of Opdivo every two 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 nine months of follow-up, the median PFS was 11.5 months for the combination, 6.9 months for Opdivo monotherapy, and 2.9 months for single-agent Yervoy.
In PD-L1—positive patients, the ligand was not found to be a biomarker for outcomes, with a PFS of 14 months in both Opdivo arms versus 3.9 months with Yervoy. 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 Opdivo and Yervoy arms, respectively.
The ORR was 50.0 percent with the combination compared with 40.0 percent and 14 percent for single-agent Opdivo and Yervoy, respectively. In the combination arm, the complete response rate was 8.9 percent versus 8.5 percent and 1.9 percent with single-agent Opdivo and Yervoy.
The benefit with the Opdivo regiments was consistent, regardless of BRAF mutation status. For those with BRAF-mutant melanoma treated with the combination of Opdivo and Yervoy (102 patients), the median PFS was 11.7 months, representing a 53 percent reduction in the risk of progression versus Yervoy. For patients with BRAF wild-type disease (212 patients), the median PFS with the combination was 11.2 months.
For those with BRAF mutations treated with single-agent Opdivo (98 patients), the median PFS was 5.6 months compared with 4.0 months with single-agent Yervoy (100 patients). In those with wild-type BRAF melanoma treated with Opdivo (218 patients), the median PFS was 7.9 months versus 2.8 months with Yervoy.
The safety data were consistent with outcomes previously reported for the drugs. All grade adverse-events (AEs) were 95.5 percent, 82.1 percent, and 86.2 percent, in the combination, Opdivo, and Yervoy arms, respectively. Rates of treatment-related discontinuations with the combination and single-agent Opdivo and Yervoy arms were 36.4 percent, 7.7 percent, and 14.8 percent, respectively.
The most common any-grade AEs in the combination arm versus the Opdivo and Yervoy arms were diarrhea (44.1 percent, 19.2 percent, 33.1 percent), rash (40.3 percent, 25.9 percent, 32.8 percent), fatigue (35.1 percent, 34.2 percent, 28.0 percent), pruritus (33.2 percent, 18.8 percent, 35.4 percent), and nausea (25.9 percent, 13.1 percent, 16.1 percent).
Grade 3/4 AEs were reported in 55 percent, 16.3 percent, and 27.3 percent of the combination, Opdivo, and Yervoy groups, respectively. The most frequent grade 3/4 toxicities reported in the Yervoy/Opdivo arm compared with Opdivo and Yervoy were diarrhea (9.3 percent, 2.2 percent, 6.1 percent) colitis (7.7 percent, 0.6 percent, 8.7 percent), increased lipase (8.6 percent, 3.5 percent, 3.9 percent), increased ALT levels (8.3 percent, 1.3 percent, and 1.6 percent) and increased AST levels (6.1 percent, 1.0 percent, 1.6 percent).
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 Opdivo and Yervoy.
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.