FDA granted accelerated approval to a combination of Opdivo (nivolumab) and Yervoy (ipilimumab) for the treatment of patients with BRAF V600 wild-type and BRAF V600 mutation-positive unresectable or metastatic melanoma.
This approval expands the original indication for the Opdivo-Yervoy regimen for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma to include patients regardless of BRAF mutational status, based on data from the phase III CheckMate-067 trial, in which PFS and overall survival were co-primary endpoints. Opdivo is sponsored by Bristol-Myers Squibb.
FDA also expanded the use of Opdivo as a single-agent to include previously untreated BRAF mutation-positive advanced melanoma patients. The use of Opdivo as a single-agent in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma is approved under accelerated approval based on progression-free survival. Opdivo was approved by the FDA in November 2015, for use in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma.
CheckMate-067 is a double-blind, randomized study that evaluated the Opdivo-Yervoy regimen or Opdivo monotherapy vs. Yervoy monotherapy in patients with previously untreated advanced melanoma.
The trial evaluated previously untreated patients, including both BRAF V600 mutant and wild-type advanced melanoma, and enrolled 945 patients who were randomized to receive the combination regimen (Opdivo 1 mg/kg plus Yervoy 3 mg/kg every 3 weeks for 4 doses followed by Opdivo 3 mg/kg every 2 weeks thereafter; n=314), Opdivo monotherapy (Opdivo 3 mg/kg every 2 weeks; n=316) or Yervoy monotherapy (Yervoy 3 mg/kg every 3 weeks for 4 doses followed by placebo every 2 weeks; n=315).
Patients were treated until progression or unacceptable toxic effects. The median duration of exposure was 2.8 months (range: 1 day to 18.8 months) for patients in the combination arm with a median of four doses (range: 1 to 39 for Opdivo; 1 to 4 for Yervoy), and 6.6 months (range: 1 day to 17.3 months) duration for the Opdivo monotherapy arm with a median of 15 doses (range: 1 to 38). The co-primary endpoints were PFS and OS; the study is ongoing and patients continue to be followed for OS.
Results from the trial demonstrated a statistically significant improvement in PFS in patients with advanced melanoma treated with the combination regimen (p<0.0001) and with Opdivo as a single-agent (p<0.0001) vs. Yervoy monotherapy.
Median PFS was 11.5 months (95% CI: 8.9-16.7) for the combination regimen and 6.9 months (95% CI: 4.3-9.5) for Opdivo monotherapy, compared to 2.9 months (95% CI: 2.8-3.4) for Yervoy alone.
The Opdivo-Yervoy regimen demonstrated a 58 percent reduction in the risk of disease progression vs. Yervoy (HR: 0.42; 95% CI: 0.34-0.51; p<0.0001), while Opdivo monotherapy demonstrated a 43 percent risk reduction vs. Yervoy monotherapy (HR: 0.57; 95% CI: 0.47-0.69; p<0.0001).
Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, encephalitis, other adverse reactions; infusion reactions; and embryofetal toxicity.
