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FDA Expands Indication for Nivolumab/Ipilimumab Combo in Metastatic Melanoma
The FDA has approved nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the treatment of patients with BRAF V600 wild-type and BRAF V600 mutation-positive unresectable or metastatic melanoma. Both drugs are marketed by Bristol-Myers Squibb.
This approval expands the original indication for the nivolumab/ipilimumab 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 3 CheckMate-067 trial, in which progression-free survival (PFS) and overall survival (OS) were coprimary endpoints.
The FDA also expanded the use of nivolumab as a single-agent to include patients with previously untreated BRAF mutation-positive advanced melanoma. Nivolumab 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 an ongoing double-blind, randomized study evaluating the nivolumab/ipilimumab regimen or nivolumab monotherapy compared with ipilimumab monotherapy in patients with previously untreated advanced melanoma. The trial enrolled 945 previously untreated patients, including those with BRAF V600 mutant or wild-type advanced melanoma, who were randomly assigned to receive the nivolumab/ipilimumab regimen (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks; n = 314); nivolumab monotherapy (3 mg/kg every two weeks; n = 316); or ipilimumab monotherapy (3 mg/kg every three weeks for four doses, followed by placebo every two weeks; n = 315).
The patients were treated until progression or unacceptable toxicity occurred. The median duration of exposure was 2.8 months for patients in the nivolumab/ipilimumab arm with a median of four doses, and 6.6 months for patients in the nivolumab monotherapy arm with a median of 15 doses.
The results from this study demonstrated a statistically significant improvement in PFS in patients with advanced melanoma treated with the nivolumab/ipilimumab regimen (P < 0.0001) or with nivolumab as a single agent (P < 0.0001) compared with ipilimumab monotherapy. The median PFS was 11.5 months for the nivolumab/ipilimumab regimen and 6.9 months for nivolumab monotherapy compared with 2.9 months for ipilimumab monotherapy. The nivolumab/ipilimumab regimen demonstrated a 58% reduction in the risk of disease progression compared with ipilimumab monotherapy (P < 0.0001), whereas nivolumab monotherapy demonstrated a 43% risk reduction compared with ipilimumab (P < 0.0001).
In addition, the nivolumab/ipilimumab regimen and nivolumab monotherapy demonstrated higher confirmed objective response rates (50% and 40%, respectively; P < 0.0001) compared with ipilimumab monotherapy (14%). The percentages of patients with a complete response were 8.9%, 8.5%, and 1.9%, favoring the nivolumab/ipilimumab regimen and nivolumab monotherapy over ipilimumab monotherapy. Partial responses were observed in 41% of patients treated with the nivolumab/ipilimumab regimen, in 31% of patients treated with nivolumab monotherapy, and in 12% of patients treated with ipilimumab monotherapy.
The nivolumab/ipilimumab regimen delivered durable responses, with 76% of patients experiencing an ongoing response of at least six months’ duration. In the nivolumab monotherapy and ipilimumab monotherapy arms, 74% and 63% of patients, respectively, experienced an ongoing response of at least six months’ duration.
Serious adverse events (73% vs. 37%), adverse events leading to discontinuation (43% vs. 14%) or dosing delays (55% vs. 28%), and grade 3 or 4 adverse events (72% vs. 44%) occurred more often in the nivolumab/ipilimumab arm compared with the nivolumab monotherapy arm. No overall differences in safety or efficacy were reported between elderly and younger patients.
The most common adverse events leading to discontinuation of the nivolumab/ipilimumab regimen compared with nivolumab as a single-agent included diarrhea (8.0% vs. 1.9%, respectively), colitis (8.0% vs. 0.6%), increased alanine aminotransferase (ALT) levels (4.8% vs. 1.3%), increased aspartate aminotransferase (AST) levels (4.5% vs. 0.6%), and pneumonitis (1.9% vs. 0.3%). The most common serious adverse events in the nivolumab/ipilimumab arm and in the nivolumab monotherapy arm included diarrhea (13.0% vs. 2.6%, respectively), colitis (10.0%vs. 1.6%), and pyrexia (10.0% vs. 0.6%).
Nivolumab is associated with immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, renal dysfunction, rash, encephalitis, and other adverse reactions; with infusion reactions; and with embryofetal toxicity.
Source: Bristol-Myers Squibb; January 23, 2016.