Conference Coverage
ASCO: Combo therapy results end reign of single-drug therapy in melanoma
Key clinical point: Nivolumab alone or combined with ipilimumab significantly improves progression-free survival and objective response rates...
Nivolumab, a programmed death receptor-1 (PD-1)–blocking antibody, has been approved for use in combination with ipilimumab for treating people with BRAF V600 wild-type, unresectable or metastatic melanoma.
Approval was based on demonstration of an increase in the objective response rate, prolonged response durations, and improvement in progression-free survival (PFS) in an international, multicenter, double-blind, randomized, two-arm, active-controlled trial in patients who were previously untreated for unresectable or metastatic, BRAF V600 wild-type melanoma, according to a Sept. 30 statement issued by the Food and Drug Administration.
Nivolumab, marketed as Opdivo Injection by Bristol-Myers Squibb, was approved in 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab therapy and, if BRAF V600 mutation positive, a BRAF inhibitor. Ipilimumab, approved in 2011 and marketed as Yervoy by BMS, is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody indicated for treating unresectable or metastatic melanoma.
“Combined nivolumab (anti–PD-1) and ipilimumab (anti–CTLA-4) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone, and results in improved antitumor responses in metastatic melanoma,” the updated nivolumab prescribing information states.
This is the first FDA approval of a cancer treatment regimen that includes two immuno-oncology agents, according to the company’s statement announcing the approval.
The phase II CheckMate 069 study enrolled 142 patients, including 109 patients with BRAF V600 wild-type melanoma, randomized in a 2:1 ratio to receive the combination or ipilimumab plus placebo; their median age was 66 years; 84% had an ECOG performance score of 0, and 15% had a score of 1. The overall response rate was 60% among those on the combination therapy vs. 11% among those on ipilimumab alone – a 49% improvement (P less than .001), according to the FDA.
Nine of the 43 patients with an objective response (ranging from 3 to 7 months) in the combination therapy group “have progressed after response, died, or received subsequent therapy,” the FDA said. Among the 34 patients who continued to have a response at the last analysis, 14 had responses that had lasted from at least 6 months to less than 9 months. The remaining 20 patients had responses that had lasted at least 9 months.
The estimated median PFS was 8.9 months in the combination group vs. 4.7 months in the ipilimumab-only arm, a 60% reduced risk (P less than .002)
Serious adverse reactions, adverse reactions resulting in permanent discontinuation or a delayed dose, and grade 3 or 4 adverse reaction were higher among those treated with the combination. Colitis, diarrhea, pyrexia, and pneumonitis were the most common serious adverse reactions among those on the combination.
The recommended dose and schedule is as follows, according to the FDA: 1 mg/kg of nivolumab administered as an IV infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for four doses. “The recommended subsequent dose of nivolumab, as a single agent, is 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.”
Both indications for nivolumab were approved as accelerated approvals, based on the “tumor response rate and durability of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials,” according to the prescribing information.
Serious adverse events associated with this therapy should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch.
