Combination Therapy with Nivolumab and Ipilimumab Superior to Monotherapy in Advanced Melanoma
Immune blockade has been shown to induce tumor regression in various types of cancer. Ipilimumab is a fully human, immunoglobulin (Ig) G1 monoclonal antibody that blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4); nivolumab is a fully human IgG4 antibody that blocks the programmed death-1 (PD-1) receptor. A new study investigated whether combined immune blockade with ipilimumab and nivolumab would increase survival in patients with advanced melanoma (Wolchok JD, et al. N Engl J Med. 2013;369:122-133).
Ipilimumab has demonstrated improved overall survival in patients with advanced melanoma. Nivolumab has produced objective responses in patients with melanoma, as well as other types of cancer.
The combination of CTLA-4 plus PD-1 blockade was shown to be complementary in regulating immune activity, and was hypothesized to increase antitumor activity in patients with advanced melanoma compared with blockade with either pathway alone.
In this phase 1 clinical trial, 53 patients received concurrent therapy with intravenous doses of nivolumab and ipilimumab every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses; this was subsequently followed by therapy every 12 weeks for up to 8 doses. In the sequenced therapy arm, 33 patients who were previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.
The objective response rate in the concurrent regimen arm was 40%, and clinical activity was seen in 65% of the patients. At the maximum allowed dose, 53% of patients showed objective response compared with only 20% of patients in the sequenced therapy group. Patients in the combined regimen had tumor reductions of ≥80%.
Grade 3 or 4 adverse events were reported in 53% of the patients in the concurrent regimen group, but these were similar to events seen with monotherapy and were reversible overall; the rate was 18% in the sequenced therapy group.
Concurrent treatment with nivolumab and ipilimumab was associated with objective response rates that exceeded the previously reported results with either agent alone. Rapid and durable responses were seen in a substantial proportion of patients in the concurrent regimen group. Of particular significance was the finding that 31% of the patients who had a response in the concurrent regimen group had tumor regression of ≥80% by week 12.
These results suggest that the combined use of nivolumab and ipilimumab in patients with advanced melanoma results in rapid and deeper clinical tumor responses than responses observed with either agent alone. These responses were durable, but longer follow-up is needed to confirm these results.