Nivolumab Plus Ipilimumab in Advanced Melanoma

There has been increased interest in developing tumor immunity as a treatment strategy for several types of cancer. Immune checkpoint blockade is one approach that has induced regressions in cancer. Ipilimumab, a fully human, IgG1 monoclonal antibody blocking cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), improved overall survival in patients with advanced melanoma. Nivolumab, a fully human, IgG4 antibody blocking the programmed death 1 (PD-1) receptor, produced durable objective responses in patients with melanoma, renal-cell cancer, and non–small-cell lung cancer.

CTLA-4 and PD-1 appear to play complementary roles in regulating adaptive immunity. Whereas PD-1 contributes to T-cell exhaustion in peripheral tissues, CTLA-4 inhibits at earlier points in T-cell activation. In preclinical models, combined blockade of PD-1 and CTLA-4 achieved more pronounced antitumor activity than blockade of either pathway alone. For this study, the authors conducted a phase 1 study to investigate the safety and efficacy of combined CTLA-4 and PD-1 blockade (with the use of ipilimumab and nivolumab, respectively) in patients with advanced melanoma [N Engl J Med. 2013;369(2):122-133].

Eligible patients were at least 18 years of age; had received a diagnosis of measurable, unresectable, stage III or IV melanoma; had an Eastern Cooperative Oncology Group performance status of 0 (asymptomatic) or 1 (ambulatory, but restricted in strenuous activity); had adequate organ function; and had a life expectancy of at least 4 months. The investigators treated successive cohorts of patients with escalating doses of intravenous nivolumab and ipilimumab administered concurrently every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (the concurrent-regimen group).

In the sequenced-regimen group, patients were required to have received at least 3 previous doses of ipilimumab, with the last dose administered 4 to 12 weeks before the administration of nivolumab. The combined treatment was subsequently continued every 12 weeks for up to 8 doses. When the 2 drugs were administered together, nivolumab was administered first. Patients could be followed for a total of 2.5 years after the initiation of therapy. Patients with a complete response, a partial response, or stable disease for at least 24 weeks and subsequent disease progression could be retreated with the original regimen.

A total of 86 patients were treated from December 2009 through February 2013; 53 patients received the concurrent regimen and 33 received the sequenced regimen. Among the 53 patients in the concurrent-regimen group, adverse events of any grade, regardless of whether they were attributed to the therapy, were observed in 98% of patients. Among the 33 patients in the sequenced-regimen group, adverse events of any grade, regardless of attribution, were observed in 29 patients (88%). In the concurrent-regimen cohorts, across all dose levels, confirmed objective responses according to modified World Health Organization criteria were observed in 21 of 52 patients (40%; 95% confidence interval [CI], 27%-55%) who had a response that could be evaluated. A total of 16 patients had tumor reduction of ≥80% at 12 weeks, including 5 with a complete response.

In the concurrent-regimen group, overall evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients (95% CI, 51%-78%).

Among patients who received the maximum doses associated with an acceptable level of adverse events (cohort 2, with nivolumab at a dose of 1 mg per kilogram and ipilimumab at a dose of  3 mg per kilogram), objective responses occurred in 9 of 17 patients (53%; 95% CI, 28%-77%), including 3 with a complete response. In the sequenced-regimen cohorts, 6 of 30 patients (20%; 95% CI, 8%-39%) had an objective response, including 1 with a complete response. A total of 4 patients (13%) had tumor reduction of ≥80% at 8 weeks.

The investigators said that these findings suggest that rapid responses of a greater magnitude may be achieved in patients treated with the combination of nivolumab and ipilimumab, compared with the previous experience with either agent alone.