[Abstract unavailable

Background In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab demonstrated a high objective response rate, including complete responses in patients with advanced melanoma. Methods In this double-blind study, 142 treatment-naïve patients with metastatic melanoma were randomized 2:1 to receive ipilimumab 3 mg/kg combined with either nivolumab 1 mg/kg or placebo every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg or placebo every 2 weeks until disease progression. The primary endpoint was investigator-assessed objective response in BRAF wild-type patients. Results Among BRAF wild-type patients, the confirmed objective response rate was 61.1% (44/72) in the nivolumab and ipilimumab combination group versus 10.8% (4/37) in the ipilimumab monotherapy group (P<0.001), with complete responses reported in 16 (22.2%) patients in the combination group; none in the ipilimumab group. Median duration of response was not reached with either treatment. Median progression-free survival was not reached for the combination versus 4.4 months for ipilimumab monotherapy (hazard ratio 0.40, 95% CI 0.23 to 0.68; P<0.001). Similar results for response and progression-free survival were also observed in 33 BRAF mutation-positive patients. Grade 3–4 drug-related adverse events were reported in 54.3% of patients receiving the combination compared with 23.9% with ipilimumab monotherapy. Select adverse events of immunological etiology were consistent with phase 1 reports, and most resolved with immune-modulating medication. Conclusion Nivolumab combined with ipilimumab significantly improved objective response rate and progression-free survival compared with ipilimumab monotherapy in treatment-naïve patients with advanced melanoma, and had a manageable safety profile. (ClinicalTrials.gov number, NCT01927419)

T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III clinical trial. T-VEC was well tolerated and resulted in a higher DRR (P < .001) and longer median OS (P = .051), particularly in untreated patients or those with stage IIIB, IIIC, or IVM1a disease. T-VEC represents a novel potential therapy for patients with metastatic melanoma.