Treatment of patients with advanced refractory or relapsed melanoma in a phase II study of tremelimumab (CP-675,206), an anti-ctla4 monoclonal antibody

The antitumor activity and safety of tremelimumab (CP-675,206), a fully human anti-CTLA4 monoclonal antibody, was assessed in a phase II, open-label, single-arm study in patients with advanced melanoma. Eligible patients had measurable, surgically incurable stage III or IV melanoma and had progressed, relapsed, or could not tolerate previous treatment. Tremelimumab (15 mg/kg) was administered intravenously every 12 weeks for up to 4 cycles (patients with clinical benefit were eligible for ≤ 4 additional doses) or until disease progression or intolerable toxicity. Proportion of confirmed objective RECIST responses per independent review was the primary endpoint, and secondary endpoints included safety, duration of response, and overall survival (OS). Among 251 enrolled patients, 246 patients (242 responseevaluable) received a median of 1 dose (range, 1 to 7). The objective response rate per RECIST, as determined by the Independent Endpoint Review Committee, was 6.6% (16 partial responses [PRs]), and all responses were durable (≥ 170 days). Eleven of these PRs are ongoing (6.0+ to 17.7+ months). The majority of PRs involved target lesions in lung, lymph nodes, and/or liver. An additional 36 patients had stable disease (SD;≥ 70 days since first dose); therefore, the clinical benefit rate was 22% (PRs + SDs). Six patients (2.5%) had a PR in target lesions per RECIST while having overall progressive disease, and these patients remain alive on study with censored OS (14.82+ to 18.23+ months). Median OS for all patients was 10.1 months, and Kaplan-Meier estimate of 12-month survival was 41%. Most treatment-related adverse events (AEs) were mild to moderate. Grade 3 or 4 AEs included diarrhea (n = 28, 11.4%), fatigue (n = 6, 2.4%), and colitis (n = 6, 2.4%). There were 2 (0.8%) treatment-related deaths (1 sudden death and 1 diverticular perforation). While this study did not demonstrate a second-line response rate exceeding 10%, duration of response to this regimen suggests a role for tremelimumab in this population, and future assessment of predictive factors of response may serve to broaden understanding of clinical benefit observed in some patients.