Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma

Abstract

PurposeIn phase I/II trials, the cytotoxic T lymphocyte–associated antigen-4–blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy.Patients and MethodsPatients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine).ResultsIn all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor.ConclusionThis study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma.

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

“…By comparison, in patients with treatment-naive, unresectable stage IIIc or IV melanoma, single-agent tremelimumab led to an ORR of 10.7% and median OS was 12.6 months . 8 In a pooled analysis of patients with advanced melanoma, treatment with single-agent ipilimumab produced a median OS of 11.4 months. 23 In CheckMate 067, objective response to ipilimumab in patients with advanced melanoma was 19%.…”

“…Although each mAb has been tested separately and shown single-agent activity in patients with advanced melanoma, 7,8 the combination has not. Tremelimumab is a fully human IgG2 anti-CTLA-4 mAb that produced clinical activity 8-10 similar to ipilimumab, although it did not improve OS when compared to chemotherapy in a randomized phase III study. 8 CP-870,893 is a fully human IgG2 agonist mAb evaluated in a single-dose study, a weekly infusion study, and studies combining CP-870,893 with chemotherapy.…”

“…Tremelimumab is a fully human IgG2 anti-CTLA-4 mAb that produced clinical activity 8-10 similar to ipilimumab, although it did not improve OS when compared to chemotherapy in a randomized phase III study. 8 CP-870,893 is a fully human IgG2 agonist mAb evaluated in a single-dose study, a weekly infusion study, and studies combining CP-870,893 with chemotherapy. 7,11–15 The most common side effect with CP-870,893 is transient, grade 1–2 cytokine release syndrome.…”

Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application

“…Tremelimumab is a fully human anti-CTLA-4 monoclonal antibody of the IgG2 isotype. Despite promising early clinical data in melanoma, tremelimumab failed to hit its primary endpoint of improved overall survival in comparison to standard of care chemotherapy for patients with previously untreated, unresectable Stage III or Stage IV melanoma (32). As a result, clinical development for melanoma was halted, but evaluation of tremelimumab in other cancers is currently ongoing.…”

Transcriptional profiling of whole blood: a rich source of immune biomarkers in cancer

“…Tremelimumab is currently being administered in experimental protocols as part of combination regimens for melanoma but it has not yet been submitted for FDA approval since it has yet to show superiority to dacarbazine. 4 However, Yervoy Ò was never directly tested against either dacarbazine or tremelimumab so the relative efficacies of the 2 antibodies remain unknown.…”