Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.

Abstract

PURPOSE:

In 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 METHODS:

Patients 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).

RESULTS:

In 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.

CONCLUSION:

This 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.

• Authors: Antoni Ribas, Richard Kefford, Margaret A Marshall, Cornelis J A Punt, John B Haanen, Maribel Marmol, Claus Garbe, Helen Gogas, Jacob Schachter, Gerald Linette, Paul Lorigan, Kari L Kendra, Michele Maio, Uwe Trefzer, Michael Smylie, Grant A McArthur, Brigitte Dreno, Paul D Nathan, Jacek Mackiewicz, John M Kirkwood, Jesus Gomez-Navarro, Bo Huang, Dmitri Pavlov, Axel Hauschild
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 31 Issue 5 Pg. 616-22 (Feb 10 2013) ISSN: 1527-7755 [Electronic] United States
• PMID: 23295794 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Ipilimumab
• tremelimumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal (adverse effects, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (adverse effects, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Colitis (chemically induced)
• Diarrhea (chemically induced)
• Drug Administration Schedule
• Drug Eruptions (etiology)
• Fatigue (chemically induced)
• Female
• Humans
• Ipilimumab
• Kaplan-Meier Estimate
• Male
• Melanoma (drug therapy, pathology)
• Middle Aged
• Nausea (chemically induced)
• Pruritus (chemically induced)
• Salvage Therapy (methods)
• Skin Neoplasms (drug therapy, pathology)
• Treatment Outcome