Tremelimumab Doesn't Live Up to Standard Chemo


CHICAGO — Add tremelimumab monotherapy to the list of treatments that showed potential for improving metastatic melanoma survival but have failed thus far to live up to their promise, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In an international multicenter phase III trial comparing the investigational antibody tremelimumab with standard single-agent chemotherapy, tremelimumab did not improve overall survival versus either temozolomide (Temodar) or dacarbazine (DTC), said Dr. Antoni Ribas, a medical oncologist at the University of California at Los Angeles Medical Center.

While tremelimumab didn't surpass standard chemotherapy, patients who received it had objective responses to the agent, many of which were sustained, Dr. Ribas said, concluding that it warrants further investigation for treatment of metastatic melanoma.

Tremelimumab is a fully humanized monoclonal antibody specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA4). It blocks negative CTLA4 signaling, and has been shown in animal models and in vitro studies to induce significant activation of T cells at concentrations of 30 mcg/mL.

In a phase I/II clinical trial in 112 patients with measurable melanoma, tremelimumab produced objective responses in 11% of patients, and ongoing durable responses of 32-64 months in 8% of patients.

The phase III study was designed to test the hypothesis that tremelimumab could improve survival in patients with surgically incurable metastatic melanoma. It was funded by Pfizer Inc., developer of tremelimumab. The investigators chose a dose of 15 mg/kg on day 1 and then every 90 days.

The primary end point was overall survival with an improvement of at least 33% over the comparator, with secondary end points including best overall response, durable response, duration of tumor response, progression-free survival 6 months after randomization, and safety.

Stages IIIc and IV melanoma patients were randomized in a 1:1:1 ratio to either tremelimumab or to single-agent chemotherapy with either 1,000 mg/m

The analysis was conducted on 324 patients who were assigned to receive tremelimumab and 319 assigned to the two chemotherapy regimens.

The trial was halted early after the second interim analysis in March 2008, when the data safety monitoring board determined that the study crossed the predetermined adjusted boundary for futility (P greater than .473), with a P value of .729.

A Kaplan-Meier estimate of overall survival among all patients in an intention-to-treat analysis showed median survival rates of 11.8 months for tremelimumab and 10.7 months for chemotherapy.

In an exploratory analysis of factors associated with overall survival, the authors found that "contrary to what had been anticipated, there is a trend toward better survival in the subset of patients with less advanced disease when treated with chemotherapy as opposed to tremelimumab," Dr. Ribas said.

In an intention-to-treat analysis of responses to therapy and 6-month progression-free survival, the complete response rate among 328 patients on tremelimumab was 1.5%, compared with 1.8% for 327 patients on chemotherapy. The partial response rates were 7.6% for patients who received the antibody and 8.3% for those on chemotherapy. The objective response rates (complete and partial responses combined) were 9.1% and 10.1%, respectively.

Six-month objective response rates (complete and partial responses combined) were 9.1% and 10.1%, respectively. Six-month progression-free survival was 18.6% for tremelimumab, vs. 14.1% for chemotherapy; this difference was not statistically significant.

Dr. Patrick Hwu, professor and chairman of medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston, questioned whether overall survival was the best end point for the study, given that a subgroup of patients had a durable response to the anti-CTLA4 antibody.

Dr. Ribas has received honoraria, research funding, and served in an advisory role to Pfizer. Three of his coauthors are employees of the company.

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