Tremelimumab did not produce a statistically significant advantage in overall survival compared to first-line standard-of-care chemotherapy in a phase III randomized trial reported in the Journal of Clinical Oncology. At final analysis, median overall survival by intent to treat was 12.6 months (95% confidence interval [CI] = 10.8–14.3) for tremelimumab vs 10.7 months (95% CI = 9.36–11.96) for chemotherapy (hazard ratio [HR] = 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 vs 13.7 months; P = .0011),” the researchers reported.
“The durable responses seen in this trial confirm that a subset of patients may derive benefit from treatment with tremelimumab,” the authors added. “Prolonged responses in a minority of patients were consistent with the effect of other types of immunotherapy, such as high-dose interleukin-2 [Proleukin]. Subset analysis by predefined baseline demographic and disease factors did not identify a factor that selects for benefit from tremelimumab compared with chemotherapy.”
Tremelimumab (CP-675206) is a cytotoxic T lymphocyte–associated antigen-4–blocking monoclonal antibody that induced durable responses in a subset of patients with advanced melanoma in phase I/II trials. In this phase III study, patients ≥ 18 years of age with treatment-naive, unresectable stage IIIC or IV melanoma were enrolled at 114 sites in 24 countries and randomly assigned to receive tremelimumab at 15 mg/kg once every 90 days, or physician’s choice of standard-of-care chemotherapy with temozolomide (Temodar) or dacarbazine.
The most common treatment-related adverse events related to tremelimumab were diarrhea, pruritus, and rash. The only grade 3 or higher treatment-related adverse events occurring in ≥ 10% of patients were diarrhea, reported in 14% of those taking tremilumumab, and neutropenia, reported in 10% of those receiving chemotherapy. Seven deaths occurring among patients taking tremelimumab and one death of a patient receiving chemotherapy were considered treatment-related.
Evolving Standard of Care
“Since the trial described in this report was initiated, the standard of care for melanoma has changed,” the authors noted. Ipilimumab (Yervoy), a CTLA4-blocking IgG1 monoclonal antibody, and the BRAF inhibitor vemurafenib (Zelboraf) “have recently been approved in several countries, including the United States, the European Union, and Australia,” the investigators wrote.
Two phase III trials have also demonstrated a survival advantage for patients with metastatic melanoma who took ipilimumab. The tremelimumab study investigators pointed out that during the conduct of their trial, ipilimumab became widely available to patients in the comparator group, both in clinical trials and through a worldwide expanded-access program.
“Use of CTLA4 blockade in both arms of this study could have decreased the power of the study to demonstrate a statistically significant difference in survival and biased the estimates of survival in the control arm,” they asserted. “Patient selection, dosing regimen, and use of another CTLA4-blocking agent (ipilimumab) as salvage therapy for patients in the comparator arm may explain the differences between the results of this phase III trial and those of two positive phase III trials with ipilimumab,” the authors concluded. ■
Ribas A, et al: J Clin Oncol. January 7, 2013 (early release online)