Tremelimumab Shows Some Activity in Chemotherapy-Resistant Advanced Malignant Mesothelioma, Phase II Study Finds
Tremelimumab is an anticytotoxic T-lymphocyte antigen 4 (CTLA4) monoclonal antibody, a class of inhibitor that has shown activity in multiple tumor types. Ipilimumab (Yervoy), another agent in this class, was found to significantly prolong overall survival in metastatic melanoma despite a relatively low response rate, and follow-up has identified a substantial proportion of patients who achieve a long-term benefit from treatment. In a phase III trial of tremelimumab in advanced melanoma, tremelimumab did not prolong overall survival but did significantly prolong duration of response. In this single-arm phase II study reported in The Lancet Oncology, Luana Calabrò, MD, of the Istituto Tuscano Tumori in Siena and colleagues found apparent beneficial effects of tremelimumab treatment despite a low response rate in patients with chemotherapy-resistant advanced malignant mesothelioma.
Study Details
In this open-label, single-arm study, 29 patients with measurable unresectable malignant mesothelioma and progressive disease after first-line platinum-based treatment received tremelimumab 15 mg/kg intravenously once every 90 days until progressive disease or severe toxicity. Eligible patients had to have a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and no history of autoimmune disease. The primary endpoint was the proportion of patients who achieved an objective response, with a target response rate of 17%.
Patients had a median age of 64 years, 72% were male, 86% had epithelioid histology, 62% had stage IV disease, and 79% had a European Organisation for Research and Treatment of Cancer prognostic score of good.
Responses
All patients received at least one dose of tremelimumab (median 2 doses, range 1-9). No patients had a complete response, and two patients (7%) had durable partial responses, one lasting 6 months and one lasting 18 months. One partial response occurred after initial progressive disease. The study thus failed to meet its primary endpoint. However, disease control was observed in nine patients (31%), median progression-free survival was 6.2 months, and median overall survival was 10.7 months.
Inducible costimulatory (ICOS) molecule, a member of the CD28/CTLA-4 family expressed at low levels on naive T cells and upregulated rapidly after T-cell activation, is considered a candidate marker for T-cell activation that could indicate potential benefit from anti-CTLA4 treatment. Circulating CD4-positive ICOS-positive T-cell levels at baseline were not associated with response to treatment. However, significantly improved overall survival was observed in patients with circulating CD4-positive ICOS-positive T-cell counts greater than the median values of 54 cells/μL at day 30 (hazard ratio [HR] = 0.21, P = .007) and 26 cells/µL at day 60 (HR = 0.38, P = .02) of the first cycle of tremelimumab treatment, and patients who achieved disease control had greater increases in counts at days 14, 30, and 60 (P = .03 at day 60) of the first cycle compared with nonresponders.
Favorable Toxicity Profile
Overall, 27 patients (93%) had at least one grade 1 or 2 adverse event, with the most frequent treatment-related adverse events including skin toxicities (62%, mainly cutaneous rash and pruritus), colitis or diarrhea (31% ), fever (24%), and arthralgia (14%). Grade 3 or 4 treatment-related adverse events occurred in four patients (14%), including grade 3 colitis/diarrhea in two patients and peripheral neuropathy in one and grade 4 ALT increase, AST increase, and amylase/lipase increase in one.
The investigators concluded, “Although the effect size was small in our phase II trial, tremelimumab seemed to have encouraging clinical activity and an acceptable safety and tolerability profile in previously treated patients with advanced malignant mesothelioma.” They further noted, “Circulating numbers of CD4-positive, ICOS-positive T cells associate with a favorable survival and could be an early prognostic marker of response in the course of treatment.”
The study was funded by the Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, Pfizer, and Fondazione Buzzi Unicem.
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