Abstract
Tremelimumab shows activity and is well tolerated in previously treated malignant mesothelioma.
Major finding: Tremelimumab shows activity and is well tolerated in previously treated malignant mesothelioma.
Clinical Relevance: Increased circulating CD4+, ICOS+ T cells may be a biomarker of response to anti-CTLA4 therapy.
Impact: Tremelimumab induces stable disease and improves survival in patients with mesothelioma.
Malignant mesothelioma is a rare tumor that affects the protective tissue that surrounds internal organs such as the lung and lines body cavities, including the peritoneum, and is tightly associated with asbestos exposure. Many patients experience tumor progression following standard-of-care treatment with platinum-based chemotherapy, underscoring the need to develop improved therapeutic strategies. Recent studies have indicated that tumor-specific immune responses may be activated in patients with malignant mesothelioma, suggesting that inhibition of the immunosuppressive receptor cytotoxic T-lymphocyte-associated protein 4 (CTLA4) may enhance antitumor T-cell activity. Calabrò and colleagues performed an open-label, single-arm phase II trial to investigate the safety and efficacy of tremelimumab, a monoclonal antibody related to ipilimumab that targets CTLA4, in 29 patients with unresectable malignant melanoma who had previously received platinum-based therapy. Although no patients had a complete response and the target response rate was not reached, tremelimumab induced disease control in 9 (31%) patients, including long-lasting stable disease with a median duration of 12.4 months in 7 (24%) patients and durable partial responses lasting at least 6 months in 2 (7%) patients. Survival rates 1 and 2 years after completion of therapy were 48.3% and 36.7%, respectively, with a median overall survival of 10.7 months and a median progression-free survival of 6.2 months. Tremelimumab was generally well tolerated; most treatment-related adverse events were low grade, including rash, colitis, and diarrhea, and grade 3–4 adverse events resolved with steroid treatment. Intriguingly, higher-than-median numbers of circulating CD4+, ICOS+ (inducible T-cell co-stimulator-positive) T cells, which are indicative of T-cell activation, following tremelimumab administration were associated with improved survival and disease control, suggesting that this may be a prognostic biomarker of response to anti-CTLA4 therapy. These results support further evaluation of tremelimumab in larger, randomized clinical trials of malignant mesothelioma.
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