Immunologic checkpoint inhibitor shows promise in malignant mesothelioma

Sep 27 2013

By Joanna Lyford, Senior medwireNews Reporter

Tremelimumab, one of a new class of immunomodulatory monoclonal antibodies, has shown encouraging clinical activity and acceptable tolerability in patients with chemotherapy-resistant malignant mesothelioma, results of a single-arm phase II study show.

The findings provide a solid foundation for the testing of tremelimumab in a large randomized phase II study, says Anna Nowak (University of Western Australia, Crawley) in a commentary accompanying the study results in The Lancet Oncology.

Tremelimumab is a monoclonal antibody that targets the cytotoxic T-lymphocyte antigen 4 (CTLA4), which is expressed on T cells after activation. Ligation of CTLA4 restricts ongoing T-cell costimulation and activation, thereby abrogating autoimmunity or antitumor immunity, and inducing tolerance. CTLA4 blockade with monoclonal antibody inhibitors reduces these negative regulatory signals and allows any endogenous antitumor response to proceed unopposed.

“Thus, these drugs have potential activity against cancers of any origin,” notes Nowak.

In this open-label phase II study, tremelimumab 15 mg/kg was given intravenously every 90 days to 29 patients with measurable, unresectable malignant mesothelioma and progressive disease after first-line platinum-based chemotherapy.

Patients received a median of two doses (range 1-9). There were no complete responses but two (7%) patients had a durable partial response. One lasted 6 months and the other, after initial disease progression, lasted 18 months. There were also seven patients with stable disease.

Thus, the rate of disease control was 31%, median progression-free survival was 6.2 months, and median overall survival was 10.7 months, report Michele Maio (University Hospital of Siena, Italy) and fellow investigators.

Twenty-seven (93%) patients had at least one grade 1/2 treatment-emergent adverse event and four (14%) patients had at least one grade 3/4 treatment-emergent adverse events; the most common adverse events were dermatologic (cutaneous rash and pruritis) and gastrointestinal (colitis and diarrhea). There were no treatment-related deaths.

Analysis of blood samples showed that numbers of circulating CD4-positive inducible costimulatory (ICOS)-positive T cells increased following each dose of tremelimumab and peaked at around day 14 before declining to basal levels. Patients with above-median levels during the first cycle had significantly better survival than those with lower levels.

“Although preliminary, the clinical and immunological findings of this study warrant further investigation of tremelimumab in patients with malignant mesothelioma, a conclusion that is also supported by preclinical evidence suggesting a synergistic effect of CTLA4 blockade and chemotherapy in malignant mesothelioma,” conclude the researchers.

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