Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial

Background Monoclonal antibodies (mAb) to cytotoxic T-lymphocyte antigen 4 (CTLA4) have shown therapeutic activity in different tumour types. We aimed to investigate the efficacy, safety and immunological activity of the anti-CTLA4 mAb, tremelimumab, in advanced malignant mesothelioma (MM). Methods This open-label, single-arm phase 2 study enrolled patients 18 years or older with measurable, unresectable MM and progressive disease (PD) after a first-line platinum-based regimen between May 27, 2009, and January 10, 2012. Eligible patients had a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and no history of autoimmune diseases. Treatment comprised tremelimumab 15 mg/kg intravenously once every 90 days until PD or severe toxicity. The primary endpoint was the proportion of patients who achieved an objective response according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) for pleural MM or RECIST for peritoneal MM.. Analyses were done per intention to treat. This trial is registered with EudraCT, number 2008-005171-95, and with ClinicalTrials.gov, number NCT01649024. Findings Twenty-nine patients with MM were enrolled, of median age 64 (47–77) years, ECOG performance status 0-2, with stage III (n=11) or IV (n=18) disease. All patients received at least one dose of tremelimumab (median 2; range 1–9). The study did not reach its primary endpoint; however, two patients experienced durable (6 and 15+ months) partial response (PR); one PR occurred after initial PD. Grade 3 or 4 AEs, seen in four patients (14%), comprised gastrointestinal (n=2), neurological (n=1), hepatic (n=2) and pancreatic (n=1) toxicity. Interpretation The limited number of patients enrolled in this non-randomized study requires to interpret the results with caution; nevertheless, tremelimumab promises to have encouraging clinical activity in pre-treated patients with advanced MM, with potential to impact on survival and an acceptable safety and tolerability profile. Funding Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, Pfizer Inc., and Fondazione Buzzi Unice