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Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. | LitMetric

AI Article Synopsis

Article Abstract

Background: CTLA4 blockade by tremelimumab 15 mg/kg every 90 days provided preliminary evidence of activity in patients with pretreated malignant mesothelioma; however, retrospective exposure-response analysis of data from patients with melanoma suggested that this schedule could result in underexposure to tremelimumab. We therefore investigated the efficacy and safety of an intensified schedule of tremelimumab in patients with advanced malignant mesothelioma.

Methods: In this open-label, single-arm, phase 2 study, participants aged 18 years or older with unresectable, advanced malignant mesothelioma (measurable in accordance with the Response Evaluation Criteria in Solid Tumors [RECIST]), a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and who had failed a first-line platinum-based regimen were enrolled at the University Hospital of Siena, Siena, Italy. Participants received tremelimumab 10 mg/kg once every 4 weeks for six doses, then every 12 weeks until disease progression, unacceptable toxic effects, or refusal to continue treatment. The primary endpoint was the proportion of patients achieving an immune-related objective response (complete or partial), assessed in all patients who received at least one dose of the study drug. This study is registered with the European Union Clinical Trials Register, number 2012-002762-12, and ClinicalTrials.gov, number NCT01655888.

Findings: Between July 30, 2012, and July 15, 2013, we enrolled 29 patients with a median age of 65 years (range 42-78), stage III (n=11) or IV (n=18) disease, and an Eastern Cooperative Oncology Group performance status of 0-1 (n=23) or 2 (n=6). Malignant mesothelioma histology was epithelioid (n=21, including one peritoneal), biphasic (n=6), sarcomatoid (n=1), or undefined (n=1). Patients received a median of six doses of tremelimumab (range 1-13). After a median follow-up of 21·3 months (IQR 18·7-25·9), four immune-related-partial responses were recorded, one at the first tumour assessment (after about 12 weeks) and three at the second tumour assessment (about 24 weeks), with two responses occurring after initial progressive disease and one response after initial stable disease. 15 (52%) of patients achieved disease control, with a median duration of 10·9 months (95% CI 8·2-13·6). According to modified RECIST, one patient (3%) achieved a partial response and 11 (38%) patients achieved disease control rate. Grade 1-2 treatment-related adverse events occurred in 26 (90%) patients and grade 3-4 adverse events in two (7%) patients. The most common treatment-related adverse events were gastrointestinal, dermatological, and fever.

Interpretation: Our results suggest that the intensified schedule of tremelimumab investigated seems to have clinical and immunological activity in patients with advanced malignant mesothelioma, and a good safety profile. The same intensified schedule is now being investigated in an ongoing randomised, double-blind, placebo-controlled, phase 2b study.

Funding: Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, and MedImmune.

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http://dx.doi.org/10.1016/S2213-2600(15)00092-2DOI Listing

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