Phase 2 study of tremelimumab plus durvalumab for previously-treated malignant pleural mesothelioma (MPM).

8549 Background: Treatment options are limited for patients (pts) with MPM who experience disease progression after first-line pemetrexed-based chemotherapy. This study was designed to explore the activity of combined CTLA-4 + PD-L1 immune checkpoint inhibition using tremelimumab plus durvalumab in previously-treated MPM. Methods: We conducted a phase 2 study of tremelimumab 75 mg plus durvalumab 1500 mg administered intravenously every 4 weeks for four cycles followed by durvalumab maintenance every 4 weeks. Eligible pts had previously received pemetrexed-based platinum doublet chemotherapy and had measurable disease using modified RECIST criteria for mesothelioma. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS), and duration of response (DoR) as well as safety and tolerability of this combination. A Simon two-stage design was employed to enroll up to 40 patients if 4 or more responses were observed among the first 19 study patients. Pre-treatment, on-treatment, and optional post-progression biopsies underwent flow cytometric immunoprofiling for correlative studies. Results: Among 19 pts enrolled in this study, the best objective response was a confirmed partial response in one patient (5%), stable disease in 9 pts (47%), progressive disease in 8 pts (42%), and not evaluable in one patient. At a median follow-up of 7.1 months, the median PFS was 2.8 months (95% CI 2.04-5.72), and the median OS was 7.8 months (95% CI 6.24-not reached). Of 17 PD-L1 evaluable cases, 10 (59%) were PD-L1 negative, and 7 (41%) had a PD-L1 tumor proportion score of ≥1%. Treatment was generally well-tolerated and there were no treatment-related study discontinuations or deaths. Flow cytometric immunologic changes over the course of treatment associated with disease control will be presented. Conclusions: Tremelimumab + durvalumab was well-tolerated in unselected pts with previously-treated MPM. This study did not meet its primary endpoint. Additional strategies are necessary to develop novel immunotherapeutics and biomarkers of response in MPM. Clinical trial information: NCT03075527.