Phase II Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemo Naive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905, NCT01064648)

Abstract

Background: Anti-angiogenic agents combined with chemotherapy have shown efficacy in unresectable malignant pleural mesothelioma (MPM). Cediranib, a vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) inhibitor, demonstrated therapeutic potential in a prior phase I trial. A phase II randomized trial of cisplatin-pemetrexed with and without cediranib was evaluated for efficacy. Methods: S0905 phase II randomized cediranib (20 mg daily) or placebo with platinum-pemetrexed for 6 cycles followed by maintenance cediranib/placebo in unresectable chemo-naive MPM patients of any histologic subtype. The primary endpoint was RECIST 1.1 progression-free survival (PFS). Secondary endpoints included overall survival, PFS by modified RECIST 1.1, response rate (RR), disease control rate, safety/toxicity. The trial was designed to detect a difference in RECIST 1.1 PFS at the 1-sided 0.1 level using a stratified log-rank test. Findings: 92 eligible patients were enrolled with 75% epithelioid and 25% biphasic or sarcomatoid histology. The cediranib arm had more grade 3-4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved median PFS by RECIST 1.1 (7.2 vs 5.6 months, HR 0.71, p=0.062) and increased RR by modified RECIST 1.1 (50% vs 20%, p=0.006) and by RECIST 1.1 (26% vs 15%, p=0.15). By modified RECIST 1.1, cediranib numerically increased median PFS (6.9 vs 5.6 months, HR 0.77, p=0.12). The median OS was numerically improved with cediranib (10 vs 8.5 months, HR 0.88, p=0.28). Interpretation: The addition of cediranib to platinum-pemetrexed improved PFS by RECIST 1.1 and RR by modified RECIST in patients with unresectable MPM. While adding anti-angiogenics to chemotherapy has been a successful strategy for some patients, the cediranib toxicity profile and small incremental survival benefit precludes further development in MPM. Strategies to incorporate immunotherapies to prolong beneficial responses and survival may be needed. Funding National Institutes of Health, National Cancer Institute grant numbers CA180888, CA180819, CA180858, CA180801, CA189830, CA189821, CA189872, CA180830 CA180835, CA189858, CA189971, CA189972 and CA180846. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Declaration of Interest: AT reports personal fees and other from AstraZeneca during the conduct of the study; grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Genentech/Roche, grants and personal fees from Lilly, grants from Millennium/Takeda, grants from Seattle Genetics, grants and personal fees from Ariad, grants and personal fees from Boehringer-Ingelheim, grants from Polaris, grants from Epizyme, grants from Merck, outside the submitted work. JVH reports grants from NIH/NCI, grants from American Cancer Society (ACS), grants from Cancer Prevention & Research Institute of Texas (CPRIT), other from EMD Serono, other from GlaxoSmithKline, other from AstraZeneca, other from Bristol-Myers Squibb, other from Merck, other from Genentech, other from Boehringer-Ingelheim, other from Spectrum, other from Eli Lilly, other from Novartis, during the conduct of the study. SG reports personal fees from Astra-Zeneca, outside the submitted work; Dr. Wistuba reports grants and personal fees from Genentech/Roche, grants and personal fees from AstraZeneca/Medimmune, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Pfizer, grants from Amgen, grants from Adaptimmune, grants from Takeda, grants and personal fees from GlaxoSmithKlein, grants from Merck, grants and personal fees from Asuragen, grants from DepArray, grants from Adaptive, Inc, grants from EMD Serono, personal fees from MSD, outside the submitted work; KK reports personal fees from AstraZeneca, outside the submitted work. Ethical Approval: The protocol and informed consent document were approved by the Cancer Therapy Evaluation Program of the National Cancer Institute and the institutional review boards of participating SWOG member sites. Written informed consent was obtained from all patients before enrollment. This study was monitored by the Data and Safety Monitoring Committee of SWOG. An additional patient consent was required for the banking and future use of specimens.