LUME-Meso: Randomised phase II/III study of nintedanib (N) + pemetrexed/cisplatin (PEM/CIS) followed by maintenance N or placebo (P) in chemo-naïve patients with malignant pleural mesothelioma (MPM)

Abstract

Background: PEM/CIS is the standard first‐line treatment for MPM, with median overall survival (OS) of 1 year. N is a triple angiokinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1‐3, platelet‐derived growth factor (PDGF) receptors a/b and fibroblast growth factor receptors 1‐3, as well as Src and Abl kinases. VEGF and PDGF overexpression are associated with poor prognosis in MPM, and N has demonstrated efficacy in preclinicalMPM models. We performed a randomised Phase II trial of N or P+ PEM/CIS inMPM followed by maintenance N or P; progression‐free survival (PFS) was the primary endpoint. An internal Data Monitoring Committee recommended the study be expanded to include a confirmatory Phase III part. With regulatory authority guidance, the Phase II data were unblinded demonstrating a PFS benefit with N (hazard ratio 0.56, 95% confidence interval 0.34‐0.91; p=0.017); these data assisted in planning the Phase III part including sample size estimation, and N was granted U.S. Food & Drug Administration orphan drug designation for the treatment ofMPMin December 2016. The Phase III part (NCT01907100) is recruiting. Trial design: For Phase III, 450 chemo‐naïve patients worldwide (>100 sites in 27 countries) aged 18 years with unresectable MPMof epithelioid histology and Eastern Cooperative Oncology Group performance score 0‐1 will be randomised 1:1 to receive up to 6 21‐day cycles of PEM (500 mg/m2)/CIS (75 mg/m2) on Day 1 plus N or P (200 mg twice daily, Days 2‐21), followed by N or P monotherapy until disease progression or undue toxicity. The primary endpoint is PFS; the key secondary endpoint is OS. An adaptive design will be used at the time of the primary PFS analysis to reassess the number of OS events for sufficient OS power. Other secondary endpoints are objective response and disease control (using modified Response Evaluation Criteria in Solid Tumors). The frequency/severity of adverse events and health‐related quality of life will also be assessed. An exploratory analysis of predictive/prognostic biomarkers is planned.