SPS-7 - Nintedanib plus pemetrexed/cisplatin in patients with MPM: Phase II findings from the placebo-controlled LUME-Meso trial

Abstract

Standard 1st-line treatment for patients (pts) with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin (PEM/CIS); median overall survival (OS) is approximately 1 year. Nintedanib (N) is an oral inhibitor of VEGFR, PDGFR and FGFR, and Src and Abl kinases. VEGF and PDGF overexpression are associated with poor prognosis in MPM, and N has shown efficacy in preclinical models. This study evaluated the efficacy and safety of N+PEM/CIS vs placebo (P)+PEM/CIS in pts with MPM. Pts with unresectable MPM (chemo-naive, ECOG PS 0-1) were stratified by histology (epithelioid/biphasic) and randomised 1:1 to receive up to 6 cycles of PEM (500 mg/m2)/CIS (75 mg/m2) on Day 1 plus N or P (200 mg bid) on Days 2-21. Pts without disease progression received maintenance N or P. The primary endpoint was progression-free survival (PFS). 87 pts were randomised to N+PEM/CIS (n = 44) or P+PEM/CIS (n = 43). Pt characteristics were comparable between the groups; 89% had epithelioid MPM. PFS was significantly improved with N vs P (HR = 0.56 [95% CI 0.34-0.91]; p = 0.0174; median PFS 9.4 vs 5.7 months). PFS benefit was also seen in the epithelioid subgroup (HR = 0.51 [95% CI 0.30-0.86]; p = 0.0101). Preliminary OS data favoured N; objective tumour response was observed in 59% of the N arm vs 44% of the P arm (all partial responses). All pts experienced at least one adverse event (AE; any grade), with 7% of the N arm discontinuing due to AEs vs 15% with P. Serious AEs occurred in 36% vs 42% of pts in the N and P arms, respectively. The most common Grade ≥3 AEs (N vs P) were neutropenia (34% vs 10%), alanine aminotransferase increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%). N+PEM/CIS demonstrated clinical efficacy with improved PFS and a tolerable safety profile in pts with unresectable MPM. Based on these promising findings, the study was extended and the Phase III part is recruiting (NCT01907100).