Background: Dysregulation of MET signalling has been reported as a key event in several malignancies and has been identified as a promising therapeutic target. Strong preclinical data on MPM and NSCLC showed that MET inhibition blocks tumor cell growth and migration (Jagadeeswaran et al, Cancer Res 2006; MA et al, Cancer Res 2005). Tivantinib (T) is a selective non-ATP competitive oral inhibitor of MET receptor. In a randomized phase III trial, the combination of T plus erlotinib improved overall survival in a subset of pts with non-squamous NSCLC and high MET expression (Scagliotti G, ESMO/ECCO 2013 abst. n°:3410). Adding T to first-line chemotherapy (CT) may improve efficacy. Methods: This Phase I-Ib study is designed to assess the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of escalating doses of T in combination with fixed doses of carboplatin (AUC 5 i.v. d1-q21) and pemetrexed (500 mg/m² i.v. d1-q21) as first line treatment for pts with advanced MPM or non-squamous NSCLC. Eligible pts must be CT naïve with ECOG Performance Status <2 and adequate bone marrow, liver and kidney functions. Sequential cohorts of 3 pts per dose level are recruited according to a standard 3 + 3 dose-escalation design starting from level 0 (T 240 mg BID). In case of DLTs in the first 3 pts, a dose level -1 (T 120 mg BID) will be investigated; in absence of DLTs, dose escalation will continue at dose level +1 (T 360 mg BID). The MTD is defined as the highest dose level at which no more than 1 of 6 pts experiences a DLT during the first cycle. If the frequency of DLTs encountered at dose-level +1 will not fulfil the MTD definition it will be accepted as the recommended dose for phase II trials. Additional pts (in order to reach 13 pts with MPM and 18 with NSCLC) will be enrolled at the MTD in an expansion cohort, to evaluate the preliminary anti-tumor activity in terms of 3-month PFS% for MPM pts and 5-month PFS% for NSCLC pts. Enrollment has begun in October 2013. The first dose level has been completed without DLTs and the first pt at dose level + 1 started treatment in January 2014. Clinical trial information: NCT02049060.