Background: Tivantinib (T) is a selective non-ATP competitive oral inhibitor of MET receptor. Preclinical data showed that MET inhibition blocks Malignant Pleural Mesothelioma (MPM) and Non Small Cell Lung Cancer (NSCLC) cell growth and migration. Adding T to standard first-line chemotherapy may improve efficacy. Methods: Patients (pts) with advanced MPM or non-squamous NSCLC were eligible to receive escalating doses of T combined with carboplatin (C) AUC 5 i.v. d1-q21 and pemetrexed (P) 500 mg/m2 i.v. d1-q21 as first-line treatment. After 6 cycles of CP, T is continued as maintenance therapy until progression. Pts must be chemo-naïve with ECOG Performance Status (PS) < 2 and adequate bone marrow, liver, and kidney functions. A standard 3+3 dose-escalation design was employed starting from dose level 0 (T 240 mg BID). The primary endpoint of the phase I study was to assess the maximum tolerated dose (MTD), defined as the highest dose level at which no more than 1 of 6 pts experiences a dose limiting toxicity (DLT) during the first cycle. To evaluate the anti-tumor activity (MPM pts: 3-month PFS%; NSCLC pts: 5-month PFS%) and the pharmacokinetics of the combination, a phase Ib trial is still ongoing. Results: From April 2013 to September 2014, 12 pts were enrolled in the phase I study; mean age was 69 years (range, 37-73 years), M/F: 9/3, ECOG PS 0/1: 5/7, MPM/NSCLC: 6/6. The MTD was reached at dose level 0 (T 240 mg BID). DLTs (2 neutropenia G4, 1 thrombocytopenia G4) were observed in 2 pts, both at dose level 1 (T 360 mg BID). The most common all-grade toxicities were nausea/vomit (67%), anemia (58%), neutropenia (50%), and asthenia (50%). G3/4 treatment-related AEs were reported in 6 pts (50%) and all were hematological (neutropenia, thrombocytopenia, anemia). All pts received 6 cycles of CT. Among 12 evaluable pts, 1 had CR, 4 PR, and 7 SD as best response. Conclusions: Adding T to CP is safe with preliminary evidence of antitumor activity. T 240 mg BID in combination with C AUC 5 i.v. d1-q21 and P 500 mg/m2 i.v. d1-q21 represents the recommended dose for phase II trials. Clinical trial information: NCT02049060