Tivantinib (T) is a selective non-ATP competitive oral inhibitor of MET receptor that blocks Malignant Pleural Mesothelioma (MPM) and Non Small Cell Lung Cancer (NSCLC) cell growth and migration. Zucali and coworkers1 postulated that adding T to standard first-line chemotherapy may improve efficacy. In this phase I study, 12 chemo-naïve patients with advanced MPM or non-squamous NSCLC received escalating doses of T combined with carboplatin (C) and pemetrexed (P) as first-line treatment. After 6 cycles of CP, T was continued as maintenance therapy until progression. The primary endpoint of the study was to assess the maximum tolerated dose (MTD) of T, 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. A separate phase Ib trial is ongoing to evaluate the anti-tumor activity and pharmacokinetics of the TCP combination. The MTD was reached at dose level 0 (T 240 mg BID). DLTs (2 neutropenia Grade 4 and 1 thrombocytopenia Grade 4) were observed, both at dose level 1 (T 360 mg BID). The most common all-grade toxicities were nausea/vomiting, anemia, neutropenia, and asthenia. Grade 3/4 treatment-related adverse events were reported in 6 patients and all were hematological (neutropenia, thrombocytopenia, anemia). Among 6 evaluable patients with NSCLC, 1 had a Complete Response, 3 had Partial Responses, and 2 had Stable Disease as their best response. The authors concluded that adding T to CP is safe with preliminary evidence of antitumor activity. T 240 mg BID in combination with C and P represents the recommended dose for phase II trials, which are ongoing.
