RESUMO
In the last decades the management of hepatocellular carcinoma (HCC) has undergone significant changes following the introduction of novel therapies such as sorafenib, which have improved patient survival. Nevertheless, HCC is still the third most common cause of cancer-related death worldwide. The evidence-based therapy for advanced HCC that is unsuitable for locoregional treatment is limited to sorafenib, with no second-line option available. This article focuses on the development of the MET inhibitor tivantinib in HCC as a promising treatment option for patients who failed sorafenib. A randomized, placebo-controlled phase II study showed activity of tivantinib in patients with high MET expression. Based on these results, the METIV-HCC phase III study in second-line treatment for MET-high patients was initiated to demonstrate the survival advantage of tivantinib compared to placebo.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirrolidinonas/uso terapêutico , Quinolinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Itália/epidemiologia , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Pirrolidinonas/farmacologia , Quinolinas/farmacologia , Sorafenibe , Falha de Tratamento , Resultado do TratamentoRESUMO
PURPOSE: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors. MATERIALS AND METHODS: A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed. RESULTS: Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD ≥8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients. CONCLUSIONS: The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors.