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Author(s) -
Borbath, Ivan,
The Liver meeting
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26033
Subject(s) - citation , world wide web , medicine , computer science , library science
Background: Tivantinib (T), a selective, oral inhibitor of MET, the hepatocyte growth factor (HGF) receptor, was successfully tested in HCC patients (pts) in Phase 1 studies as monotherapy and with sorafenib. Methods: Multi center RCT; key selection criteria: unresectable HCC, 1 prior systemic therapy, PS <2; no Child-Pugh B-C. Randomization: 2:1 to T or placebo (P); dose: 360 mg bid (TA; after 57 patients were treated, dose was reduced to 240 mg bid (TB) in all patients due to G≥3 neutropenia rate); stratification: PS, vascular invasion (VI). Tumor evaluation: by CT / MRI every 6 weeks; central radiology review by RECIST 1.1. Crossover to open label T was allowed after PD. Endpoints included: time to tumor progression (TTP) in the intent-to-treat (ITT) population; disease control rate (DCR), progression free survival (PFS), overall survival (OS), efficacy in MET Diagnostic High (MET >2+ in >50% of tumor cells by immunohistochemistry) patients, safety. Results: 107 enrolled patients, 71 on T (TA: 38, TB: 33), 36 on P. Pt characteristics were generally well balanced, also when grouped by MET status. In ITT, median TTP was: 1.6 vs 1.4 mos (HR 0.64, 90%CI 0.43-0.94; P=0.04). Most promising results were obtained in the MET High group, TTP: 2.7 vs 1.4 mos (HR 0.43, 95%CI 0.19-0.97; P=0.03), DCR (95%CI): 50% (28–72%) vs 20% (4–48%), OS 7.2 vs 3.8 mos (HR 0.38, 95%CI 0.18-0.81, P=0.01). Prognostic role of several factors was evaluated in the P group: MET High patients had a 60% higher risk of progression and a 195% higher risk of death; high HGF (cutoff: median value of 2307 pg/mL) patients showed a similar trend in terms of TTP and OS. In MET High patients on T, the most common AEs were fatigue (7, 31.7%) and asthenia (6, 27.3%). Blood levels (PK) of T were higher than in non HCC studies. No relation between MET and HBV/HCV, HGF or PK was observed. Strict dose reduction guidelines and the TB starting dose dramatically reduced the G≥3 neutropenia rate without changing efficacy. Conclusions: This study showed MET positivity is an independent, strong, negative prognostic factor in pretreated HCC patients. MET High patients on tivantinib achieved a 163% survival improvement compared to placebo. Biopsy is key to establish the MET status. Larger studies with tivantinib are being planned in MET High HCC patients