Background: Tivantinib is a selective MET inhibitor that is extensively metabolized in the liver. In a randomized, placebo-controlled phase 2 study in patients with advanced HCC, tivantinib monotherapy improved time to progression by 56%. However, in that study at the standard phase 2 dose of 360 mg twice-daily (BID), tivantinib exposure was increased, and the absolute incidence of severe neutropenia increased approximately 6% compared to patients with solid tumors from previous studies. An exposure-response analysis was conducted to explore the relationship between neutropenia and tivantinib pharmacokinetics (PK).
Methods: Tivantinib plasma concentration and incidence of grade ≥ 2 neutropenia were pooled from phase 1/1b and phase 2 studies. A population PK model (NONMEM v.7.1.0) was used to predict tivantinib exposure in HCC. The relationship between tivantinib exposure and neutropenia was evaluated by logistic regression analysis (S-plus v8.0).
Results: Data were available from 289 cancer patients, including 73 patients with HCC and mild-to-moderate hepatic impairment. Cases of grade ≥ 3 (n = 28) and grade ≥ 2 (n = 40) neutropenia were included in the analysis. Based on the population PK analysis tivantinib clearance was reduced approximately 67% in HCC patients, resulting in an approximately 3-fold higher exposure compared to other cancer patients. There was a significant (P <0.001) relationship between tivantinib exposure and incidence of grade ≥2/3 neutropenia. By reducing the tivantinib starting dose from 360 to 240 mg twice-daily, the incidence of grade ≥ 3 neutropenia was modeled to decreased from 28% to 16% in HCC patients. Further reduction in the risk of neutropenia (~6%) was achieved with intensive clinical monitoring and an aggressive dose-reduction schema.
Conclusions: Based on the current analysis, the increased incidence of neutropenia in HCC patients compared to patients with other solid tumors resulted from increased tivantinib exposure due to hepatic impairment. Consistent with the model, the risk of neutropenia was successfully managed in HCC patients by implementing dose reduction and tighter clinical monitoring without compromising efficacy.
(Presented at ESMO meeting 2012)