A phase II study of the efficacy and safety of the MET inhibitor capmatinib (INC280) in patients with advanced hepatocellular carcinoma

Abstract

Background: The objectives of this phase II study were to determine the clinical activity of the MET tyrosine kinase inhibitor capmatinib (INC280) in patients with MET-dysregulated advanced hepatocellular carcinoma (HCC) and to assess the safety, pharmacokinetics, and correlation of biomarkers with the response.

Methods: This phase II, open-label, single-arm study evaluated twice daily (BID) oral capmatinib in a dose-determining stage, utilizing a Bayesian Logistic Regression Model (BLRM) subject to Escalation with Overdose Control criteria, safety, pharmacokinetics, and pharmacodynamic information to determine a recommended dose for expansion (RDE) evaluating efficacy in patients with MET-dysregulated HCC.

Results: A total of 38 patients received treatment. In the dose-determining stage, patients received capmatinib 300 mg BID capsules (n = 8), and in the expansion, patients received 600 mg BID capsules (n = 28) or 400 mg BID tablets (n = 2) based on the BLRM and other relevant clinical data. No predefined qualifying adverse events (AEs) were observed during the first 28 days of treatment, and the RDE was 600 mg BID capsules (equivalent pharmacokinetics to 400 mg BID tablets). The most common any causality AEs were nausea (42%), vomiting (37%), and diarrhea (34%). In the expansion stage, in a subgroup of 10 patients with MET-high HCC, the overall response rate was 30%, including 1 durable complete response (>600 days) and 2 partial responses [1 durable (>600 days)].

Conclusions: Single agent capmatinib at the RDE is tolerable with a manageable safety profile. Antitumor activity was seen in a subset of patients with MET-dysregulated (MET-high) HCC.

Trial registration: ClinicalTrials.gov: NCT01737827. https://ichgcp.net/clinical-trials-registry/NCT01737827.

Keywords: HCC; INC280; MET inhibitor; capmatinib; phase II.

Conflict of interest statement

Conflict of interest statement: Su Pin Choo received funding, nonfinancial support, and honoraria from BMS, nonfinancial support and honoraria from Bayer, and honoraria from Novartis, Shire, Sirtex, Eisai, and Celgene. Virote Sriuranpong has received research support from Novartis. Shukui Qin, Stephen Lam Chan, Wattana Sukeepaisarnjaroen, Guohong Han, Hongming Pan, Thomas Yau, Yabing Guo, Minshan Chen, Zhenggang Ren, Jianming Xu, Chia-Jui Yen, Zhong-Zhe Lin, and Tawesak Tanwandee have no competing financial interests. Yi Gu, Yongjian Sun, Lu Hao, and Wenjie Song are employees of Novartis. Luigi Manenti and Ralph Tiedt are employees of Novartis and hold stock with Novartis.

© The Author(s), 2019.

Figures

Figure 1.

Duration of exposure and overall response (per RECIST v1.1; investigator assessed), dose-expansion stage (full analysis set). > Represents the ongoing patient. RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 2.

Best percentage change from baseline in target lesions (RECIST v1.1; investigator assessed), dose-expansion stage (full analysis set). n, number of patients with a baseline and at least one post-baseline assessment of target lesions (investigator assessed);N, the total number of patients. Percentage changes from baseline >100% are set to 100%. Patients with missing best percentage change from baseline are not included. FISH GCN is provided on top of the bars. FISH, fluorescence in situ hybridization; GCN, gene copy number; NA, not available; RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 3.

Best percentage change from baseline in tumor lesions by baseline serum HGF level. CR, complete response; HGF, hepatocyte growth factor; PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown.