Background

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults.1 Its incidence is rising alongside increasing rates of chronic liver disease. For many years, the only approved targeted systemic therapy for advanced HCC was the non-selective multikinase inhibitor sorafenib.2,3 This agent provides only a modest improvement in overall survival (OS) and may not be as well tolerated by Asian patients compared with those of other ethnicities.4,5 Newer first-line treatment options include the multikinase inhibitor lenvatinib and the immunotherapy atezolizumab (in combination bevacizumab), which have been approved following positive data from randomised Phase 3 trials versus sorafenib.3,6,7,8

MET is the tyrosine kinase receptor for hepatocyte growth factor (HGF).9 Approximately 50% of patients with HCC may harbour MET alterations,9 and 28% of patients with advanced HCC show evidence of MET overexpression.10 These patients may derive therapeutic benefit from selective MET inhibition.9,11 In vitro, MET inhibitors can reduce the growth of MET-positive HCC cell line-derived xenograft models.11

Tepotinib is an orally available, potent and highly selective MET inhibitor that has shown pronounced antitumour activity in MET-dependent preclinical mouse models in vivo.12,14,15 Furthermore, in combination with gefitinib, tepotinib has demonstrated improved efficacy compared with chemotherapy in patients with advanced epidermal growth factor receptor-mutant non-small cell lung cancer and MET-driven resistance to epidermal growth factor receptor (EGFR) inhibitors16 and a Phase 2 study of tepotinib plus osimertinib in patients with acquired resistance to first-line osimertinib due to MET amplification is ongoing (INSIGHT 2, NCT03940703). A Phase 2 study is also underway investigating tepotinib in combination with cetuximab in patients with RAS/BRAF wild-type left-sided metastatic colorectal cancer and acquired resistance to anti-EGFR antibody-targeted therapy due to MET amplification (NCT04515394).

Following preclinical data demonstrating activity of tepotinib against primary liver cancer explants with MET overexpression,12 two Phase 1b/2 studies were designed to investigate tepotinib in patients with HCC with MET overexpression. In the first of these (NCT02115373), tepotinib demonstrated clinical activity and was generally well tolerated in US/European patients in whom prior sorafenib treatment had failed.17 Here, we present the second trial in HCC, which was conducted in Asian patients (NCT01988493). Since patients with hepatic impairment were excluded from the first-in-human trial,15,17,19 and no unexpected AEs were reported. Patients treated with tepotinib reported fewer overall and Grade ≥3 treatment-related AEs compared with sorafenib.

With the 500 mg dose in the Phase 1b study, tepotinib AUCτ was 61% and Cmax was 63% of that observed in the first-in-human trial.13 This is expected given findings from a population pharmacokinetic analysis showing a reduction in tepotinib exposure in patients with cirrhosis, as well as from a dedicated pharmacokinetic hepatic impairment trial.32 In the latter study, patients with moderate hepatic impairment (Child–Pugh B) had 12% lower AUC from time 0 to infinity and 29% lower Cmax compared with control subjects without hepatic impairment. Lower exposure relative to the first-in-human trial was also observed in the Phase 1b/2 study in sorafenib pre-treated advanced HCC with MET overexpression.33

The selection of sorafenib, as the control treatment, for the present study reflects the standard of care for first-line treatment at the time of study conception. Since then, both the multikinase inhibitor lenvatinib and the combination of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) plus bevacizumab (anti-vascular endothelial growth factor [VEGF]) have been approved in the first-line setting.6,7 After sorafenib failure, approved options include the anti-VEGF receptor-2 agent ramucirumab (for patients with elevated serum alpha-fetoprotein), the multikinase inhibitors regorafenib and cabozantinib and the immune checkpoint inhibitors pembrolizumab and nivolumab (± ipilimumab).21,30,34,35,36,37,38 While durable responses to nivolumab were observed in both sorafenib-naive and sorafenib pre-treated patients in the Phase 1/2 CheckMate 040 study,37,39 first-line nivolumab did not show an OS benefit compared with sorafenib in the Phase 3 CheckMate 459 trial.40 Other immunotherapy-containing strategies currently undergoing Phase 3 evaluation in previously untreated disease include durvalumab (anti-PD-L1), alone or in combination with a second immunotherapy (tremelimumab, anti-cytotoxic T-lymphocyte-associated protein-4; NCT03298451), lenvatinib plus pembrolizumab (LEAP-002; NCT03713593) and cabozantinib plus atezolizumab (COSMIC-312;41 NCT03755791). Given the favourable safety profile of tepotinib and the immunosuppressive function of MET signalling,42 use of tepotinib in combination with immunotherapies could be an interesting area for future study.

Strengths of the current study include the randomised design, which permitted evaluation of tepotinib efficacy relative to an established standard of care in this setting. Limitations include the non-blinded treatment assignment and the low proportions of patients with MET amplification or MET IHC 3+ status, which limited explorations of the impact of MET-based biomarkers on efficacy. The study was also underpowered following early termination of enrolment due to slow accrual, but nonetheless demonstrated significant improvements in activity endpoints with tepotinib versus sorafenib. As has been discussed for other studies in HCC with biomarker-driven patient selection,23,24 one challenge in this setting is the potential for patients with the most aggressive forms of disease to be excluded, due to rapid progression and/or clinical deterioration, while central biomarker assessments are ongoing, which could have contributed to ineligibility at screening. Finally, it is not known to what extent these results obtained in Asian patients, who were predominantly male with BCLC stage B, can be generalised to other populations.

In the Phase 1b part of this study, no DLTs were reported and the RP2D was established as 500 mg QD. Evidence of antitumour activity was seen at the 500 mg and 1,000 mg dose levels. In Phase 2, first-line tepotinib (500 mg QD) demonstrated clinical activity in Asian patients with advanced HCC with MET overexpression (IHC 2+/3+), with a significant improvement versus sorafenib in the primary endpoint of TTP, as well as PFS and ORR. Tepotinib was generally well tolerated and no new safety signals were observed.