Phase I trial of the MET inhibitor tepotinib in Japanese patients with solid tumors

Abstract

Objectives Tepotinib (MSC2156119J) is an oral, potent and highly selective small molecule mesenchymal-epithelial transition factor (MET) inhibitor for which the recommended Phase II dose of 500 mg once daily has been defined, based on the first-in-man trial conducted in the USA and Europe. We carried out a multicenter Phase I trial with a classic `3 + 3' design to determine the recommended Phase II dose in Japanese patients with solid tumors (NCT01832506). Methods Patients aged ≥20 years with advanced solid tumors (refractory to standard therapy or for whom no effective standard therapy was available) received tepotinib at 215, 300 or 500 mg once daily in a 21-day cycle. Occurrence of dose-limiting toxicities during cycle 1 was used to determine the maximum tolerated dose. Efficacy, safety and pharmacokinetics were also evaluated to support the dose assessment. Results Twelve patients were treated. Tepotinib was generally well tolerated with no observed dose-limiting toxicities; treatment-related adverse events were mainly grades 1–2. The tolerability profile of tepotinib was similar to that observed in non-Japanese populations. Pharmacokinetics in Japanese and Western patients was comparable. One patient with gastric cancer and one patient with urachal cancer had stable disease of ≥12 weeks in duration. The observed safety profile and pharmacokinetics are comparable with those in patients from the USA and Europe, and the recommended Phase II dose of tepotinib in Japanese patients was confirmed as 500 mg once daily. Conclusions These results, including initial signals of antitumor activity, support further development of tepotinib in Japanese patients with cancer.

Activity and bioavailability of tepotinib for leptomeningeal metastasis of NSCLC with MET exon 14 skipping mutation

“…In our case, tepotinib concentration in CSF was 30.6 ng/mL, which was enough to exceed the IC50. Moreover, Shitara and colleagues [10] conducted a phase I trial on Japanese patients, and observed an average steady‐state concentration of tepotinib in the plasma, ranging from 760.3 ng/mL to 1126.8 ng/mL. Thus, the concentration of tepotinib in the CSF exceeded the IC50.…”

Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression

“…This dosing level is consistent with studies of tepotinib in other tumour types, and in Asian patients with HCC with MET overexpression. 24,28,30 Preliminary anti-tumour activity was observed in Phase 1b with tepotinib: two patients achieved PR and four patients achieved SD. Following results from Phase 1b, Phase 2 investigated the efficacy and safety of tepotinib dosed at 500 mg QD in patients with HCC tumours with MET overexpression who had previously been treated with sorafenib.…”

“…The safety profile observed in Phase 2 was consistent with Phase 1b and with other studies of tepotinib. 24,25,28,30 Treatment-related AEs were reported in 83.7% of patients overall and at Grade ≥3 in 28.6%. The most common Grade ≥3 treatment-related AEs were peripheral oedema and increased lipase, which are both known safety signals with tepotinib.…”

Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly selective oral MET inhibitor tepotinib in healthy volunteers

“…In this study, a single 500 mg dose of tepotinib was well tolerated by healthy volunteers; although 75% experienced TEAEs, most were mild and resolved rapidly. Tepotinib has also been found to be well tolerated in phase I/Ib and phase II clinical trials in patients with solid tumors, which have further characterized its side-effect profile [9,17,18,21,35,36]. Ongoing phase II trials in NSCLC and hepatocellular carcinoma will add further insight into the side-effect profile and efficacy of tepotinib [16-18, 20-22, 35].…”