Shukui Qin¹, Ho yeong Lim², Baek-yeol Ryoo³, Cindy Li⁴, Huiling Xiong⁴, Christian Ihling⁵, Ann-lii Cheng⁶

¹Medical Oncology Department, Nanjing Bayi Hospital, Nanjing, China, ²Department of Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, ³Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea, ⁴Merck Serono Pharmaceutical R&D Co., Ltd., Beijing, China, ⁵Merck KGaA, Darmstadt, Germany, ⁶Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

Objective:The overall prognosis of advanced hepatocellular cancer (HCC) remains poor, with c-Met abnormalities associated with a particularly poor prognosis. The highly selective c-Met inhibitor tepotinib (MSC2156119J) demonstrated promising antitumor activity in a phase I trial. The results of the phase Ib part of a phase Ib/II trial of tepotinib as first-line therapy for Asian patients (pts) with advanced HCC (NCT01988493) are reported. Method: Adults with confirmed, advanced HCC of BCLC Stage C, Child-Pugh Class A liver function without encephalopathy, and ECOG status 0–2 were eligible for this open-label, single-arm, 3+3 dose-escalation study (tepotinib 300 or 500 mg p.o./day; 21-day cycle). Twelve pts were planned to be enrolled at the RP2D (total enrolment of up to 18 pts). c-Met status was determined at study entry, although Met+ status (c-Met protein overexpression of 2+/3+ on immunohistochemistry) was not required for eligibility for the phase Ib trial. Result: 20 pts were enrolled (median age, 57 [38-69] years; ECOG PS 0/1, 9/11; prior sorafenib, 19); 6 received tepotinib 300 mg/day and 14 received tepotinib 500 mg/day. At data cut-off, 16 patients had discontinued therapy, 14 due to disease progression. No dose-limiting toxicities were observed with either dose of tepotinib. 15 pts had tepotinib-related adverse events. The majority were grade 1/2 in severity; nine grade 3/4 events were observed, with three instances of grade 3 increased lipase levels. 6 of 15 pts with c-Met-negative disease had a best overall response (BOR) of stable disease (SD); BOR in the other 9 pts was progressive disease (PD). Of 3 pts with c-Met-positive disease, 1 had a partial response (PR), 1 SD, and 1 PD; all were treated with tepotinib 500 mg/day. BOR in the other 2 pts was PD (c-Met status indeterminate) and SD (c-Met status missing). Conclusion:Phase Ib data show that tepotinib at a dose up to 500 mg/day is well tolerated by Asian pts with advanced HCC. A PR was observed in a pt with a c-Met-positive tumor. Enrolment to the phase II part of the trial, in which pts with c-Met-positive tumors will be randomized to receive tepotinib 500 mg/day or sorafenib 400 mg twice-daily, is ongoing.

Key Words: hepatocellular cancer