A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC).
Andrew X. Zhu, Richard S. Finn, Masafumi Ikeda, Max W. Sung, Ari David Baron, Masatoshi Kudo, Takuji Okusaka, Masahiro Kobayashi, Hiromitsu Kumada, Shuichi Kaneko, Marc Pracht, K. G Mamontov, Tim Meyer, Kalgi Mody, Tomoki Kubota, Corina E. Dutcus, Kenichi Saito, Abby B. Siegel, Leonid Dubrovsky, Josep M. Llovet
Abstract
4519 Background: LEN is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT, approved for first line (1L) treatment of uHCC. PEMBRO, an anti-PD-1 monoclonal antibody, was granted accelerated approval for the treatment of patients (pts) with HCC after sorafenib therapy. We assessed the safety and efficacy of LEN + PEMBRO in uHCC. Methods: In this phase 1b trial (NCT03006926), pts received LEN 12 mg/day (bodyweight [BW] ≥60 kg) or 8 mg/day (BW <60 kg) orally + PEMBRO 200 mg IV on Day 1 of a 21-day cycle. Primary endpoints were safety and tolerability for Part 1 and objective response rate (ORR) and duration of response (DOR) by mRECIST and RECIST v1.1 per independent imaging review (IIR) in the 1L setting for Part 2. Results: 104 pts (part 1, n=6; part 2, n=98) were enrolled. No DLTs were reported in Part 1; 100 pts were included in the 1L analysis of LEN + PEMBRO–4 pts (part 1) excluded due to prior sorafenib. At data cutoff (October 31, 2019) and median follow-up of 10.6 months, 37 pts continued treatment (LEN only, n=3; both drugs, n=34); median duration of treatment was 7.9 months (LEN, 7.6 months; PEMBRO, 7.4 months). Median OS was 22.0 months (95% CI 20.4–not estimable [NE]), median PFS was 8.6 months (95% CI 7.1–9.7), and ORR was 36% (95% CI 26.6–46.2) (RECIST v1.1 per IIR). Additional efficacy outcomes are shown in the table. Treatment-emergent adverse events (TEAEs) occurred in 99% of pts (grade ≥3, 85%; grade ≥4, 23%). The most common grade ≥3 TEAE was hypertension (18% of pts). Treatment-related AEs (TRAEs) occurred in 95% of pts (grade ≥3, 67%; grade ≥4, 4%). The most common grade ≥3 TRAE was hypertension (17% of pts). 36% of pts had serious TRAEs and 3 pts died from a TRAE (acute respiratory failure/acute respiratory distress syndrome, n=1; intestinal perforation, n=1; abnormal hepatic function, n=1). Conclusions: LEN + PEMBRO has promising antitumor activity with a tolerable safety profile. An ongoing phase 3 trial (NCT03713593) is assessing LEN + PEMBRO vs LEN alone as 1L therapy for uHCC. Clinical trial information: NCT03006926 . [Table: see text]