A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC).

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]