Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma

Abstract

Purpose: The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti-PD-1 antibody) in unresectable HCC (uHCC).

Patients and methods: In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase).

Results: A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified.

Conclusion: Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

Trial registration: ClinicalTrials.gov NCT03006926.

FIG 1.

Kaplan-Meier estimates of (A) progression-free survival (PFS) by modified RECIST per independent imaging review (IIR), (B) PFS by RECIST version 1.1 per IIR, and (C) overall survival (OS; efficacy analysis set). NE, not estimable.

FIG 2.

Percentage change from baseline in sums of diameters of target lesions by (A) modified RECIST (mRECIST) per independent imaging review (IIR), (B) mRECIST per investigator review, and (C) RECIST version 1.1 per IIR. CR, complete response; HCC-1L, hepatocellular carcinoma first line; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease. (a) Unconfirmed PR. (b) Non-CR/non-PD. (c) No. of patients with both baseline and postbaseline sums of diameters of target lesions.

FIG 3.

Percentage change from baseline in sums of diameters of target lesions by (A) modified RECIST per independent imaging review (IIR) and (B) RECIST version 1.1 per IIR. (a) Value (127.8%) beyond y-axis limit is truncated and not displayed.

FIG A1.

Kaplan-Meier estimate of duration of response by (A) modified RECIST and (B) RECIST version 1.1 per independent imaging review. NE, not estimable.

FIG A2.

Duration of treatment and response assessments by (A) modified RECIST and (B) RECIST version 1.1 per independent imaging review. BOR, best overall response; CR, complete response; DLT, dose-limiting toxicity; EXP, expansion; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease. (a) Non-CR/non-PD. (b) Unconfirmed PR.

FIG A3.

Kaplan-Meier estimate of time to progression (TTP) by (A) modified RECIST and (B) RECIST version 1.1 per independent imaging review.