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.

Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities

“…Co-targeting the PD-(L)1 and VEGF signaling axes is the most extensively studied combination approach for advanced HCC (188,189). Results from single-arm studies showed that combinations of VEGF and PD-(L)1 inhibitors were associated with a manageable safety profile and promising antitumor activity, with ORRs of 11% to 50% (190)(191)(192)(193)(194)(195).…”

Lenvatinib for Hepatocellular Carcinoma: A Literature Review

“…Accordingly, immune checkpoint inhibitors will gain an important position in the treatment of HCC. A phase 1b study of lenvatinib plus pembrolizumab showed an ORR of 46%, as assessed by mRECIST and 36%, as assessed by RECIST ver.1.1 [109]. The median PFS, as assessed by mRECIST and RECIST ver.1.1, was 9.3 months (95% CI 5.6-9.7) and 8.6 months (95% CI 7.1-9.7), respectively, while the median OS was 22.0 (20.4-not estimable) months [109].…”

“…A phase 1b study of lenvatinib plus pembrolizumab showed an ORR of 46%, as assessed by mRECIST and 36%, as assessed by RECIST ver.1.1 [109]. The median PFS, as assessed by mRECIST and RECIST ver.1.1, was 9.3 months (95% CI 5.6-9.7) and 8.6 months (95% CI 7.1-9.7), respectively, while the median OS was 22.0 (20.4-not estimable) months [109]. These results of the phase 1b study of lenvatinib plus pembrolizumab demonstrated promising antitumor effects in advanced HCC.…”

Diffusion-Weighted Magnetic Resonance Imaging in Hepatocellular Carcinoma as a Predictor of a Response to Cisplatin-Based Hepatic Arterial Infusion Chemotherapy

“…To overcome this heterogeneity, studies have investigated the synergic benefits of combination therapy for advanced HCC (40). Lenvatinib combined with pembrolizumab or bevacizumab with atezolizumab demonstrated unprecedented objective response rates (41,42). These reports suggest that the resistance to immune checkpoint inhibitors can be overcome by the combination of drugs with different mechanisms of action.…”