In a phase Ib trial reported in the Journal of Clinical Oncology, Richard S. Finn, MD, and colleagues found that the combination of lenvatinib and pembrolizumab produced durable responses in patients with unresectable hepatocellular carcinoma who had received no prior systemic chemotherapy.

As stated by the investigators, “The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with PD-1 signaling inhibitors in hepatocellular carcinoma.”

Richard S. Finn, MD

Study Details

The international study included six patients in a dose-limiting toxicity phase and 100 in a dose-expansion phase (primary analysis set) who were enrolled between February 2017 and April 2019. Patients received daily lenvatinib at 12 mg for individuals weighing ≥ 60 kg or 8 mg for individuals weighing less, and pembrolizumab at 200 mg on day 1 of 21-day cycles.

Responses

No dose-limiting toxicities were reported. The median duration of follow-up was 10.6 months. In the expansion phase, objective response on independent imaging review was observed in 46 patients (46.0%) on modified Response Evaluation Criteria in Solid Tumors (mRECIST; including complete response in 11 patients) and in 36 patients (36.0%) on RECIST version 1.1 criteria (including complete response in 1 patient). Median durations of response were 8.6 months (95% confidence interval [CI] = 6.9 months­–not estimable; 83% of responses ≥ 6 months) on mRECIST and 12.6 months (95% CI = 6.9 months­–not estimable; 73% of responses ≥ 6 months) on RECIST version 1.1.

An additional 42% and 52% of patients had stable disease. Disease control rates were 88% in both analyses.

Median progression-free survival was 9.3 months (95% CI = 5.6–9.7 months) on modified RECIST and 8.6 months (95% CI = 7.1–9.7 months) on RECIST version 1.1. Median overall survival was 22 months (95% CI = 20.4 months–not estimable).

Adverse Events

The most common treatment-related adverse events of any grade were hypertension (in 36% of patients), diarrhea (35%), fatigue (30%), decreased appetite (28%), and hypothyroidism (25%). Grade ≥ 3 treatment-related adverse events occurred in 67% of patients, with the most common being hypertension (17%; all grade 3) and increased aspartate transaminase (11%; all grade 3).

Treatment-related serious adverse events were reported in 36% of patients. Adverse events led to death in 13 patients (13%). Three deaths were considered related to treatment, with causes consisting of acute respiratory failure/acute respiratory distress syndrome, abnormal hepatic function, and intestinal perforation in one patient each.

The investigators concluded, “Lenvatinib plus pembrolizumab has promising antitumor activity in unresectable hepatocellular carcinoma. Toxicities were manageable, with no unexpected safety signals.”

Josep M. Llovet, MD, of Icahn School of Medicine at Mount Sinai, is the corresponding author for the Journal of Clinical Oncology article. 

Disclosure: The study was supported by Eisai and Merck Sharp & Dohme, a subsidiary of Merck & Co. For full disclosures of the study authors, visit ascopubs.org.