Lenvatinib/Pembrolizumab Combo Shows Early Promising Activity in Unresectable HCC

The combination of the VEGFR/FGFR inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab induced a confirmed overall response rate of 26.9% (95% CI, 11.6%-47.8%) in patients with unresectable hepatocellular carcinoma, according to results from a 2-part, phase Ib trial.

The combination of the VEGFR/FGFR inhibitor lenvatinib (Lenvima) and the PD-1 inhibitor pembrolizumab (Keytruda) induced a confirmed overall response rate (ORR) of 26.9% (95% CI, 11.6%-47.8%) in patients with unresectable hepatocellular carcinoma (uHCC), according to results from a 2-part, phase Ib trial.1

The ORR was 42.3% (95% CI, 23.4%-63.1%) when investigators included unconfirmed responses, in findings presented in a poster at the 2018 ASCO Annual Meeting.

“Most of the patients obtained extremely favorable tumor shrinkage effect and durable responses,” lead investigator Masafumi Ikeda, MD, chief of the Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, in Chiba, Japan, said in an email toTargeted Oncology. “Although the ORR was not so surprising, the results were preliminary and the follow-up periods were only 3.6 months. In the final analysis, more favorable response rates will be presented.”

Thirty patients, 6 in part 1 and 24 in part 2, were enrolled in the open-label, multicenter study as of March 22, 2018. Patients in part 1 were ineligible for other therapies and patients in the expansion cohort were naïve to systemic therapy.

Eligible patients had BCLC stage B or C disease or Child-Pugh class A disease, ECOG performance status of 0 to 1, and ≥1 measurable target lesion according to mRECIST criteria. Patients <60 kg (26.7%) received 8 mg of oral lenvatinib once daily and those ≥60 kg (73.3%) received 12 mg. All patients received 200 mg of pembrolizumab once every 3 weeks.

The overall median age was 69 years (range, 48-86), men made up 83.3% of the patient population, and a majority of the patients (76.7%) were also Asian. Eight patients (26.7%) had hepatitis B virus and 11 (36.7%) had hepatitis C virus. Four patients (66.7%) in part 1 had received prior sorafenib (Nexavar).

There were no dose-limiting toxicities reported in part 1 and all patients remained on study. Results from all 30 patients were included in the safety analysis. The efficacy analysis included 26 patients.

“The protocol was amended and the part 2 cohort was expanded to 94 patients to evaluate the efficacy and safety of this combo,” Ikeda said. “A large-scale, randomizedphase III trial is warranted.

Twenty-three patients remain on treatment in the study as of the data cutoff. Four patients discontinued due to adverse events (AEs), and 3 discontinued due to radiological disease progression.

The median time to response was 1.41 months (95% CI, 1.35-2.83). Overall, 1 patient (3.8%) had a complete response and 10 (38.5%) had partial responses across both parts of the study. Fifteen (57.7%) achieved stable disease. No patients experienced progression.

“All patients except 3 patients had tumor reduction,” said Ikeda. “Even in 3 patients who had progression the best tumor response was stable disease.”

The median duration of treatment at the data cutoff was 9.8 months (range, 8-12) for lenvatinib and 10.0 months (range, 8-12) for pembrolizumab in part 1. In part 2, the median duration of treatment was 3.0 months (range, 1-7) and 2.8 months (range, 1-8), respectively. Median follow-up was 11.1 months in part 1 and 3.6 months in part 2.

Investigators added that the responses appeared to be durable.

The median duration of progression-free survival was 9.69 months (95% CI, 5.55-not evaluable).

There were 3 deaths on the study, including 2 (acute respiratory distress syndrome and intestinal perforation) deemed to be related to treatment. The third patient died of bacterial peritonitis. An additional 5 patients had serious AEs.

Sixty percent of patients had a dose interruption or reduction of lenvatinib and/or pembrolizumab due to treatment-emergent AEs.

Decreased appetite and hypertension (53.3% each) were the most common any-grade treatment-emergent AEs, followed by diarrhea (43.3%) and fatigue (40%). The most common (≥10%) grade ≥3 AEs were hypertension (16.7%), aspartate aminotransferase increase (16.7%), decreased white blood cell count (13.3%), and hyponatremia (10.0%).

Ikeda said that investigators observed no cardiotoxicity.

In January, the FDA granted a breakthrough therapy designation to the lenvatinib/pembrolizumab combination for the treatment of patients with advanced and/or metastatic renal cell carcinoma (RCC).

The designation is based on the RCC cohort of the multicenter, open-label phase Ib/II Study 111 (n = 30). Patients treated with the combination had an objective response rate (ORR) of 63.3% (95% CI, 43%-80%). The phase Ib portion of Study 111 enrolled 13 patients with metastatic solid tumors, 8 of whom had RCC that progressed after treatment with approved therapies and who had an ECOG performance status ≤1.2

ORR at 24 weeks was 83% (95% CI, 52%-98%) in treatment-naïve patients and 50% in those who had received previous treatment. All responses were partial responses.

The median duration of response was not yet reached for the total cohort and the treatment-naïve cohort. The median duration of response was 8.5 months in the pretreated cohort. The median progression-free survival had not yet been reached (95% CI, 9.9 months-not evaluable) at the March 1, 2017, data cutoff.


  1. Ikeda M, Sung MW, Kudo M, et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC).J Clin Oncol. 2018;36(suppl; abstr 4076). meetinglibrary.asco.org/record/160119/abstract.
  2. Lee C, Makker V, Rasco D, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma. Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract 847O.