LEAP-002 trial results support use of lenvatinib monotherapy in UCHC, despite lack of co-primary endpoints


Although the combined use of lenvatinib and pembrolizumab did not induce statistically significant differences in the co-primary endpoints, the LEAP-002 trial elicited the longest median overall survival observed with lenvatinib in monotherapy in patients with unresectable HCC.

Results from the Phase 3 LEAP-002 study (NCT03713593) support the use of lenvatinib (Lenvima) as first-line therapy for patients with unresectable hepatocellular carcinoma (uHCC), although the trial is missing its two primary endpoints when evaluating the agent in combination with pembrolizumab (Keytruda), according to a final analysis of the study presented at ESMO Congress 2022.1-2

“Lenvatinib continues to demonstrate its importance as a treatment option for advanced HCC,” said Richard S. Finn, MD, professor of medicine, Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, in a presentation of the data.

After a median follow-up of 17.6 months (range: 11.3-26.6) for overall survival (OS), the median was 21.2 months (95% CI, 19.0-23.6) with lenvatinib plus pembrolizumab compared with 19.0 months (95% CI, 17.2-21.7) with lenvatinib monotherapy. Similarly, OS rates at 24 months were 43.7% versus 40.0%, respectively (HR, 0.840; 95% CI, 0.708-0.997; P = 0.0227). Finn noted, “However, this did not reach the safe threshold of 0.0185.”

Subgroup analysis favored the combined diet as demonstrated in a forest plot; in particular, Finn highlighted those associated with high-risk features such as macrovascular invasion/extrahepatic spread (HR, 0.78; 95% CI, 0.63-0.95) and elevated AFP [alpha-fetoprotein] status (HR, 0.67; 95% CI, 0.50-0.90).

After a median follow-up of 32.1 months (range: 25.8-41.1) for progression-free survival (PFS), the median was 8.2 months (95% CI, 6.3-8.3 ) with the combined treatment, compared to 8.1 months (95% CI, 6.3-8.3) with the monotherapy. PFS rates at 12 months were 34.1% and 29.3%, respectively, and rates at 24 months were 16.7% and 9.3% (HR, 0.834; 95% CI, 0.712- 0.978). These results did not reach statistical significance according to the pre-specified statistical plan.

However, Finn explained, although the trial did not meet its co-primary endpoints, the trial demonstrated trends toward improved OS and PFS among those who received the combination regimen. .

Additionally, he added that the median OS induced by lenvatinib monotherapy in the trial was longer than that seen in previously reported clinical trials evaluating the single agent in CuHC.

“The median OS of 19.0 months with lenvatinib supports its role as the standard of care in advanced frontline HCC,” Finn said.

In the final analysis, the median duration of response (DOR) according to RECIST v1.1 by blinded independent committee (BICR) in the lenvatinib plus pembrolizumab arm was 16.6 months (range, 2.0+ to 33 .6+), versus 10.4 months (range, 1.9-35.1+) with lenvatinib alone. Median DORs according to BICR-modified RECIST v1.1 were 11.2 months (range, 1.4+ to 35.3) and 8.5 months (1.9+ to 35.3+), respectively.

Combination treatment resulted in an overall response rate (ORR) of 26.1% compared to 17.5% with lenvatinib alone, including a complete response rate (CR) of 1.5% in both arms, progressive disease (PD) rates of 12.2% versus 15.0%, respectively, and stable disease (SD) rates of 55.2% and 60.9% according to RECIST v1.1 by BICR. According to modified RECIST v1.1, ORR with lenvatinib plus pembrolizumab was 40.8% compared to 34.1% with lenvatinib alone, including CR rates of 9.4% and 9.5%, respectively, PD rates of 9.4% and 10.3%, respectively, and DS rates of 43.5% and 49.1%, respectively.

The safety profile of the combined treatment was consistent with previously reported data.

Adverse events (AEs) of any grade occurred in 381 patients (96.5%) in the combination arm compared to 378 patients (95.7%) in the monotherapy arm. In total, there were 4 Grade 5 events with lenvatinib plus pembrolizumab, and 3 with lenvatinib alone. The combined regimen led to the discontinuation of all treatment in 71 patients (18%), compared with 42 patients (10.6%) in the monotherapy arm.

The most common AEs in the combination versus monotherapy arms included hypertension (43.3% versus 46.8%, respectively), diarrhea (40.3% versus 33.9%), hypothyroidism (40.0% versus 35.7%), EPI syndrome (33.2% versus 30.6%). , proteinuria (30.6% vs 34.9%), decreased appetite (30.1% vs 23.3%), fatigue (27.3% vs 20.8%), increased aspartate levels aminotransferase (22.0% vs 15.4%), platelet count decreased (21.0% vs 21.0%), weight decreased (20.3% vs 13.4%), blood glucose levels increased alanine transaminase (19.2% vs 14.9%), increased blood bilirubin (19.2% vs 16.7%), dysphonia (19.0% vs 17.2%) and nausea (17.7% against 14.4%).

The most common immune-mediated AE in both groups was hypothyroidism (42.3% versus 39.5%, respectively).

A total of 174 patients in the lenvatinib/pembrolizumab combination arm subsequently received subsequent systemic cancer treatment, compared with 208 patients on lenvatinib alone.

“The treatment landscape has changed significantly for advanced liver cancer over the past few years and as a result there will be an impact of post-progression treatment,” Finn explained. “Both arms then received post-systemic treatment. It was higher in the lenvatinib alone arm, but the majority of patients received either a tyrosine kinase inhibitor or a VEGF-focused agent. If you look at any (given) immunotherapy after progression, 23% of patients in the (monotherapy arm) versus 14% (in the combination arm received immunotherapy after trial treatment), Finn said.

In the global, phase 3, randomized, double-blind study, patients were randomized 1:1 to receive either lenvatinib at a dose of 12 mg orally once daily for patients with screening body weight of at least 60 kg, or a dose of 8 mg orally once daily for patients with a screening body weight of less than 60 kg plus pembrolizumab 200 mg IV on day 1 of each 3-week cycle ( n=395); or the lenvatinib plus placebo regimen administered on Day 1 of each 3-week cycle (n=399). Lenvatinib was given until disease progression or unacceptable toxicity, while pembrolizumab and placebo were given for up to 35 cycles.

“Now there is this evolving preclinical data to suggest that the combination of a multikinase inhibitor such as lenvatinib in combination with IO [immuno-oncology]can be synergistic,” Finn said. “The single-arm Phase 1b study 116/KEYNOTE-524 [NCT03006926]3 evaluated this combination in a front-line setting which demonstrated highly exciting activity, with an objective response rate of approximately 36% according to RECIST v1.1, and a median survival of just over 21 months. With this in mind, LEAP-002 was initiated as a first-line, double-blind, placebo-controlled study.

To be eligible, patients had to have a confirmed diagnosis of HCC, no prior systemic therapy for advanced HCC, were not eligible for curative therapy, had Child-Pugh Class A disease, an ECOG performance status of 0 or 1, had undergone esophagogastroduodenoscopy within 3 months of randomization, and noted, according to Finn, no invasion of the main portal vein.

PFS according to RECIST v1.1 by BICR and OS served as co-primary endpoints. Secondary endpoints included ORR, DOR per RECIST v1.1 and RECIST modified by BICR, and safety/tolerability. Post-treatment follow-up assessed safety, disease status, and survival status.

In the combined arm, the median age was 66.0 years (range, 19-88) and the majority of patients were male (80.3%).

Lenvatinib monotherapy is approved by the FDA for the first-line treatment of patients with CuHCC based on data from the Phase 3 REFLECT trial (NCT01761266), which demonstrated that the receptor tyrosine kinase inhibitor was not inferior to sorafenib (Nexavar) in SG.4

Lenvatinib in combination with pembrolizumab plus transarterial chemoembolization is currently being studied in the Phase 3 LEAP-012 study (NCT04246177), Finn concluded.

Guest commentator R. Kate Kelley, MD, professor of clinical medicine, Department of Medicine (Hematology/Oncology), UCSF, noted that prognosis has improved for patients with advanced first-line HCC. “The advent of multiple front-line and post-treatment options marks tremendous progress in HCC and provides a new opportunity to individualize treatment decisions,” she said.


1. Finn RS, Kudo M, Merle P, et al. Main results of the phase III LEAP-002 study: lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) treatment for advanced hepatocellular carcinoma (HCCCa). Anne Oncol. 2022;33(suppl_7):S808-S869. doi:10.1016/j.announce.2022.08.031.

2. Merck press release. Merck and Eisai provide an update on the Phase 3 LEAP-002 trial evaluating Keytruda (pembrolizumab) plus Lenvima (lenvatinib) versus Lenvima monotherapy in patients with unresectable hepatocellular carcinoma. Posted: August 3, 2022. Accessed: September 10, 2022. https://bit.ly/3d1kx6P

3. Finn RA, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020;38:2960-2970. doi:10.1200/JCO.20.00808.

4. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in the first-line treatment of patients with unresectable hepatocellular carcinoma: a phase 3 randomized non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1.


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