First-Line Lenvatinib plus Pembrolizumab for Hepatocellular Carcinoma: Post hoc Analysis of Japanese Patients from the Phase 3 LEAP-002 Trial

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death in Asia, where risk factors for HCC such as hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are especially common [1]. Historically, up to 70% of HCC cases were attributed to HCV infection in Japan [1, 2]; more recently, the proportion of patients in Japan who present with non-HBV and non-HCV (NBNC) HCC has increased [3‒5]. The approval of direct-acting antiviral medications for patients infected with HCV and their coverage by the Japanese universal health insurance system are expected to further reduce the incidence of HCC in patients with HCV [6].

Standard-of-care treatment for advanced HCC in Japan is typically atezolizumab plus bevacizumab, lenvatinib, or durvalumab plus tremelimumab [7]. Patients who require second- or subsequent-line therapies may receive sorafenib, lenvatinib, atezolizumab plus bevacizumab, or durvalumab plus tremelimumab if they did not receive these agents in the first-line setting or regorafenib, ramucirumab, or cabozantinib [8, 9]. These treatment choices are financially supported by the Japanese universal health insurance system so long as physician recommendations are consistent with product labeling. It has been hypothesized that combining the multikinase inhibition of lenvatinib with the programmed cell death protein 1 inhibition of pembrolizumab may improve antitumor activity compared with either agent as monotherapy [10, 11]. The phase 1b study 116/KEYNOTE-524 trial evaluated lenvatinib plus pembrolizumab in the first-line setting for 100 patients with advanced HCC [12] and demonstrated a confirmed response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by independent investigator review of 36% and a median progression-free survival (PFS) of 8.6 months. The phase 3 LEAP-002 trial evaluated the efficacy and safety of lenvatinib plus pembrolizumab versus lenvatinib plus placebo as first-line therapy for advanced HCC in 794 patients [13]. The median overall survival (OS) was 21.2 months in the lenvatinib plus pembrolizumab group and 19.0 months in the lenvatinib plus placebo group. Median PFS was 8.2 months in the lenvatinib plus pembrolizumab group and 8.0 months in the lenvatinib plus placebo group. The hazard ratio (HR) was 0.84 (95% CI: 0.71–1.00; p = 0.023) for OS and 0.87 (95% CI: 0.73–1.02; p = 0.047) for PFS. Results suggested improved antitumor activity of lenvatinib plus pembrolizumab compared with lenvatinib alone with manageable safety, although statistical significance was not reached [13]. We report results from an exploratory post hoc analysis for the LEAP-002 study of lenvatinib plus pembrolizumab or placebo for patients enrolled at sites in Japan.

LEAP-002 (NCT03713593) was a global, randomized, double-blind phase 3 trial [13]. Adults aged ≥18 years with previously untreated, advanced HCC confirmed by radiology, histology, or cytology; Child-Pugh class A liver score; ≥1 RECIST-measurable HCC lesion; and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 were eligible for enrollment. Patients with macrovascular invasion of the portal vein (Vp2 or Vp3) or major hepatic vein (Vv2) were included. Key exclusion criteria included esophageal or gastric variceal bleeding, macrovascular invasion of the inferior vena cava (Vv3), macrovascular invasion of the main portal vein (Vp4), and cardiac involvement of HCC based on imaging. Full eligibility criteria are provided in the protocol (online suppl. File; for all online suppl. material, see https://doi.org/10.1159/000542572).

Random assignment was performed centrally using an interactive response technology system. Patients were stratified at randomization by geographic region (Asia without Japan vs. Japan and Western regions); ECOG PS (0 vs. 1); macroscopic portal vein invasion or extrahepatic spread or both (yes vs. no); and α-fetoprotein level (≤400 ng/mL vs. >400 ng/mL). Patients were randomly assigned in a 1:1 ratio to receive oral lenvatinib (8 mg for bodyweight <60 kg or 12 mg for bodyweight ≥60 kg) once daily plus either intravenous pembrolizumab 200 mg every 3 weeks or matching placebo for up to 35 cycles (approximately 2 years). Treatment continued until confirmed radiographic disease progression or unacceptable toxicity. Patients who experienced clinical benefit after 35 treatment cycles could continue lenvatinib monotherapy until disease progression or unacceptable toxicity. Crossover between treatment arms was not allowed.

Tumor imaging was performed with computed tomography or magnetic resonance imaging at screening (computed tomography preferred) and every 9 weeks thereafter. Assessment of response and disease progression was performed per RECIST v1.1 by blinded independent central review (BICR). Survival status was assessed every 12 weeks during the follow-up phase. Adverse events (AEs) were monitored throughout the study and for up to 90 days after the last dose (120 days for serious AEs) and were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

Dual primary end points were OS (defined as the time from randomization to death from any cause) and PFS (defined as the time from randomization to the first documented disease progression or death from any cause, whichever occurred first) per RECIST v1.1 by BICR. Secondary end points included objective response rate (ORR, the percentage of patients with a confirmed CR or partial response [PR]), duration of response (DOR, defined as the time from the first documented evidence of complete response or PR until the first documented disease progression or death from any cause, whichever occurred first), and time to progression (defined as the time from randomization to the first documented disease progression), all per RECIST v1.1 and HCC-specific modified RECIST v1.1 (mRECIST) [14] by BICR, PFS per mRECIST by BICR, and safety and tolerability. The present post hoc analysis assessed these end points in the subgroup of patients enrolled in Japan.

Efficacy analyses excluding DOR were conducted in the intention-to-treat (ITT) population, consisting of all randomly assigned patients. DOR was analyzed in the population of patients whose disease responded to treatment (CR or PR). Safety analyses were conducted in all randomly assigned patients who received at least one dose of study treatment. Event rates over time were estimated using the Kaplan-Meier method. ORR and disease control rate (DCR) and their 95% CIs were compared between treatment groups using the stratified Miettinen and Nurminen method with weights proportional to the stratum size. HRs were estimated using a stratified Cox regression model with the Efron method of tie handling. No formal hypothesis testing was performed in this post hoc subgroup analysis.

A total of 1,309 patients were screened for enrollment globally in LEAP-002. Between January 17, 2019, and April 28, 2020, 794 patients from 172 sites were randomly assigned to receive lenvatinib plus pembrolizumab (n = 395) or lenvatinib plus placebo (n = 399) (Fig. 1). Of these patients, 80 (∼10%) were enrolled at Japanese sites (Japan ITT); 39 received lenvatinib plus pembrolizumab and 41 received lenvatinib plus placebo. The median time from randomization to the database cutoff date (June 21, 2022) in the Japan ITT population was 34.1 months (range: 26.9–39.6). Baseline demographic and disease characteristics in the Japan ITT population were generally similar between treatment groups (Table 1). All patients in the Japan subgroup received at least one dose of assigned treatment. At the time of data cutoff, 3 patients (8%) in the lenvatinib plus pembrolizumab group had completed treatment, and 1 patient (3%) was still receiving lenvatinib; all 41 patients (100%) in the lenvatinib plus placebo group had discontinued treatment (Fig. 1). The most common reason for discontinuation in both groups was progressive disease (n = 20 [51%] for lenvatinib plus pembrolizumab and n = 33 [80%] for lenvatinib plus placebo). In the Japan ITT population, 22 patients (56%) in the lenvatinib plus pembrolizumab group and 33 patients (80%) in the lenvatinib plus placebo group received a subsequent systemic anticancer therapy after treatment discontinuation (Table 2).

As of the data cutoff date, 50 patients in the Japan subgroup had died (20 [51%] in the lenvatinib plus pembrolizumab group; 30 [73%] in the lenvatinib plus placebo group). The HR for death was 0.55 (95% CI: 0.31–0.96). The median OS for lenvatinib plus pembrolizumab was 31.4 months (95% CI: 21.2–not reached [NR]) and 21.4 months (95% CI: 14.4–25.4) for lenvatinib plus placebo (Fig. 2). The median PFS for lenvatinib plus pembrolizumab was 10.4 months (95% CI: 6.2–18.5) and 6.5 months (95% CI: 6.0–8.3) for lenvatinib plus placebo (Fig. 3). The HR was 0.54 (95% CI: 0.32–0.90). HRs generally favored lenvatinib plus pembrolizumab across subgroups for both OS and PFS (Fig. 2, 3).

In the Japan subgroup, the confirmed ORR per RECIST v1.1 by BICR was 36% (95% CI: 21.2–52.8) in the lenvatinib plus pembrolizumab group and 24% (95% CI: 12.4–40.3) in the lenvatinib plus placebo group; the between-group difference was 12% (95% CI: −8.7 to 31.1) (Table 3). The DCR was 90% (95% CI: 75.8–97.1) for the lenvatinib plus pembrolizumab group and 83% (95% CI: 67.9–92.8) for the lenvatinib plus placebo group. The median DOR was NR (range: 4.3 to 33.3+ months) in the lenvatinib plus pembrolizumab group and 7.0 months (range: 3.9 to 17.0+) in the lenvatinib plus placebo group.

Efficacy analyses per mRECIST v1.1 by BICR were consistent with the RECIST v1.1 results. The median PFS was 10.5 months (95% CI: 6.3–20.5) in the lenvatinib plus pembrolizumab group and 6.5 months (95% CI: 6.0–8.3) in the lenvatinib plus placebo group. The HR was 0.49 (95% CI: 0.28–0.84). The ORR was 54% (95% CI: 37.2–69.9) in the lenvatinib plus pembrolizumab group and 39% (95% CI: 24.2–55.5) in the lenvatinib plus placebo group (online suppl. Table 1). The DCR was 95% (95% CI: 82.7–99.4) in the lenvatinib plus pembrolizumab group and 85% (95% CI: 70.8–94.4) in the lenvatinib plus placebo group. The median DOR was 14.3 months (range, 4.1 to 33.3+) in the lenvatinib plus pembrolizumab group and 7.6 months (2.0+ to 17.0+) in the lenvatinib plus placebo group (online suppl. Table 1).

The median duration on therapy was 9.5 months (range: 1.5–28.3) for patients in the lenvatinib plus pembrolizumab group and 8.3 months (range: 0.3–29.3) for patients in the lenvatinib plus placebo group. The median dose intensity was 7.6 mg/day for the lenvatinib plus pembrolizumab group and 7.3 mg/day for the lenvatinib plus placebo group. Treatment-related AEs occurred in all patients in both groups; 26 patients (67%) in the lenvatinib plus pembrolizumab group and 24 patients (59%) in the lenvatinib plus placebo group experienced grade 3 or 4 AEs (Table 4). The most common treatment-related AEs in the lenvatinib plus pembrolizumab group were hypothyroidism (67%), hypertension (64%), and palmar-plantar erythrodysesthesia syndrome (62%). The most common treatment-related AEs in the lenvatinib plus placebo group were hypertension (61%), decreased appetite (56%), and proteinuria (56%). Treatment-related AEs led to discontinuation of any treatment for 11 patients (28%) in the lenvatinib plus pembrolizumab group and 2 patients (5%) in the lenvatinib plus placebo group. Serious treatment-related AEs occurred in 12 patients (31%) in the lenvatinib plus pembrolizumab group and 3 patients (7%) in the lenvatinib plus placebo group. No treatment-related deaths occurred in either group (online suppl. Table 2).

Overall, 30 patients (77%) in the lenvatinib plus pembrolizumab group and 24 patients (59%) in the lenvatinib plus placebo group experienced immune-mediated AEs or infusion reactions; 8 patients (21%) and 2 patients (5%), respectively, experienced grade 3 or 4 events (online suppl. Table 3). The most common immune-mediated AEs (≥10% incidence) were hypothyroidism (n = 26; 67%), severe skin reactions (n = 5; 13%), and pneumonitis (n = 4; 10%) in the lenvatinib plus pembrolizumab group and hypothyroidism (n = 21; 51%) in the lenvatinib plus placebo group. A total of 10 patients (33%) in the lenvatinib plus pembrolizumab group and 2 patients (8%) in the lenvatinib plus placebo group received systemic corticosteroids to treat immune-mediated AEs or infusion reactions.

The LEAP-002 study did not meet prespecified statistical significance boundaries for superiority of lenvatinib plus pembrolizumab versus lenvatinib plus placebo for the dual primary end points of OS and PFS in a global population of patients with previously untreated advanced HCC [13]. Despite not meeting statistical significance, OS, PFS, and ORR trended toward improvement with lenvatinib plus pembrolizumab versus lenvatinib plus placebo in the global population. Similar trends were observed in the Japan subgroup, although no formal hypothesis testing was performed in this post hoc analysis. OS and PFS HRs were lower in the Japan subgroup compared to the global population (OS: 0.55 [95% CI: 0.31–0.96] vs. 0.84 [95% CI: 0.71–1.00]; PFS: 0.54 [95% CI: 0.32–0.90] vs. 0.87 [95% CI: 0.73–1.02]). Although the number of patients in the Japan subgroup was relatively small, ORR and DOR per RECIST v1.1 were improved in the lenvatinib plus placebo group in the Japan subgroup (ORR = 36%; DOR = NR [95% CI: 4.3 to 33.3+ months]) compared with the global population (ORR = 26%; DOR = 16.6 months [95% CI: 2.0+ to 33.6+]). In addition, results in the lenvatinib plus placebo group were consistent between the global population (OS = 19.0 months; PFS = 8.0 months) and the Japan subgroup (OS = 21.4 months; PFS = 6.5 months) [13]. Rates of grade 3–5 treatment-related AEs were comparable between the Japan and global populations (67% vs. 63%, respectively, for lenvatinib plus pembrolizumab and 59% vs. 58%, respectively, for lenvatinib plus placebo). Although the Japan subgroup included more patients aged ≥65 years and had an ECOG PS score of 0, baseline demographic and clinical characteristics were generally similar between the Japan and global ITT populations.

AEs were well managed with drug interruption or dose reduction per protocol. In the Japan subgroup, the median duration on treatment in the lenvatinib plus pembrolizumab group (9.5 months) was slightly longer than the lenvatinib plus placebo group (8.3 months). In contrast, in the global ITT population, the median duration on therapy was slightly longer for the lenvatinib plus placebo group (9.5 months) than the lenvatinib plus pembrolizumab group (8.6 months) [13]. The median dose intensity for the Japan subgroup was also numerically lower than that of the global ITT cohort for both the lenvatinib plus pembrolizumab group (7.6 mg/day vs. 8.4 mg/day) and the lenvatinib plus placebo group (7.3 mg/day vs. 8.3 mg/day), although differences in body weight between the Japan and global populations may be a contributing factor [13]. The longer treatment duration and lower dose intensity could result in a larger improvement of OS in the lenvatinib plus pembrolizumab group for the Japan subgroup than in the global results (HR = 0.55 vs. 0.84, respectively). A lower dose of lenvatinib could be sufficient to improve the suppressive tumor immune microenvironment, and a longer treatment duration could be crucial to improving ORR and PFS with lenvatinib plus pembrolizumab. Similar percentages of patients discontinued study treatment in the Japan (lenvatinib plus pembrolizumab, 89.7%; lenvatinib plus placebo, 100%) and global (lenvatinib plus pembrolizumab, 88.4%; lenvatinib plus placebo, 93.7%) populations. Rates of subsequent anticancer therapy use were similar between the Japan and global populations for the lenvatinib plus pembrolizumab group (56% vs. 44%), but more patients in the lenvatinib plus placebo group received subsequent therapy in the Japan subgroup than the global population (80% vs. 52%). In addition, more patients in the Japan subgroup received immunotherapy and immunotherapy/vascular endothelial growth factor therapy (lenvatinib plus pembrolizumab, 31%; lenvatinib plus placebo, 39%) than in the global population (lenvatinib plus pembrolizumab, 14%; lenvatinib plus placebo, 23%). The rate of surgery or locoregional therapy after study medication in the Japan population (lenvatinib plus pembrolizumab, 49%; lenvatinib plus placebo, 59%) was higher than the rate of the global population (lenvatinib plus pembrolizumab, 19%; lenvatinib plus placebo, 23%). Postprogression survival (PPS; defined as median OS minus median PFS) in the Japan population (lenvatinib plus pembrolizumab, 21.0 months; lenvatinib plus placebo, 14.9 months) was longer than the PPS observed for the global population (lenvatinib plus pembrolizumab, 13.0 months; lenvatinib plus placebo, 11.0 months) [13]. The increased use of subsequent anticancer therapy in the Japan subgroup may also have affected the difference in outcomes because receipt of subsequent therapy was associated with significant improvement in OS compared with best supportive care in a global retrospective study of patients with advanced HCC [15].

Prior to 2018, sorafenib was the only first-line treatment for HCC approved in Japan [7]. First-line lenvatinib was then approved based on the results of the phase 3 REFLECT study, which showed lenvatinib was non-inferior to sorafenib in patients with previously untreated unresectable HCC (OS HR = 0.92 [95% CI: 0.79–1.06]) [16]. A subgroup analysis of patients from the REFLECT study who were enrolled in Japan showed an OS HR of 0.90 (95% CI: 0.62–1.29) for lenvatinib versus sorafenib [17]. The LAUNCH study further examined the real-world efficacy and safety of lenvatinib in Japan, which included patients who were excluded from the REFLECT study (e.g., patients with >50% intrahepatic tumor volume) [18]. Lenvatinib demonstrated safety and efficacy in patients with advanced HCC and Child-Pugh class A status; the rate of discontinuation due to AEs was low [18]. A prospective observational postmarketing study also showed that lenvatinib demonstrated clinically meaningful antitumor activity with acceptable tolerability in patients with unresectable HCC in Japan [19]. Combination therapy with atezolizumab and bevacizumab is now most commonly recommended for first-line treatment in Japan based on the results of the IMbrave150 study, which showed atezolizumab and bevacizumab improved OS (HR = 0.58 [95% CI: 0.42–0.79]; p < 0.001) and PFS (HR = 0.59 [95% CI: 0.47–0.76]; p < 0.001) versus sorafenib in patients with previously untreated unresectable HCC after 8.6 months of follow-up [7, 20]. OS continued to improve with atezolizumab and bevacizumab after a median follow-up of 15.6 months (HR = 0.66 [95% CI: 0.52–0.85]; p = 0.0009) [21].

Lenvatinib continues to demonstrate its importance as a first-line treatment option for patients with advanced HCC in Japan. Although the sample size was small, there was a promising trend toward greater benefit with the addition of pembrolizumab to lenvatinib in the Japan subgroup compared with the global population. Safety was manageable, with no new safety signals. In addition to the known benefit of lenvatinib monotherapy in advanced HCC, these results confirm the value of further exploring the combination of lenvatinib with pembrolizumab in this population.

The authors thank the patients and their families for participating in the study, all investigators, and site personnel. Leonid Dubrovsky and Abby B. Siegel, both of Merck & Co., Inc., Rahway, NJ, USA, provided critical review of the manuscript. Medical writing assistance was provided by Shane Walton, PhD, CMPP, and Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA), and was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Eisai, Inc., Nutley, NJ, USA.

This study was conducted in accordance with the Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. All patients provided written informed consent. Institutional review boards or independent ethics committees at each site approved the protocol. The full list of participating sites and ethics committees can be found in the supplement. Data were collected by the investigators and monitored by an external data monitoring committee.

Masatoshi Kudo reports grants from Otsuka, Chugai, Eisai, EA Pharma, Taiho, GE Healthcare, and AbbVie; consulting fees from Chugai, Eisai, AstraZeneca, and Roche; and personal honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Chugai, Eisai, Eli Lilly, and Takeda. Masafumi Ikeda reports consulting fees from AbbVie, AstraZeneca, Bayer, Chugai, Eisai, Eli Lilly Japan, MSD, and Ono; personal honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly Japan, Gilead, MSD, Sumitomo Dainippon, and Takeda; and institutional research grants from AstraZeneca, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly Japan, MSD, Ono, Merck Serono, and Novartis. Hiroshi Aikata reports personal honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Eisai Co., Ltd. and Chugai Pharmaceutical Co., Ltd. Tetsuya Hosaka reports personal honoraria for speakers bureaus from Eisai. Naoya Kato reports personal honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer Yakuhin Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., and Takeda Pharmaceutical Co., Ltd. Masayuki Kurosaki reports personal honoraria for lectures, presentations, speakers bureaus from Eisai, Chugai, AstraZeneca, AbbVie, and Gilead. Tatsuya Yamashita reports personal honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Eisai, AstraZeneca, and Chugai. Naoyoshi Yatsuzuka is an employee of MSD K.K. and owns stock or stock options in Merck & Co., Inc. Satoshi Nagao is an employee of Eisai Co., Ltd. Hiromitsu Kumada reports personal honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Sumitomo-pharma, Eisai, AbbVie, and Gilead Sciences. Shuichi Kaneko, Hironori Koga, Hiroyuki Marusawa, Tsutomu Masaki, Manabu Morimoto, Kazushi Numata, and Masato Suzuki have no conflicts to disclose.

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck and Co., Inc., Rahway, NJ, USA, and Eisai, Inc., Nutley, NJ, USA. The funders contributed to the study design, data collection, data analysis, and data interpretation in collaboration with the authors; all authors had full access to the data. Investigators and site personnel collected data, which was housed on MSD’s database. The funder provided financial support for editorial and writing assistance. The corresponding author had full access to all the data and had final responsibility for the decision to submit for publication.

Conception, design, or planning of the study: Masafumi Ikeda and Masatoshi Kudo. Acquisition of the data: Hiroshi Aikata, Tetsuya Hosaka, Masafumi Ikeda, Naoya Kato, Masatoshi Kudo, Hiromitsu Kumada, Masayuki Kurosaki, Hiroyuki Marusawa, Tsutomu Masaki, Manabu Morimoto, Kazushi Numata, and Tatsuya Yamashita. Analysis of the data: Naoya Kato, Hiroyuki Marusawa, Tsutomu Masaki, and Masato Suzuki. Interpretation of the results: Masafumi Ikeda, Shuichi Kaneko, Hironori Koga, Masatoshi Kudo, Hiromitsu Kumada, Satoshi Nagao, Tatsuya Yamashita, and Naoyoshi Yatsuzuka. Drafted manuscript: Shuichi Kaneko, Masatoshi Kudo, and Manabu Morimoto. All authors critically reviewed or revised the manuscript for important intellectual content.

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