Abstract
Introduction
The phase 3 REFLECT trial demonstrated the efficacy and safety of lenvatinib versus sorafenib in the first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC). We report results from STELLAR, a non-interventional post-marketing study. The primary objectives were to characterize hepatotoxicity and overall safety of lenvatinib in patients from Western regions with uHCC.
Methods
STELLAR was a prospective, open-label, observational, phase 4 study of patients treated with lenvatinib (n = 193). A cohort of sorafenib-treated patients (n = 123) was included as an internal reference group. The treating physician made the decision to treat patients with lenvatinib or sorafenib before enrollment. Study drugs were administered according to the Summary of Product Characteristics guidelines. Safety and efficacy evaluations were performed according to standard clinical practice at each site. The primary endpoint was safety. Secondary endpoints included treatment exposure and overall survival.
Results
The median duration of treatment with lenvatinib or sorafenib was 6.5 months (range, 0.2–33.1 months) and 4.4 months (range, 0.5–30.7 months), respectively. Hepatotoxicity treatment-emergent adverse events (TEAEs) were observed in 26.9% of lenvatinib-treated patients and 33.3% of sorafenib-treated patients. The most frequently reported hepatotoxicity TEAEs were hepatic encephalopathy (7.8%; lenvatinib cohort) and ascites (11.4%; sorafenib cohort), respectively. Overall, 85.0% of lenvatinib-treated patients and 84.6% of sorafenib-treated patients experienced ≥1 TEAE. Median overall survival (95% CI) was 16.9 months (14.1–not estimable) in lenvatinib-treated patients.
Conclusion
Our findings support the established safety and efficacy of lenvatinib in first-line patients with uHCC.
Keywords: Lenvatinib, Sorafenib, Hepatocellular carcinoma, Phase 4
Introduction
Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancer cases worldwide [1], and 10% of HCC cases occur in Europe [2]. HCC is the third most common cause of cancer-related deaths globally, with a <20% 5-year survival rate for advanced-stage disease [3]. Lenvatinib is a potent oral multiple receptor tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor α, RET, and KIT [4–7]. The randomized, open-label, phase 3 REFLECT trial demonstrated the efficacy and safety of lenvatinib versus sorafenib in first-line treatment of patients with unresectable HCC (uHCC) [8]. Overall survival (OS) with lenvatinib was non-inferior to sorafenib in REFLECT, with a median OS of 13.6 months (95% confidence interval [CI] 12.1–14.9) for lenvatinib and 12.3 months (95% CI: 10.4–13.9) for sorafenib [8]. Lenvatinib also showed a greater objective response rate than sorafenib (24.1% vs. 9.2%; odds ratio, 3.13 [95% CI: 2.15–4.56]; p < 0.0001) and treatment-emergent adverse events (TEAEs) occurred at 99% in both arms of the study [8]. As a result, lenvatinib [7] was approved for the first-line treatment of patients with uHCC and is considered a standard-of-care treatment option for this population [9, 10].
Liver toxicities are known adverse events for tyrosine kinase inhibitors [11, 12]. Notably, liver-related serious adverse events (SAEs) were reported at a higher frequency in patients treated with lenvatinib versus sorafenib in REFLECT (hepatic encephalopathy, 4.4% vs. 0.6%; hepatic failure, 2.9% vs. 1.7%, respectively) [13]. Overall, the most frequently reported any-grade TEAEs occurring in the lenvatinib arm of REFLECT (affecting ≥25% of patients) were hypertension, diarrhea, decreased appetite, decreased weight, fatigue, and palmar-plantar erythrodysesthesia [8].
We report the final analysis of STELLAR, a non-interventional post-marketing phase 4 study of a Western patient population, which was requested by the Pharmacovigilance Risk Assessment Committee (PRAC) during the assessment of lenvatinib for the treatment of adult patients with uHCC who had received no prior systemic therapy. The primary objectives of this analysis were to characterize hepatotoxicity and overall safety of lenvatinib in patients from Western regions with uHCC. Secondary objectives included assessment of treatment patterns (treatment duration, incidence of dose interruptions, dose reductions, relative dose intensity, etc.) and overall survival in patients with uHCC treated with lenvatinib.
Methods
Study Design
STELLAR was an international, prospective, open-label, observational, phase 4 study of lenvatinib conducted in a real-world Western population of patients with uHCC. In response to the PRAC’s request during review of the protocol, STELLAR included a cohort of patients treated with sorafenib [14] as an “internal calibration.” Both treatments were to be administered according to guidelines outlined in the respective Summary of Product Characteristics [15, 16]; thus, lenvatinib was administered to treatment-naïve patients, and sorafenib was administered regardless of line of therapy. The decision to treat a patient with lenvatinib or sorafenib was made by the treating physician (investigator) before the decision to enroll the patient into the study; thus, patients came from a heterogeneous, minimally selected population and were not randomly assigned to treatment cohorts. All treatment decisions (e.g., dose and duration of treatment) were not mandated by the study protocol, but rather they were made at the discretion of the patient’s healthcare provider (investigator), based on the recommendations included in the locally approved product information. Safety and effectiveness evaluations were performed during routine clinical visits according to standard clinical practice at each site. STELLAR was not designed for between-treatment comparisons, and no statistical comparisons were made between the lenvatinib and sorafenib cohorts. We present final analysis data (data cutoff: March 27, 2024) from 44 sites in 10 countries (Australia, Austria, Germany, Italy, Portugal, Russia, Spain, Sweden, the UK, and the USA [online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000552115]). All patients provided informed consent before participation.
Patients
Eligible patients had a diagnosis of uHCC and were from Western countries. STELLAR aimed to enroll a minimally selected population (i.e., recruited with no study-specific exclusion criteria and few screen failures) to ensure the study’s real-world nature. Patients had to be eligible to receive treatment with lenvatinib or sorafenib in accordance with local prescribing conditions of the approved product label and were required to provide signed informed consent to participate in the study within 31 days of initiating treatment with lenvatinib or sorafenib. Because no study-specific exclusion criteria were applied, all consecutive patients who met the eligibility criteria and agreed to participate were enrolled. Enrollment of eligible patients took place from the time the decision to treat with lenvatinib or sorafenib was made and up to 31 days after treatment initiation. The number of patients per site treated with lenvatinib or sorafenib was monitored during patient screening.
Endpoints and Assessments
The primary endpoint was the safety of lenvatinib in patients with uHCC, defined as hepatic-related toxicity and the overall safety profile. For the overall safety profile, variables included adverse events (AEs), grade 3–5 AEs, dose modifications and discontinuations due to AEs, AE type, National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade, AE seriousness, and relationship to lenvatinib or sorafenib treatment. Clinically significant TEAEs (group terms describing pre-identified AEs of special interest) were established and recorded for lenvatinib. Clinically significant TEAEs were not pre-identified for sorafenib, and those recorded for sorafenib-treated patients were based on the clinically significant TEAEs identified for lenvatinib. Safety data were collected from the time of first prescription to 28 days after treatment discontinuation or to the end of the observation period. Hepatic-related and overall AEs were coded using the Medical Dictionary for Regulatory Activities version 25.0 and graded using CTCAE version 5.0; serious AEs were defined as any untoward medical occurrence or effect that: results in death, is life-threatening, requires or prolongs hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect. Secondary endpoints included treatment disposition, treatment exposure, and OS. OS medians were estimated using the Kaplan-Meier method, and 95% CIs were estimated with the Brookmeyer and Crowley method. Patients lost to follow-up were censored on the last date the patient was known to be alive, and patients who remained alive were censored on the data cutoff date.
Results
Patients
Patient disposition is shown in Figure 1. Between April 09, 2021, and December 13, 2023, a total of 193 patients were treated with lenvatinib (with ≥1 follow-up visit or reported AE), and 123 patients were treated with sorafenib (with ≥1 follow-up visit or reported AE). The data cutoff date was March 27, 2024. All patients in the lenvatinib cohort were treated in the first line; 67.5% of patients in the sorafenib cohort received first-line treatment. Treatment was ongoing in 17.1% of patients who received lenvatinib and 9.8% of patients who received sorafenib. The most common reason for treatment discontinuation in both cohorts was disease progression (lenvatinib, 29.5%; sorafenib, 40.7%). Demographic and baseline characteristics are shown in Table 1. The median age of patients treated with lenvatinib or sorafenib was 69 years (for both cohorts). Of patients treated with lenvatinib, 31.6% were ≥75 years of age, and 28.5% of patients treated with sorafenib were in this age group. Most treated patients were male (lenvatinib, 77.7%; sorafenib, 82.9%), white (lenvatinib, 82.4%; sorafenib, 87.8%), and had an Eastern Cooperative Oncology Performance Status (ECOG PS) of 0 (lenvatinib, 44.6%; sorafenib, 51.2%) and Child-Pugh class A (lenvatinib, 58.0%; sorafenib, 56.1%). The majority of patients had underlying cirrhosis (lenvatinib, 67.9%; sorafenib, 71.5%).
Fig. 1.
Treatment disposition and discontinuation. Nineteen patients (5.7%) failed screening and were not included in the reported data analysis sets. aPrimary reason for treatment discontinuation was not reported; thus, end of study status is presented. AE, adverse event; SAE, serious adverse event.
Table 1.
Demographic and baseline characteristics
| Variable | Lenvatinib (n = 193) | Sorafenib (n = 123) |
|---|---|---|
| Median age (range), years | 69 (28, 88) | 69 (28, 88) |
| Male sex, n (%) | 150 (77.7) | 102 (82.9) |
| Age group, n (%) | ||
| <65 years | 53 (27.5) | 36 (29.3) |
| ≥65 to <75 years | 79 (40.9) | 52 (42.3) |
| ≥75 years | 61 (31.6) | 35 (28.5) |
| Race, n (%) | ||
| White | 159 (82.4) | 108 (87.8) |
| Black or African American | 7 (3.6) | 4 (3.3) |
| Asian | 6 (3.1) | 4 (3.3) |
| Unknown/other/cannot aska | 21 (10.9) | 7 (5.7) |
| Median weight (range), kg | 75 (42.0, 131.0) | 73 (47.0, 124.0) |
| Baseline serum alpha-fetoprotein, n (%) | ||
| <200 ng/mL | 46 (23.8) | 37 (30.1) |
| ≥200 ng/mL | 30 (15.5) | 26 (21.1) |
| Missing | 117 (60.6) | 60 (48.8) |
| ECOG Performance status, n (%)b | ||
| 0 | 86 (44.6) | 63 (51.2) |
| 1 | 58 (30.1) | 31 (25.2) |
| 2 | 15 (7.8) | 7 (5.7) |
| 3 | 0 | 2 (1.6) |
| Missing | 34 (17.6) | 20 (16.3) |
| Child-Pugh class, n (%)c | ||
| A | 112 (58.0) | 69 (56.1) |
| 5 | 86 (44.6) | 41 (33.3) |
| 6 | 26 (13.5) | 28 (22.8) |
| B | 28 (14.5) | 21 (17.1) |
| C | 2 (1.0) | 1 (0.8) |
| Unknown/not assessed/missing | 51 (26.4) | 32 (26.0) |
| BCLC stage, n (%)d | ||
| 0/A: Very early/early stage | 29 (15.0) | 17 (13.8) |
| B: Intermediate stage | 53 (27.5) | 28 (22.8) |
| C: Advanced stage | 53 (27.5) | 33 (26.8) |
| D: End-stage disease | 3 (1.6) | 3 (2.4) |
| Unknown/missing | 55 (28.5) | 42 (34.1) |
| Extrahepatic spread, n (%) | 60 (31.1) | 46 (37.4) |
| Vascular invasion status and portal vein thrombosis, n (%) | ||
| None | 87 (45.1) | 53 (43.1) |
| Hepatic vein tumor invasion | 12 (6.2) | 10 (8.1) |
| Vp1 (segmental portal vain) | 4 (2.1) | 5 (4.1) |
| Vp2 (right anterior/posterior portal vein) | 1 (0.5) | 5 (4.1) |
| Vp3 (right or left portal vein) | 14 (7.3) | 10 (8.1) |
| Vp4 (main trunk) | 2 (1.0) | 3 (2.4) |
| Unknown/not assessed/missing | 73 (37.8) | 37 (30.1) |
| Underlying cirrhosis, n (%)e | ||
| Yes | 131 (67.9) | 88 (71.5) |
| No | 41 (21.2) | 29 (23.6) |
| Unknown/missing | 21 (10.9) | 6 (4.9) |
| Underlying liver disease, n (%)f | ||
| Alcoholic liver disease | 64 (33.2) | 47 (38.2) |
| Hepatitis B | 25 (13.0) | 15 (12.2) |
| Hepatitis C | 56 (29.0) | 38 (30.9) |
| Nonalcoholic fatty liver disease/Nonalcoholic steatohepatitis | 15 (7.8) | 14 (11.4) |
| Varices, n (%)g | 15 (7.8) | 16 (13.0) |
| Line of therapy, n (%)h | ||
| 1 | 193 (100) | 83 (67.5) |
| 2 | NA | 31 (25.2) |
| 3 | NA | 9 (7.3) |
Numbers for each variable may not add to the total number of patients in cases of unknown or missing data.
BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; NA, not applicable.
aPer local regulation.
bThirty-four patients treated with lenvatinib and 20 patients treated with sorafenib had missing data for this parameter.
cFifty-one patients treated with lenvatinib and 32 patients treated with sorafenib had missing or unknown Child-Pugh data.
dFifty-five patients treated with lenvatinib and 42 patients treated with sorafenib had missing or unknown BCLC stage data.
eTwenty-one patients treated with lenvatinib and 6 patients treated with sorafenib had missing or unknown cirrhosis data.
fPatients may be counted in multiple categories. Categories are listed only if they had ≥5 patients in either cohort.
gBased on investigator entered comments, including esophageal varices, esophageal varices grade 2, esophageal varices grade 3, esophageal varices hemorrhage, esophageal varices, F1 esophageal varices without red markings, esophageal varices F1, esophageal varices grade 1–2, grade 2 varices, esophageal varices, small fundus varices, colostomy varices, gastric varices, gastroesophageal varices grade 2.
hRefers to the line of therapy of the study drug (lenvatinib or sorafenib) received in the STELLAR trial.
Treatment Exposure
The median duration of treatment with lenvatinib or sorafenib was 6.5 months (range, 0.2–33.1 months) and 4.4 months (range, 0.5–30.7 months), respectively. Total exposure (the sum of treatment duration, including dose interruption, for all patients in each cohort) was 135.2 patient-years for the lenvatinib cohort and 67.7 patient-years for the sorafenib cohort.
Hepatotoxicity Analysis
Clinically significant hepatotoxicity TEAEs that occurred in patients treated with lenvatinib and in those treated with sorafenib are shown in Figure 2. Overall, 26.9% of patients who received lenvatinib experienced clinically significant hepatotoxicity TEAEs. The most frequently reported hepatotoxicity TEAEs with lenvatinib were hepatic encephalopathy (15 patients, 7.8%) and ascites (13 patients, 6.7%); hepatic encephalopathy was also the most commonly reported hepatotoxicity SAE (13 patients; 6.7%). Lenvatinib treatment was discontinued due to the following clinically significant hepatotoxicity TEAEs: hepatic encephalopathy (9 patients, 4.7%) and alanine aminotransferase increased, ascites, blood bilirubin increased, hepatic function abnormal and jaundice (1 patient each, 0.5%).
Fig. 2.
Hepatotoxicity analysis: clinically significant TEAEs. a, b, cAdverse events terms were coded using MedDRA version 25.0 and graded using CTCAE version 5.0. aClinically significant TEAEs are preidentified TEAEs of special interest established for lenvatinib. Clinically significant TEAEs were not preidentified for sorafenib, and those presented for sorafenib-treated patients are based on the clinically significant TEAEs identified for lenvatinib. bAdverse events that occurred in ≥2 patients in either cohort are included. cFigure reports clinically significant TEAEs in the hepatotoxicity category only. CTCAE v5.0, Common Terminology Criteria for Adverse Events version 5.0; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event.
Overall, 33.3% of patients who received sorafenib experienced clinically significant hepatotoxicity TEAEs. The most frequently reported hepatotoxicity TEAEs were ascites (14 patients, 11.4%) and aspartate aminotransferase increased (11 patients, 8.9%) (Fig. 2). Hepatic encephalopathy (4.9%) was the only SAE reported for ≥5 patients. The most frequent TEAEs leading to sorafenib discontinuation were ascites (4 patients, 3.3%) and hepatic encephalopathy (2 patients, 1.6%).
Overall Safety Analysis
In patients treated with lenvatinib, 85.0% experienced ≥1 TEAE, 45.1% had grade 3–5 TEAEs, 50.8% had TEAEs leading to treatment modification (treatment interruption or dose reduction), and 29.5% had TEAEs leading to lenvatinib discontinuation (Table 2). The TEAEs leading to treatment discontinuation reported for >3 patients in the lenvatinib cohort were hepatic encephalopathy (4.7%), decreased appetite (3.1%), fatigue and nausea (2.6% each), and acute kidney injury, asthenia, and diarrhea (2.1% each) (online suppl. Table 2). Fatal TEAEs were reported for 11.4% of patients who received lenvatinib (Table 2; online suppl. Table 2). Among these, cardiorespiratory arrest was reported for 5 patients (2.6%), and cardiac arrest and septic shock were reported for 2 patients each (1.0%); all other fatal TEAEs were reported for 1 patient each. Three fatal TEAEs (duodenal perforation, hepatic encephalopathy, and infection; 1 patient each) were judged to be treatment-related.
Table 2.
Overview of TEAEs: full analysis set
| TEAEs | Lenvatinib (n = 193), n (%) | Sorafenib (n = 123), n (%) |
|---|---|---|
| Patients with any TEAEs | 164 (85.0) | 104 (84.6) |
| Patients with any treatment-related TEAEs | 134 (69.4) | 86 (69.9) |
| Patients with grade ≥3 TEAEs | 87 (45.1) | 54 (43.9) |
| Patients with grade ≥3 treatment-related TEAEs | 48 (24.9) | 22 (17.9) |
| Patients with serious TEAEs | 74 (38.3) | 42 (34.1) |
| Patients with fatal TEAEsa | 22 (11.4) | 6 (4.9) |
| Patients with nonfatal serious TEAEs | 60 (31.1) | 39 (31.7) |
| Patients with TEAEs leading to: | ||
| Study drug discontinuation | 57 (29.5) | 25 (20.3) |
| Study drug dose reduction | 50 (25.9) | 19 (15.4) |
| Study drug interruption | 72 (37.3) | 39 (31.7) |
| Study drug dose reduction or interruption | 98 (50.8) | 53 (43.1) |
Adverse events were coded using MedDRA version 25.0 and graded using CTCAE version 5.0.
CTCAE, Common Terminology Criteria for Adverse Events; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event.
aThree fatal TEAEs in the lenvatinib treatment cohort (duodenal perforation, hepatic encephalopathy, infection; 1 patient each) were judged by the investigator to be treatment-related.
Among patients treated with sorafenib, 84.6% experienced ≥1 TEAE, 43.9% had grade 3–5 TEAEs, 43.1% had TEAEs leading to treatment modification (treatment interruption or dose reduction), and 20.3% had TEAEs leading to discontinuation (Table 2). Ascites and diarrhea (3.3% each) were the only TEAEs that led to treatment discontinuation in >2 patients in the sorafenib cohort. Fatal TEAEs were reported for 4.9% of patients treated with sorafenib; none of these events were considered treatment-related.
Any-grade TEAEs occurring in ≥10% of patients in either treatment cohort are shown in Figure 3. The most common TEAEs in both cohorts were decreased appetite (lenvatinib, 28.5%; sorafenib, 26.0%) and diarrhea (lenvatinib, 25.9%; sorafenib, 31.7%).
Fig. 3.
TEAEs of any grade occurring in ≥10% of patients in either treatment cohort. Adverse events were coded using MedDRA version 25.0 and graded using CTCAE version 5.0. MedDRA preferred terms “neoplasm progression,” “malignant neoplasm progression,” and “disease progression,” which are unrelated to the study drug, are excluded. CTCAE v5.0, Common Terminology Criteria for Adverse Events version 5.0; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event.
Serious TEAEs occurred in 38.3% of lenvatinib-treated patients and in 34.1% of sorafenib-treated patients (Table 2). In lenvatinib-treated patients, the most frequently reported serious TEAE was hepatic encephalopathy (6.7%), followed by acute kidney injury (4.7%). In sorafenib-treated patients, the most frequently reported serious TEAE was hepatic encephalopathy (4.9%), followed by hemorrhage (4.1%).
Aside from hepatotoxicity (the most commonly occurring clinically significant treatment-emergent adverse event in both the lenvatinib [26.9%] and sorafenib [33.3%] treatment cohorts), clinically significant TEAEs occurring in ≥10% of patients treated with lenvatinib were hypothyroidism (16.1%) and hypertension (13.5%). Clinically significant TEAEs occurring in ≥10% of patients treated with sorafenib were hemorrhage (13.8%) and palmar-plantar erythrodysesthesia syndrome (13.0%) (online suppl. Table 3).
Overall Survival
For lenvatinib-treated patients, the median OS was 16.9 months (95% CI: 14.1–not estimable [NE]); OS rates at 6 and 12 months were 80.4% (95% CI: 74.0–85.4) and 61.6% (95% CI: 54.1–68.3), respectively (Fig. 4a). For sorafenib-treated patients, the median OS was 11.0 months (95% CI: 8.7–15.2); OS rates at 6 and 12 months were 78.1% (95% CI: 69.6–84.6) and 48.8% (95% CI: 39.2–57.7), respectively (Fig. 4b). When assessing OS by line of therapy, the median OS in patients treated with sorafenib in the first line (n = 83) was 13.6 months (95% CI: 8.8–9.5), and the median OS in patients treated with sorafenib in the second line (n = 31) was 7.4 months (95% CI: 5.6–NE). Median OS was not summarized in patients treated with sorafenib in the third line (n = 9) due to low patient numbers.
Fig. 4.
Overall survival in lenvatinib-treated (a) and sorafenib-treated (b) patients. The median duration of survival follow-up was 23.5 months (95% CI: 20.3–25.2) for lenvatinib-treated patients and 20.5 months (95% CI: 17.1–23.6) for sorafenib-treated patients. CI, confidence interval; NE, not estimable; OS, overall survival.
Subsequent Therapy
Overall, 15.5% of lenvatinib-treated patients and 21.1% of sorafenib-treated patients received systemic therapy for HCC after study treatment discontinuation. The most frequent therapy was sorafenib (8.3%) for lenvatinib-treated patients and cabozantinib (9.8%) for sorafenib-treated patients (online suppl. Table 4).
Discussion
The STELLAR trial evaluated the hepatotoxicity and overall safety profile of lenvatinib in a heterogeneous, minimally selected population of Western patients with first-line uHCC treated in a routine clinical care setting. There were no study-specific exclusion criteria, and the low number of patients who were screen failures (19 patients, 5.7%) supports the classification of these patients as a real-world population. Furthermore, the inclusion of patients with more severe disease (ECOG PS of 2, Child-Pugh class B or C) and a broad age range (including patients ≥75 years of age) is reflective of a real-world clinical population. In these patients, lenvatinib had a manageable safety profile consistent with its known safety profile as observed in REFLECT [8] and the approved product label [15]. No new safety signals were identified. Adverse events were effectively managed by standard clinical practice as applicable for treatment with lenvatinib. With regard to hepatotoxicity, no new findings were identified; the incidence and severity of hepatic-related toxicity was consistent with the known safety profile of lenvatinib in uHCC, and hepatotoxic adverse events were effectively managed. The overall safety profile of sorafenib in STELLAR was consistent with that observed in REFLECT [8] and with the approved product label [16].
OS in patients treated with lenvatinib in STELLAR (median, 16.9 months [95% CI: 14.1–NE]) was consistent with survival outcomes in REFLECT (median, 13.6 months [95% CI: 12.1–14.9]) [8] and with the lenvatinib plus placebo arm of LEAP-002 [17] (median, 19.0 months [95% CI: 17.2–21.7]); however, STELLAR cannot be directly compared with these randomized, controlled trials because the patient population in STELLAR was purposely heterogeneous and treated in a routine clinical care setting. Notably, patients were permitted to enroll in STELLAR who would not be eligible to enroll in REFLECT [8]; the patients in STELLAR were generally more diverse with poorer liver function and more advanced disease features than those included in REFLECT (e.g., patients with ECOG PS scores of 2 or higher, higher Child-Pugh scores, HCC with 50% or more liver occupation, clear invasion into the bile duct, or main portal branch invasion [Vp4]). These expanded clinical characteristics support the generalizability of STELLAR results to the Western population of patients with HCC eligible for first-line treatment with lenvatinib. Other real-world studies have also effectively highlighted the contrasting patient populations between the REFLECT and STELLAR trials in HCC. Maruta et al. [18] noted REFLECTs stringent inclusion criteria (such as predominantly Child-Pugh A liver function and exclusion of patients with high tumor burden or specific types of invasion), which provide a more uniform cohort for establishing efficacy in a pivotal phase 3 setting. In a real-world setting, patients with compromised liver function (particularly those classified as Child-Pugh B) would require careful dose modification due to increased risk of adverse events and potentially reduced efficacy. Conversely, the STELLAR trial was a phase 4 observational study, where patient enrollment was guided by the treating physician discretion along with lenvatinib’s approved product label. This real-world design inherently allowed for a broader spectrum of HCC patients, including those with poorer liver function or more extensive disease, who would typically be excluded from the more controlled REFLECT trial, thereby providing valuable data on lenvatinib’s performance in a more diverse clinical setting.
Given the observational nature of the current study, a notable limitation is the number of missing data from baseline characteristics (including ECOG PS, Child-Pugh score, and BCLC stage); as such, these results should be interpreted with caution. Overall, these data continue to support the established safety profile and efficacy of lenvatinib for first-line treatment of patients with uHCC.
Statement of Ethics
This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol was reviewed and approved by the relevant Ethics Committees at each participating site in accordance with local regulations and ICH GCP. European approvals were granted under Directive 2001/20/EC, prior to implementation of harmonized ethics decision identifiers under Regulation (EU) 536/2014. All participants provided written informed consent before study participation.
Conflict of Interest Statement
Markus Peck-Radosavljevic: research funding paid to his institution (Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria) from Eisai, BMS, Roche, Ipsen, MSD, and Gilead; travel/accommodation/expenses from Gilead, Bayer, Roche, Ipsen, and Advanz; honoraria from AstraZeneca, Bayer, Eisai, BMS, Roche, MSD, Gilead, AbbVie, Advanz, Ipsen, Sobi, and Shionogi; consulting/advisory role for AstraZeneca, Bayer, Eisai, BMS, Roche, MSD, Gilead, AbbVie, Advanz, Ipsen, Sobi, and Shionogi. Akhmed Abdelgafur, Alessandro Granito, and Antonio Gasbarrini: nothing to disclose. Yuk Ting Ma: research funding paid to institutions (The Cancer Centre, University Hospitals Birmingham NHS Foundation Trust, and University of Birmingham, Birmingham, UK) from Eisai, AstraZeneca/Merck, Faron Pharmaceuticals, and Mina Therapeutics; consulting/advisory role for Roche, AstraZeneca/MedImmune, Faron Pharmaceuticals, and Incyte. Edward Mena: research funding paid to institution (Pasadena Liver Center, California Liver Research Institute, Pasadena, CA, USA) from Madrigal Pharmaceuticals, Gilead Sciences, Merck, Galectin, HighTide, Novo Nordisk, Altimmune, Akero, Salix, and CymaBay Therapeutics; honoraria from Gilead Sciences, Salix, Eli Lilly, and AbbVie; consulting/advisory role for Galectin; speakers’ bureau for Gilead Sciences, Salix, Eli Lilly, and AbbVie. José Luis Lledó-Navarro: consulting/advisory role for Eisai, MSD, Roche, and AstraZeneca; travel/accommodations/expenses from Roche. José Presa: consulting/advisory role for Roche, Eisai, AstraZeneca, Gilead Sciences, AbbVie, Advanz Pharma, and Orphalan; speakers’ bureau for Roche, Eisai, AstraZeneca, Gilead Sciences, AbbVie, Advanz Pharma, and Orphalan; travel/accommodations/expenses from Roche, Eisai, AstraZeneca, Gilead Sciences, AbbVie, Advanz Pharma, and Orphalan. Arndt Weinmann: consulting/advisory role for AstraZeneca, MSD, BMS, and Servier; speakers’ bureau for AstraZeneca, and AbbVie. Miriam T. Levy: consulting/advisory role for Gilead Sciences, AstraZeneca; research funding from Gilead Sciences and AbbVie; travel sponsorship from Ipsen. Adriano Pellicelli: consulting/advisory role for Eisai, MSD, and Gilead Sciences; speakers’ bureau for Eisai and Gilead Sciences. Dirk-Thomas Waldschmidt: speakers’ bureau for AstraZeneca, Boehringer Ingelheim, Eisai, BMS, Incyte, Falk Foundation, MSD, Novartis, Roche Pharma AG, Servier, and Ipsen; travel/accommodations/expenses from AstraZeneca, Ipsen, Roche Pharma AG, and Servier. Henrik Toft Sørensen: the Department of Clinical Epidemiology, Aarhus University, receives funding for other studies in the form of institutional research grants to (and administered by) Aarhus University. None of these studies has any relation to the present study. Lipika Goyal: research funding paid to institution from Alyssum, Genentech; consulting/advisory role for Alentis Therapeutics, QED Therapeutics, AstraZeneca, Taiho Pharmaceutical, Incyte, Sirtex Medical, Genentech, Exelixis, TransThera Biosciences, Merck, Black Diamond Therapeutics, Synthekine, Eisai/H3 Biomedicine, Tyra Biosciences, Compass Therapeutics, Blueprint Medicines, Servier, AbbVie, Cogent Biosciences, and Surface Oncology. Min Ren, Hakim Saal, and Chinyere E. Okpara: employees of Eisai. Tim Meyer: research funding paid to institution (Royal Free London NHS Foundation Trust) from Ipsen, Bayer, and BTG; consulting/advisory role for Eisai, Ipsen, BTG, BeiGene, MSD, Roche, Bayer, AstraZeneca, and Signant Health. Markus Peck-Radosavljevic, Arndt Weinmann, and Tim Meyer were members of the journal’s Editorial Board at the time of submission.
Funding Sources
The study was funded by Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. At least one of the funders contributed to either 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. The corresponding author had full access to all the data and had final responsibility for the decision to submit the publication. Medical writing support was provided by Oxford PharmaGenesis, Wilmington, DE, USA, and was funded by Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Author Contributions
Conceptualization, investigation, methodology, resources, writing – original draft, and writing – review and editing: M. Peck-Radosavljevic, A. Abdelgafur, A. Granito, A. Gasbarrini, Y.T. Ma, E. Mena, J.L. Lledó-Navarro, J. Presa, A. Weinmann, M.T. Levy, A. Pellicelli, D.-T. Waldschmidt, H.T. Sørensen, L. Goyal, M. Ren, H. Saal, C.E. Okpara, and T. Meyer; data curation: M. Ren and H. Saal; and formal analysis: M. Ren.
Funding Statement
The study was funded by Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. At least one of the funders contributed to either 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. The corresponding author had full access to all the data and had final responsibility for the decision to submit the publication. Medical writing support was provided by Oxford PharmaGenesis, Wilmington, DE, USA, and was funded by Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Data Availability Statement
The data will not be available for sharing at this time because the data are commercially confidential. However, Eisai Inc. will consider written requests to share the data on a case-by-case basis. Further inquiries can be directed to the corresponding author.
Supplementary Material.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data will not be available for sharing at this time because the data are commercially confidential. However, Eisai Inc. will consider written requests to share the data on a case-by-case basis. Further inquiries can be directed to the corresponding author.