Introduction
Hepatocellular carcinoma (HCC) is a major global cause of cancer-related deaths [
1,
2]. The worldwide estimate of liver cancer mortality in 2018 was 8.2%, equating to approximately 780,000 deaths [
1]. Unfortunately, most patients will eventually reach a stage of HCC when potentially curative therapies such as resection or transplantation are no longer clinically indicated [
3].
At the time of the REFLECT study, sorafenib was the only approved first-line systemic treatment for HCC, but the approval of lenvatinib provided another option [
2,
4,
5]; more recently atezolizumab in combination with bevacizumab became another front-line option [
6]. Lenvatinib is a multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor
α, RET, and KIT [
7‐
10]. Lenvatinib monotherapy is approved for the treatment of patients with locally recurrent or metastatic, progressive, radioactive-iodine-refractory, differentiated thyroid cancer, and for the first-line treatment of patients with unresectable HCC (uHCC) [
4]. Lenvatinib is metabolized in the liver, and impaired hepatic function in patients with uHCC may impact lenvatinib metabolism; as such, dose adjustments based on weight are required for this patient population [
11].
Diseases of the liver pose a unique dilemma for dose determination because many drugs are metabolized in the liver, and impaired hepatic function can impact pharmacokinetic parameters. As specific measures do not currently exist to estimate to what degree hepatic impairment might affect these pharmacokinetic parameters, clinical studies in patients with hepatic impairment are valuable in determining appropriate doses for this vulnerable population [
12]. The US Food and Drug Administration recommends that a pharmacokinetic study be conducted in patients with hepatic impairment if hepatic metabolism and/or excretion pathways account for a substantial portion of the elimination process of a parent drug or active metabolite, or if the drug has a narrow therapeutic range [
12].
Previously, the phase 2 Study 202 (NCT00946153) examined the efficacy and safety of lenvatinib in Asian patients (
N = 46) with HCC [
13]. No differences have been found in the metabolism of lenvatinib in Asian versus non-Asian populations [
14]. Although lenvatinib displayed promising antitumor activity at the 12 mg/day dose, most patients (74%) required a dose reduction to address increased rates of adverse events. A correlation was found between lower body weight and early study drug discontinuation or a need for dose reduction of lenvatinib [
13]. Pharmacokinetic results and exposure–response analyses of data from patients with HCC who were enrolled in Study 202 showed that lower body weight was associated with greater lenvatinib area under the plasma concentration–time curve (AUC), and with dose reduction or earlier treatment discontinuation [
15]. Specifically, a relationship was observed between treatment-emergent adverse events (TEAEs) leading to dose reduction or discontinuation and baseline body weight [
15]. Taken together, data from these pharmacokinetic simulations suggested a body weight-based dose regimen in patients with HCC of lenvatinib 8 mg daily for patients weighing < 60 kg and lenvatinib 12 mg daily for patients weighing ≥ 60 kg [
15].
This body-weight-based lenvatinib dose regimen was used in REFLECT, a phase 3 study that assessed lenvatinib as first-line therapy for patients with uHCC. In REFLECT, lenvatinib treatment met the primary endpoint of noninferiority to sorafenib in terms of overall survival (OS) [
16]. In addition, lenvatinib treatment resulted in statistically significant improvements in secondary endpoints (ie, PFS and ORR) compared with sorafenib.
In this exploratory post hoc analysis, efficacy and safety outcomes from the randomized phase 3 REFLECT trial were analyzed by the lenvatinib starting dose, based on patients’ body weights.
Discussion
This exploratory post hoc analysis used data from REFLECT to examine the efficacy and safety profiles of lenvatinib when patients were stratified by a body-weight-adjusted starting dose (ie, patients weighing < 60 kg received lenvatinib 8 mg/day; those weighing ≥ 60 kg received lenvatinib 12 mg/day). The results indicate that the efficacy of lenvatinib, as demonstrated by OS, PFS, and ORR outcomes, was comparable between the two body weight groups. Additionally, body weight did not appear to impact sorafenib efficacy. The safety profiles among patients who received lenvatinib were also comparable, with generally similar TEAE rates and types between the body weight groups. This confirms that the body weight-based dosing regimen for lenvatinib is appropriate for this indication, as there was no loss in efficacy with the lower dose.
Prior to this analysis, the impact of body weight on lenvatinib pharmacokinetics and safety was analyzed in patients with HCC in Study 202 (
N = 46) [
13]. While efficacy results were positive in Study 202 (median OS of 18.7 months), all patients exhibited at least 1 TEAE [
13]. The most common TEAEs were hypertension (76%), palmar-plantar erythrodysesthesia syndrome (65%), decreased appetite (61%), and proteinuria (61%). Within Study 202, a high percentage of patients (74%) required a dose reduction, and 22% of patients discontinued lenvatinib treatment due to adverse events. Furthermore, 48% of patients experienced a dose reduction or discontinuation as a result of a TEAE < 30 days after the onset of lenvatinib treatment [
13].
Further exploration of this situation suggested that low body weight could be a risk factor for early study-drug dose reduction, which led to a pharmacokinetic analysis in patients with HCC to determine the optimal dose of lenvatinib [
15]. This analysis revealed that when dosing was adjusted for body weight (patients weighing < 60 kg received a starting dose of 8 mg/day lenvatinib, while patients weighing ≥ 60 kg received a starting dose of 12 mg/day lenvatinib), the AUC between the two groups was similar. Using data from Study 202, correlations between rates of dose reduction or discontinuation and factors including body weight and body surface area were assessed. Ultimately the results of Study 202 [
13] and the pharmacokinetic data [
15] led to the decision to implement body weight-based dosing in REFLECT due to its clinical versatility. The goal of body weight-based dosing was to maintain efficacy while decreasing study-drug-related adverse events.
In support of the use of body weight-based lenvatinib dosing in patients with uHCC, efficacy and safety findings in REFLECT were similar between the two lenvatinib dosing groups. The primary endpoint of this analysis of data from REFLECT was OS, and median OS durations were similar in both lenvatinib groups (13.4 months in the lower body weight group, 13.7 months in the higher body weight group) (Fig.
1). Additionally, the TEAE profiles were also similar between the lenvatinib groups, with the five most common types of events in each group being hypertension, diarrhea, decreased appetite, decreased weight, and fatigue (Table
3). In REFLECT, 27.8% of patients in the lenvatinib lower body weight group and 41.2% of patients in the lenvatinib higher body weight group underwent dose reductions (Table
2). Treatment-related TEAEs led to lenvatinib discontinuation in 10.6% of patients in the lower body weight group and 8.0% in the higher body weight group. When the higher body weight group of REFLECT was analyzed further in a post hoc analysis specifically examining patients with body weights > 80 kg, the efficacy (PFS by investigator-assessed mRECIST 9.2 months; OS 14.9 months) and safety profiles of lenvatinib in this group were comparable to those of patients within the current study [
18].
While data from Study 202 were used to support the lenvatinib dose regimen utilized in REFLECT, there are several key differences in baseline patient characteristics. REFLECT was a phase 3 study with most patients (
n = 476 patients who received lenvatinib) coming from two regions (Table
1). Approximately two-thirds of all patients were from the Asia–Pacific region. In contrast, all patients in Study 202 were from either Japan (
n = 43) or South Korea (
n = 3) [
13]. Most patients from Study 202 had an etiology of hepatitis B (35%) or C (45%), and 15% had an etiology of alcohol; one patient (5%) had an unknown etiology [
13]. Within the lenvatinib arm of REFLECT, baseline characteristics were similar between the lenvatinib dosing groups, including measurements of disease severity such as ECOG PS and BCLC. Among all patients receiving lenvatinib, approximately 60% had an ECOG PS of 0, while approximately 80% of patients were assessed as having a BCLC rating of stage C. However, in Study 202, 83% of patients had an ECOG PS of 0, and 59% had a BCLC rating of stage C [
13]. Finally, patients were excluded from REFLECT if they had received prior systemic therapy for HCC, whereas in Study 202 some patients had received prior chemotherapy (13% had received sorafenib, 11% had received other systemic chemotherapy, and 11% had received hepatic intra-arterial chemotherapy [
13]).
Discussion regarding oncology treatment dose selection has indicated that dosing assessment should be an ongoing process, with adjustments made based on indications and special populations [
19]. Pharmacokinetic evaluation is particularly valuable in these assessments because it can determine the balance between peak efficacy and adverse events [
19]. The pharmacokinetic analysis conducted to determine the optimal lenvatinib dose regimen for patients with uHCC used in REFLECT is one such example of the need for, and effectiveness of, these assessments [
15].
To our knowledge, REFLECT was the first phase 3 trial of patients with advanced HCC that utilized body weight-based dosing with a multikinase inhibitor [
16] and, thus could provide valuable information for future clinical trials and study-drug administration procedures. In addition to the pharmacokinetic analysis demonstrating comparable lenvatinib AUC between the two body weight groups [
16], the similar efficacy and safety results between the two body weight groups presented in this post hoc analysis of data from REFLECT support the use of a body weight-adjusted lenvatinib dosing regimen for patients with uHCC.
Acknowledgements
This study was funded by Eisai Inc., Woodcliff, NJ, USA, and also by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing support was provided by Heather A. Mitchell, PhD, Oxford PharmaGenesis Inc., Newtown, PA, USA, and was funded by Eisai Inc., Woodcliff, NJ, USA, and also by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Declarations
Conflict of interest
Takuji Okusaka: reports research funding from Novartis Pharma, AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd, Bristol Myers K.K., and Baxter. Kenji Ikeda: reports no conflicts of interest. Masatoshi Kudo: reports advisory role for Eisai Co., Ltd, Ono, MSD, Bristol Myers Squibb, and Roche; honoraria from Eisai Co., Ltd, Bayer, MSD, Bristol Myers Squib, Lilly, and EA Pharma; grants from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, Abbvie, and Eisai Co., Ltd. Richard S. Finn: reports honoraria from Eisai and Merck. Shukui Qin reports no conflicts of interest. Kwang-Hyub Han: reports no conflicts of interest. Ann-Lii Cheng: reports honoraria from AstraZeneca, Bristol-Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix, IPSEN Innovation, Bayer Healthcare, Merck Sharp & Dohme, Roche/Genentech, BeiGene, CSR Pharma Group, F. Hoffmann-La Roche, and IQVIA. Fabio Piscaglia: reports honoraria from Alkermes, AstraZeneca, Bayer, Bracco, Bristol Myers Squibb, Eisai, GE, Ipsen, La Force Guerbet, Roche, Siemens Healthcare, and Tiziana Life Sciences; research contract with Esaote. Masahiro Kobayashi: reports honoraria from Eisai Co., Ltd. Max W. Sung: reports honoraria from Eisai, AstraZeneca, Bayer. Minshan Chen: reports no conflicts of interest. Lucjan Wyrwicz: reports no conflicts of interest. Jung-Hwan Yoon: reports research grants from AstraZeneca, Bayer HealthCare Pharmaceuticals, Daewoong Pharmaceuticals, and Bukwang Pharmaceuticals. Zhenggang Ren: reports no conflicts of interest. Kalgi Mody: employee of Eisai Inc., Woodcliff, NJ, USA. Corina E. Dutcus: employee of Eisai Inc., Woodcliff, NJ, USA. Toshiyuki Tamai: employee of Eisai Co. Ltd, Tokyo, Japan. Min Ren: employee of Eisai Inc., Woodcliff, NJ, USA. Seiichi Hayato: employee of Eisai Co. Ltd, Tokyo, Japan. Hiromitsu Kumada: reports honoraria from MSD, Sumitomo Dainippon, AbbVie, Gilead Sciences, Inc., and Eisai.
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