Optimal management of lenvatinib therapy for patients with unresectable hepatocellular carcinoma by balancing the therapeutic effect with the relative dose intensity

2021 ◽  
Author(s):  
Takayuki Tokunaga ◽  
Masakuni Tateyama ◽  
Kentaro Tanaka ◽  
Satoshi Narahara ◽  
Hiroki Inada ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Effect ◽  
Dose Intensity ◽  
Relative Dose Intensity ◽  
Optimal Management ◽  
Unresectable Hepatocellular Carcinoma

scholarly journals Relationship between outcomes and relative dose intensity of lenvatinib treatment in patients with advanced hepatocellular carcinoma

2020 ◽  
Vol 4 (4) ◽  
pp. 199-205
Author(s):  
Takamasa Ohki ◽  
Koki Sato ◽  
Mayuko Kondo ◽  
Eriko Goto ◽  
Takahisa Sato ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dose Intensity ◽  
Relative Dose Intensity ◽  
Advanced Hepatocellular Carcinoma

scholarly journals Impact of Relative Dose Intensity of Early-phase Lenvatinib Treatment on Therapeutic Response in Hepatocellular Carcinoma

2019 ◽  
Vol 39 (9) ◽  
pp. 5149-5156 ◽  
Author(s):  
AYA TAKAHASHI ◽  
MICHIHISA MORIGUCHI ◽  
YUYA SEKO ◽  
HIROKI ISHIKAWA ◽  
TAKAHARU YO ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Early Phase ◽  
Therapeutic Response ◽  
Dose Intensity ◽  
Relative Dose Intensity

scholarly journals REFLECT—a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset

2019 ◽  
Vol 55 (1) ◽  
pp. 113-122 ◽  
Author(s):  
Tatsuya Yamashita ◽  
Masatoshi Kudo ◽  
Kenji Ikeda ◽  
Namiki Izumi ◽  
Ryosuke Tateishi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Japanese Population ◽  
Objective Response ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Unresectable Hepatocellular Carcinoma

Abstract Background A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79–1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported. Methods The intent-to-treat population enrolled in Japan was analyzed. Results Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62–1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm. Conclusions The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC. Trial registration ID ClinicalTrials.gov. No. NCT01761266.

scholarly journals Changes in Serum Growth Factors during Lenvatinib Predict the Post Progressive Survival in Patients with Unresectable Hepatocellular Carcinoma

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 232
Author(s):  
Zijian Yang ◽  
Goki Suda ◽  
Osamu Maehara ◽  
Masatsugu Ohara ◽  
Sonoe Yoshida ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multivariate Analysis ◽  
Growth Factors ◽  
Growth Factor ◽  
Progressive Disease ◽  
Dose Intensity ◽  
Patient Characteristics ◽  
Complete Response ◽  
Unresectable Hepatocellular Carcinoma ◽  
Best Response

Serum growth factor changes and their effect on prognosis during lenvatinib for unresectable hepatocellular carcinoma (HCC) remain underexplored. The sequential changes in serum growth factors during lenvatinib for unresectable HCC were evaluated in 58 patients using complete clinical data, and preserved serum was used to investigate changes in FGF-19, ANG-2, HGF, VEGF, and EGF. Patients with a complete response (CR), partial response (PR), and stable disease (SD) were evaluated for growth factor changes between the best response and progressive disease (PD) points, classified based on these changes, and evaluated by post progression survival (PPS). A total of 8, 24, 18, and 8 patients showed CR, PR, SD, and PD, respectively. Multivariate analysis revealed that age, relative dose intensity, and baseline ANG-2 were significantly associated with treatment response. Growth factor changes between the best response and PD points revealed that patients could be classified into four groups based on the EGF, ANG-2, and HGF changes. Although patient characteristics at baseline and PD, their response to lenvatinib, and PFS were similar among those groups, patients with an increase in all growth factors had significantly shorter PPS (median PPS was 553, 323, and 316 versus 173 days in groups 1–4 p = 0.032). We revealed that the evaluation of the changes in growth factors during lenvatinib could predict PPS.

scholarly journals Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib

2020 ◽  
Vol 12 ◽  
pp. 175883592092205
Author(s):  
Atsushi Ono ◽  
Hiroshi Aikata ◽  
Masami Yamauchi ◽  
Kenichiro Kodama ◽  
Waka Ohishi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dose Intensity ◽  
Serum Levels ◽  
Angiogenic Factors ◽  
Phase Iii ◽  
Relative Dose Intensity ◽  
Advanced Hepatocellular Carcinoma ◽  
Baseline Serum ◽  
Advanced Hcc ◽  
Circulating Cytokines

Background: Although lenvatinib was recently approved for treatment of advanced unresectable hepatocellular carcinoma (HCC) based on the phase III REFLECT trial, no biomarkers for management of lenvatinib treatment have been established. The aim of this study is to identify predictive biomarkers for the management of lenvatinib treatment in advanced HCC patients. Methods: A total of 41 patients with advanced HCC were enrolled in this retrospective study. Serum levels of 22 circulating cytokines and angiogenic factors (CAFs) were measured by multiplex Luminex assay. Profiles of CAFs, clinical chemistry/hematology parameters, and clinical background were evaluated to explore biomarkers associated with clinical outcomes. Results: Relative dose intensity (RDI) decreased significantly between weeks 1–2 and 3–4 ( p < 0.001), and RDI during weeks 3–4 was a prominent indicator of progression-free survival (PFS). A signature based on baseline serum levels of nine CAFs associated with low RDI was identified. In a multivariate Cox regression analysis, patients with a favorable 9-CAFs signature [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.18–0.96, p = 0.040] had lower risk, and Child-Pugh grade B (HR 1.6, 95% CI 1.1–8.3, p = 0.026) and presence of macrovascular invasion (MVI; HR 2.9, 95% CI 1.0–8.3, p = 0.045) had higher risk of shorter PFS. Conclusion: This study demonstrates that RDI is an important predictive factor for longer PFS during lenvatinib treatment. In this hypothesis-generating exploratory analysis, we report that a CAF-signature associated with adverse events and RDI could predict PFS, which might contribute to improved management of lenvatinib treatment in HCC patients.

A multicenter observational study of lenvatinib for unresectable hepatocellular carcinoma in Japan.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16118-e16118
Author(s):  
Namiki Izumi ◽  
Masatoshi Kudo ◽  
Kenta Motomura ◽  
Yoshitaka Inaba ◽  
Yoshio Katamura ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatic Encephalopathy ◽  
Observational Study ◽  
Incidence Rate ◽  
Systemic Therapy ◽  
Kinase Inhibitor ◽  
Dose Intensity ◽  
Multicenter Observational Study ◽  
Unresectable Hepatocellular Carcinoma ◽  
Grade 3

e16118 Background: Lenvatinib is an oral tyrosine kinase inhibitor that has been available for treatment of unresectable hepatocellular carcinoma (uHCC) in Japan since March 2018. We conducted a multicenter prospective observational study to evaluate the safety and efficacy of lenvatinib in clinical practice. Methods: This study conducted as a prospective study, and enrolled patients with uHCC initially receiving lenvatinib as systemic therapy who gave informed consent from July 2018 through January 2019. The observation period per patient was 12 months and e-CRF was used. Results: 713 patients were registered at 133 clinical sites. The safety analysis set and efficacy analysis set were 703 patients. Patient baseline characteristics included median age:73.0 years (25 to 94), male/ female: 564/139, bodyweight: < 60kg/≥60kg: 323/380, HBV/HCV/alcohol/NAFLD or NASH: 137/287/167/88, Child-Pugh classification A/B or higher: 624/75, BCLC stage A/B/C/D: 57/291/332/11, Vp 0/1/2/3/4: 520/31/52/60/22, with/without extrahepatic metastasis: 236/461. Previous treatment (local and systemic therapy) for hepatocellular carcinoma is with/without TACE: 513/190, median number of TACE treatment: 3.0 times (1 to 26), with/without HAIC: 74/629, with/without TKI pretreatment: 131/572. The initial dose was 8 mg (80.5%) and 12 mg (68.2%) in patients with < 60 kg and ≥60 kg, respectively. Median relative dose intensity was 64.2% and the treatment continuation rate at 3 and 12 months after administration of lenvatinib were 67.3% and 24.8%. Regarding safety, the incidence of treatment-related adverse events (TRAEs) was 84.9% (grade 3 or higher: 42.5%). Common TRAEs (incidence rate ≥10%) were decreased appetite (23.9%), malaise (21.8%), hypertension (21.3%), proteinuria (18.3%), palmar-plantar erythrodysesthesia syndrome (16.5%), hypothyroidism (15.8%), and diarrhea (13.9%). TRAEs of grade 3 or higher （incidence rate ≥2.5%） were proteinuria (6.7%), hypertension (6.4%), malaise (3.8%), decreased appetite (3.6%), platelet count decreased (3.3%), palmar-plantar erythrodysesthesia syndrome (2.7%), diarrhea (2.7%) and hepatic encephalopathy (2.6%). The incidence of TRAEs leading to discontinuation of lenvatinib was 32.9％, and main TRAEs leading to discontinuation of lenvatinib were (incidence rate ≥2%) decreased appetite (6.3%), malaise (4.7%), proteinuria (3.3%) and hepatic encephalopathy (2.4%). Regarding efficacy, the ORR and DCR was 39.5% (95% CI: 35.1, 43.9) and 78.9% (75.1, 82.5) in 494 patients who were evaluated for the best response by mRECIST. The median OS was 498.0 days (95% CI: 439.0, -) in 703 patients. Conclusions: The incidence of TRAEs leading to discontinuation of lenvatinib tended to be higher than in phase 3 REFLECT trials (19.7%), but the safety profile and effectiveness findings for lenvatinib in this study were consistent with previous reports.

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