The efficacy and safety of lenvatinib for advanced hepatocellular carcinoma in a real-world setting

Obi, Shuntaro; Sato, Takahisa; Sato, Shinpei; Kanda, M.; Tokudome, Yuta; Kojima, Yuichiro; Suzuki, Yoshio; Hosoda, Kei; Kawai, Toshihiro; Isomura, Yoshihiro; Ohyama, Hiroshi; Nakagomi, Keiko; Ashizawa, Hiroshi; Miura, Yuko; Amano, Hiroyuki; Mochizuki, Hitoshi; Omata, Masao

doi:10.1007/s12072-019-09929-4

Cited by 36 publications

(41 citation statements)

References 23 publications

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“…Physicians sometimes reduce lenvatinib doses due to lenvatinib‐related AEs . In the present study, the most frequent cause that led to dose reduction or discontinuation of lenvatinib within 6 weeks was appetite loss (72.5%), and the median 2–6 W‐RDI (69.6%) was significantly lower than the median 0–2 W‐RDI (100%) due to the dose reduction or temporary interruption of lenvatinib.…”

Section: Discussionmentioning

confidence: 51%

“…There have been several reports on the evaluation of antitumor response to lenvatinib using initial imaging, which were assessed from 4 to 8 weeks after lenvatinib introduction, in clinical practice. [14][15][16][17][22][23][24][25][26] These reports showed ORRs of 29.4-45.0% and DCRs of 60.0-93.0%. Similarly, the present study showed that relative to the image at baseline, the 6 W-ORR and 6 W-DCR were 50.0% and 90.0%, respectively.…”

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Favorable radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma

Kuzuya

Ishigami

Ito

et al. 2019

Hepatology Research

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Aim We aimed to investigate the radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma in real‐world practice. Methods This retrospective study enrolled 40 patients who received lenvatinib. Radiological antitumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors. Results The objective response rate at 2 weeks and best overall response on confirmation of complete response, partial response (PR), and stable disease required (confirmed response) were 57.5% and 32.5%, respectively. Based on confirmed response, the overall survival rate was significantly longer in patients with an objective response rate than in those with stable disease or progressive disease after 12 months (73.2% and 54.2%, P = 0.0358). All 13 patients with an objective response rate on confirmed response were evaluated as PR at 2 weeks. The alpha‐fetoprotein ratio at 2 weeks was a significant factor associated with PR of response rate at 2 weeks. The median relative dose intensity from 2 to 6 weeks was significantly lower than that from 0 to 2 weeks (69.6% vs. 100%, P < 0.0001). Stratified by the antitumor response at 6 weeks considering the image evaluation at 2 weeks, the median relative dose intensity from 2 to 6 weeks was significantly lower in patients with progressive disease than in those with PR or stable disease (45.2% vs. 72.6%, P = 0.0482). Conclusions The radiological antitumor response at 2 weeks was favorable. Information on a favorable visible therapeutic response very early after lenvatinib initiation can help patients maintain their motivation for treatment, and allow physicians to continue treatment effectively and safely.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 91%

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Favorable radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma

Kuzuya

Ishigami

Ito

et al. 2019

Hepatology Research

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“…To date, lenvatinib showed a higher ORR of 41.3% compared with sorafenib in a randomized phase II non‐inferiority trial, and it also showed the ORR of 37.5–40.7% assessed by modified Response Evaluation Criteria in Solid Tumors in clinical settings . Meanwhile, a relative higher ORR of 61.3% was reported in patients with intermediate‐stage HCC according to the Japanese subgroup analysis of a randomized phase III study .…”

Section: Discussionmentioning

confidence: 95%

“…To date, lenvatinib showed a higher ORR of 41.3% compared with sorafenib in a randomized phase II noninferiority trial, 5 and it also showed the ORR of 37.5-40.7% assessed by modified Response Evaluation Criteria in Solid Tumors in clinical settings. [25][26][27][28] Meanwhile, a relative higher ORR of 61.3% was reported in patients with intermediate-stage HCC according to the Japanese subgroup analysis of a randomized phase III study. 29 However, Ueshima et al reported that patients with Child-Pugh score 5 and ALBI grade 1 showed better tolerability and it was easier to maintain the initial dose of lenvatinib than those with poor hepatic function, insisting that ALBI grade 1 was the favorable factor affecting the ORR in the multivariate analysis.…”

Section: Discussionmentioning

confidence: 99%

Analyses of objective response rate, progression‐free survival, and adverse events in hepatocellular carcinoma patients treated with lenvatinib: A multicenter retrospective study

Hatanaka

Kakizaki

Nagashima

et al. 2019

Hepatology Research

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Aim The aim of this study was to investigate the predictive factors of objective response rate (ORR) and progression‐free survival (PFS), and the correlation of albumin‐bilirubin (ALBI) grade with decreased appetite and fatigue in hepatocellular carcinoma patients treated with lenvatinib. Methods From March 2018 to December 2018, a total of 94 patients was included in this retrospective multicenter study. Results The median age of all patients was 73 years (interquartile range 66–79.3 years), and approximately 78% patients were men. The ALBI grade was 1, 2, and 3 in 27 (28.7%), 64 (68.1%), and three patients (3.2%), respectively. The Barcelona Clinic Liver Cancer stage was early, intermediate, and advanced in one (1.1%), 22 (23.4%), and 71 patients (75.5%), respectively. Best radiological response was determined to complete response, partial response, stable disease, and progressive disease in 0 (0.0%), 24 (30.4%), 38 (48.1%), and 17 patients (21.5%), respectively, giving the ORR of 30.4%. The 3‐, 6‐, and 12‐month PFS was calculated to be 78.7% (95% CI 70.3–87.1%), 46.7% (95% CI 36.1–57.3%), and 17.4% (95% CI 6.6–28.2%). Multivariate analysis showed that the Barcelona Clinic Liver Cancer intermediate stage was shown to be the only significant factor affecting the ORR (odds ratio 3.78, 95% CI 1.14–12.5, P = 0.030) and PFS (hazard ratio 0.49, 95% CI 0.26–0.94, P = 0.030). The incidence of all grades of decreased appetite and fatigue was significantly less in patients with ALBI grade 1 compared with ALBI grade 2 + 3. Conclusions The Barcelona Clinic Liver Cancer intermediate stage was the predictive factor affecting the ORR and PFS, and ALBI grade was a good predictive factor affecting the incidence of fatigue and decreased appetite.

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Cancer‐associated fibroblast‐derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib

Eun

Yoon

Ahn

et al. 2023

Cancer Communications

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Background Cancer‐associated fibroblasts (CAFs) play an important role in the induction of chemo‐resistance. This study aimed to clarify the mechanism underlying CAF‐mediated resistance to two tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma (HCC). Methods We performed a systematic integrative analysis of publicly available gene expression datasets and whole‐transcriptome sequencing data from 9 pairs of CAFs and para‐cancer fibroblasts isolated from human HCC and para‐tumor tissues, respectively, to identify key molecules that might induce resistance to TKIs. We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms. The associations of plasma secreted phosphoprotein 1 (SPP1) expression levels before sorafenib/lenvatinib treatment with progression‐free survival (PFS) and overall survival (OS) of 54 patients with advanced HCC were evaluated using Kaplan‐Meier and Cox regression analysis. Results Bioinformatic analysis identified CAF‐derived SPP1 as a candidate molecule driving TKI resistance. SPP1 inhibitors reversed CAF‐induced TKI resistance in vitro and in vivo. CAF‐derived SPP1 activated rapidly accelerated fibrosarcoma (RAF)/mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) through the integrin‐protein kinase C‐alpha (PKCα) signaling pathway and promoted epithelial‐to‐mesenchymal transition (EMT). A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS ( P = 0.026) and OS ( P = 0.047) in patients with advanced HCC after TKI treatment. Conclusions CAF‐derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion. Its inhibition represents a promising therapeutic strategy against TKI resistance in HCC. Moreover, plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.

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The efficacy and safety of lenvatinib for advanced hepatocellular carcinoma in a real-world setting

Cited by 36 publications

References 23 publications

Favorable radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma

Favorable radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma

Analyses of objective response rate, progression‐free survival, and adverse events in hepatocellular carcinoma patients treated with lenvatinib: A multicenter retrospective study

Cancer‐associated fibroblast‐derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib

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