Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT

Takuji Okusaka; Kenji Ikeda; Masatoshi Kudo; Richard Finn; Shukui Qin; Kwang Hyub Han; Ann Lii Cheng; Fabio Piscaglia; Masahiro Kobayashi; Max Sung; Minshan Chen; Lucjan Wyrwicz; Jung Hwan Yoon; Zhenggang Ren; Kalgi Mody; Corina Dutcus; Toshiyuki Tamai; Min Ren; Seiichi Hayato; Hiromitsu Kumada

doi:10.1007/s00535-021-01785-0

Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT

Takuji Okusaka, Kenji Ikeda, Masatoshi Kudo, Richard Finn, Shukui Qin, Kwang Hyub Han, Ann Lii Cheng, Fabio Piscaglia, Masahiro Kobayashi, Max Sung, Minshan Chen, Lucjan Wyrwicz, Jung Hwan Yoon, Zhenggang Ren, Kalgi Mody, Corina Dutcus, Toshiyuki Tamai, Min Ren, Seiichi Hayato, Hiromitsu Kumada

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Background: REFLECT was an open-label, phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). Based on phase 2 study (Study 202) results, body weight-based dosing for lenvatinib was used in REFLECT to minimize dose disruptions and modifications needed to address dose-related adverse events. This post hoc analysis of REFLECT data assessed lenvatinib efficacy and safety by body weight group. Methods: The study randomly administered lenvatinib (n = 476) or sorafenib (n = 475) to patients with untreated (no prior systemic therapy) uHCC. Lenvatinib starting-dose data were stratified by body weight: patients weighing < 60 kg received 8 mg/day; patients weighing ≥ 60 kg received 12 mg/day. Overall survival (OS), progression-free survival (PFS), objective response rate, and safety were assessed. Results: Survival outcomes and safety profiles appeared similar between the two body-weight-based lenvatinib starting-dose groups. Median OS for patients in the < 60 kg body weight group (n = 153) was 13.4 months [95% confidence interval (CI) 10.5–15.7] compared to 13.7 months (95% CI 12.0–15.6) in the ≥ 60 kg body weight group (n = 325). In both lenvatinib groups, PFS was 7.4 months (< 60 kg group: 95% CI 5.4–9.2; ≥ 60 kg group: 95% CI 6.9–9.0). Treatment-emergent adverse events (TEAEs) required dose modifications in 43.0% in the < 60 kg body weight group and 57.5% in the ≥ 60 kg body weight group. Conclusions: This exploratory analysis of data from REFLECT indicated that body weight-based lenvatinib dosing in patients with uHCC was successful in maintaining efficacy, with comparable rates of TEAEs and dose modifications in the two body weight groups. Clinincal trial: Trial registration ID: ClinicalTrials.gov # NCT01761266.

Original language	English
Pages (from-to)	570-580
Number of pages	11
Journal	Journal of Gastroenterology
Volume	56
Issue number	6
DOIs	https://doi.org/10.1007/s00535-021-01785-0
Publication status	Published - 2021 Jun

Bibliographical note

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2021, The Author(s).

All Science Journal Classification (ASJC) codes

Gastroenterology

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10.1007/s00535-021-01785-0

Cite this

Okusaka, T., Ikeda, K., Kudo, M., Finn, R., Qin, S., Han, K. H., Cheng, A. L., Piscaglia, F., Kobayashi, M., Sung, M., Chen, M., Wyrwicz, L., Yoon, J. H., Ren, Z., Mody, K., Dutcus, C., Tamai, T., Ren, M., Hayato, S., & Kumada, H. (2021). Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT. Journal of Gastroenterology, 56(6), 570-580. https://doi.org/10.1007/s00535-021-01785-0

@article{a1ce9ef4a7c74e64939b289d0a58fdc3,

title = "Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT",

abstract = "Background: REFLECT was an open-label, phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). Based on phase 2 study (Study 202) results, body weight-based dosing for lenvatinib was used in REFLECT to minimize dose disruptions and modifications needed to address dose-related adverse events. This post hoc analysis of REFLECT data assessed lenvatinib efficacy and safety by body weight group. Methods: The study randomly administered lenvatinib (n = 476) or sorafenib (n = 475) to patients with untreated (no prior systemic therapy) uHCC. Lenvatinib starting-dose data were stratified by body weight: patients weighing < 60 kg received 8 mg/day; patients weighing ≥ 60 kg received 12 mg/day. Overall survival (OS), progression-free survival (PFS), objective response rate, and safety were assessed. Results: Survival outcomes and safety profiles appeared similar between the two body-weight-based lenvatinib starting-dose groups. Median OS for patients in the < 60 kg body weight group (n = 153) was 13.4 months [95% confidence interval (CI) 10.5–15.7] compared to 13.7 months (95% CI 12.0–15.6) in the ≥ 60 kg body weight group (n = 325). In both lenvatinib groups, PFS was 7.4 months (< 60 kg group: 95% CI 5.4–9.2; ≥ 60 kg group: 95% CI 6.9–9.0). Treatment-emergent adverse events (TEAEs) required dose modifications in 43.0% in the < 60 kg body weight group and 57.5% in the ≥ 60 kg body weight group. Conclusions: This exploratory analysis of data from REFLECT indicated that body weight-based lenvatinib dosing in patients with uHCC was successful in maintaining efficacy, with comparable rates of TEAEs and dose modifications in the two body weight groups. Clinincal trial: Trial registration ID: ClinicalTrials.gov # NCT01761266.",

author = "Takuji Okusaka and Kenji Ikeda and Masatoshi Kudo and Richard Finn and Shukui Qin and Han, {Kwang Hyub} and Cheng, {Ann Lii} and Fabio Piscaglia and Masahiro Kobayashi and Max Sung and Minshan Chen and Lucjan Wyrwicz and Yoon, {Jung Hwan} and Zhenggang Ren and Kalgi Mody and Corina Dutcus and Toshiyuki Tamai and Min Ren and Seiichi Hayato and Hiromitsu Kumada",

note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jun,

doi = "10.1007/s00535-021-01785-0",

language = "English",

volume = "56",

pages = "570--580",

journal = "Journal of Gastroenterology",

issn = "0944-1174",

publisher = "Springer Japan",

number = "6",

}

Okusaka, T, Ikeda, K, Kudo, M, Finn, R, Qin, S, Han, KH, Cheng, AL, Piscaglia, F, Kobayashi, M, Sung, M, Chen, M, Wyrwicz, L, Yoon, JH, Ren, Z, Mody, K, Dutcus, C, Tamai, T, Ren, M, Hayato, S & Kumada, H 2021, 'Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT', Journal of Gastroenterology, vol. 56, no. 6, pp. 570-580. https://doi.org/10.1007/s00535-021-01785-0

TY - JOUR

T1 - Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT

AU - Okusaka, Takuji

AU - Ikeda, Kenji

AU - Kudo, Masatoshi

AU - Finn, Richard

AU - Qin, Shukui

AU - Han, Kwang Hyub

AU - Cheng, Ann Lii

AU - Piscaglia, Fabio

AU - Kobayashi, Masahiro

AU - Sung, Max

AU - Chen, Minshan

AU - Wyrwicz, Lucjan

AU - Yoon, Jung Hwan

AU - Ren, Zhenggang

AU - Mody, Kalgi

AU - Dutcus, Corina

AU - Tamai, Toshiyuki

AU - Ren, Min

AU - Hayato, Seiichi

AU - Kumada, Hiromitsu

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2021, The Author(s).

PY - 2021/6

Y1 - 2021/6

N2 - Background: REFLECT was an open-label, phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). Based on phase 2 study (Study 202) results, body weight-based dosing for lenvatinib was used in REFLECT to minimize dose disruptions and modifications needed to address dose-related adverse events. This post hoc analysis of REFLECT data assessed lenvatinib efficacy and safety by body weight group. Methods: The study randomly administered lenvatinib (n = 476) or sorafenib (n = 475) to patients with untreated (no prior systemic therapy) uHCC. Lenvatinib starting-dose data were stratified by body weight: patients weighing < 60 kg received 8 mg/day; patients weighing ≥ 60 kg received 12 mg/day. Overall survival (OS), progression-free survival (PFS), objective response rate, and safety were assessed. Results: Survival outcomes and safety profiles appeared similar between the two body-weight-based lenvatinib starting-dose groups. Median OS for patients in the < 60 kg body weight group (n = 153) was 13.4 months [95% confidence interval (CI) 10.5–15.7] compared to 13.7 months (95% CI 12.0–15.6) in the ≥ 60 kg body weight group (n = 325). In both lenvatinib groups, PFS was 7.4 months (< 60 kg group: 95% CI 5.4–9.2; ≥ 60 kg group: 95% CI 6.9–9.0). Treatment-emergent adverse events (TEAEs) required dose modifications in 43.0% in the < 60 kg body weight group and 57.5% in the ≥ 60 kg body weight group. Conclusions: This exploratory analysis of data from REFLECT indicated that body weight-based lenvatinib dosing in patients with uHCC was successful in maintaining efficacy, with comparable rates of TEAEs and dose modifications in the two body weight groups. Clinincal trial: Trial registration ID: ClinicalTrials.gov # NCT01761266.

AB - Background: REFLECT was an open-label, phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). Based on phase 2 study (Study 202) results, body weight-based dosing for lenvatinib was used in REFLECT to minimize dose disruptions and modifications needed to address dose-related adverse events. This post hoc analysis of REFLECT data assessed lenvatinib efficacy and safety by body weight group. Methods: The study randomly administered lenvatinib (n = 476) or sorafenib (n = 475) to patients with untreated (no prior systemic therapy) uHCC. Lenvatinib starting-dose data were stratified by body weight: patients weighing < 60 kg received 8 mg/day; patients weighing ≥ 60 kg received 12 mg/day. Overall survival (OS), progression-free survival (PFS), objective response rate, and safety were assessed. Results: Survival outcomes and safety profiles appeared similar between the two body-weight-based lenvatinib starting-dose groups. Median OS for patients in the < 60 kg body weight group (n = 153) was 13.4 months [95% confidence interval (CI) 10.5–15.7] compared to 13.7 months (95% CI 12.0–15.6) in the ≥ 60 kg body weight group (n = 325). In both lenvatinib groups, PFS was 7.4 months (< 60 kg group: 95% CI 5.4–9.2; ≥ 60 kg group: 95% CI 6.9–9.0). Treatment-emergent adverse events (TEAEs) required dose modifications in 43.0% in the < 60 kg body weight group and 57.5% in the ≥ 60 kg body weight group. Conclusions: This exploratory analysis of data from REFLECT indicated that body weight-based lenvatinib dosing in patients with uHCC was successful in maintaining efficacy, with comparable rates of TEAEs and dose modifications in the two body weight groups. Clinincal trial: Trial registration ID: ClinicalTrials.gov # NCT01761266.

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U2 - 10.1007/s00535-021-01785-0

DO - 10.1007/s00535-021-01785-0

M3 - Article

C2 - 33948712

AN - SCOPUS:85105882122

SN - 0944-1174

VL - 56

SP - 570

EP - 580

JO - Journal of Gastroenterology

JF - Journal of Gastroenterology

IS - 6

ER -

Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT

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