TY - JOUR
T1 - Reverce
T2 - A randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients
AU - Shitara, K.
AU - Yamanaka, T.
AU - Denda, T.
AU - Tsuji, Y.
AU - Shinozaki, K.
AU - Komatsu, Y.
AU - Kobayashi, Y.
AU - Furuse, J.
AU - Okuda, H.
AU - Asayama, M.
AU - Akiyoshi, K.
AU - Kagawa, Y.
AU - Kato, T.
AU - Oki, E.
AU - Ando, T.
AU - Hagiwara, Y.
AU - Ohashi, Y.
AU - Yoshino, T.
N1 - Funding Information:
This study was funded by Bayer Yakuhin Ltd (no grant number applies). The funder of the study had no role in study design, data collection, analysis, or interpretation, or writing of the report.
Funding Information:
KS reports personal fees from Astellas Pharma, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Novartis, Abbvie, and Yakult; grants from Lilly, Ono Pharmaceutical, Dainippon Sumitomo Pharma, Daiichi Sankyo, Taiho Pharmaceutical, Chugai, outside the submitted work. TY reports personal fees from Takeda, Boehringer Ingelheim, Chugai Pharmaceutical, Taiho Pharmaceutical, Merck Serono, Gilead Sciences, Sysmex, Huya Bioscience International, AstraZeneca, and Bayer; grants from Takeda Pharmaceutical, Taiho Pharmaceutical, outside the submitted work. TD reports grants from MSD, Sanofi, Boehringer Ingelheim, personal fees from Yakult Honsha Co., Ltd., Chugai Pharmaceutical, Taiho Pharmaceutical, outside the submitted work. YT has received honoraria from Merck Serono, Eli Lilly, Chugai, Taiho, Ono, Daiichi Sankyo, Yakult Honsha, Eisai and Medicon outside the submitted work. KS reports personal fees for lecture from Chugai Pharm, Takeda, Mochida Pharm, Merck Serono, Taiho Pharm, Yakult Honsha, Astellas Pharma Inc., Novartis Pharma K.K., Eisai, Eli Lilly, Shionogi & Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Asahi Kasei Pharma Co., and MSD. YK reports personal fees from Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Novartis, Yakult, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, and Bayer; grants from Lilly, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical and Chugai Pharma, outside the submitted work. JF reports personal fees from Bayer, Merck Serono, Taiho, Chugai, Yakult, Sumitomo Dainippon, Eli Lilly, Astellas, Ono, Pfizer, Novartis, Takeda, Eisai, MSD, Shionogi, J-pharma, Daiichi Sankyo, Nippon Kayaku, Mochida, EA pharma, Sawai, and Teijin pharma; grants from Bayer, Merck Serono, Taiho, Chugai, Yakult, Sumitomo Dainippon, Eli Lilly, Astellas, Ono, Pfizer. Novartis, Takeda, Eisai, MSD, Shionogi, J-pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Sanofy, Sandoz, Otsuka, Zeria, Fujifilm, Astra Zeneca, Asahi Kasei, and Shire, outside the submitted work. TK reports personal fees from Lilly, Takeda, Yakult, Taiho Pharmaceutical, Chugai Pharma, Sanofi, Merc Serono, outside the submitted work. EO reports lecturer fee from Bayer Yakuhin Japan, Ltd. YH reports personal fees from EP-CRSU during the conduct of the study. YO reports personal fees from Statcom, Sanofi, Eisai, Chugai, Taiho, Shionogi, Kowa, Public Health Research Foundation, and Daiicchi-Sankyo; grants from Eisai, and Yakult Honsha, outside the submitted work. TY reports personal fees from Sanofi K.K., Chugai Pharmaceutical Co., Eli Lilly Japan K.K, and Merck Serono Co., Ltd.; grants from MSD K.K, Sumitomo Dainippon Pharma Cp., Ltd, Chugai Pharmaceutical Co GlaxoSmithKline K.K., and Nippon Boehringer Ingelheim Co., Ltd, outside the submitted work. All remaining authors have declared no conflicts of interest.
Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - Background The objective of this randomized phase II trial was to evaluate efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib, as the current standard sequence for metastatic colorectal cancer patients. Patients and methods Patients with KRAS exon 2 wild-type metastatic colorectal cancer after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with regorafenib followed by cetuximab ± irinotecan (R-C arm), or the reverse sequence [cetuximab ± irinotecan followed by regorafenib (C-R arm)]. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and quality of life. Exploratory end points included serial biomarker analyses, including oncogenic alterations from circulating tumor DNA or multiple serum or plasma proteins. Results One-hundred one patients were randomized and eligible for efficacy analysis. Sequential treatment was successful in 86% patients in both arms. Median OS for R-C and C-R was 17.4 and 11.6 months, respectively (P = 0.0293), with a hazard ratio (HR) of 0.61 for OS [95% confidence interval (CI) 0.39-0.96]. The HR for PFS1 (regorafenib in R-C versus cetuximab in C-R) was 0.97 (95% CI 0.61-1.54), and PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI 0.17-0.50). No unexpected safety signals were observed. The quality of life scores during the entire treatment period was not significantly different between the two arms. Circulating biomarker analyses showed emerging oncogenic alterations in RAS, BRAF, EGFR, HER2, and MET, which were more commonly detected after cetuximab than after regorafenib. Conclusions The therapeutic sequence of regorafenib followed by cetuximab suggests a longer OS than the current standard sequence.
AB - Background The objective of this randomized phase II trial was to evaluate efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib, as the current standard sequence for metastatic colorectal cancer patients. Patients and methods Patients with KRAS exon 2 wild-type metastatic colorectal cancer after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with regorafenib followed by cetuximab ± irinotecan (R-C arm), or the reverse sequence [cetuximab ± irinotecan followed by regorafenib (C-R arm)]. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and quality of life. Exploratory end points included serial biomarker analyses, including oncogenic alterations from circulating tumor DNA or multiple serum or plasma proteins. Results One-hundred one patients were randomized and eligible for efficacy analysis. Sequential treatment was successful in 86% patients in both arms. Median OS for R-C and C-R was 17.4 and 11.6 months, respectively (P = 0.0293), with a hazard ratio (HR) of 0.61 for OS [95% confidence interval (CI) 0.39-0.96]. The HR for PFS1 (regorafenib in R-C versus cetuximab in C-R) was 0.97 (95% CI 0.61-1.54), and PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI 0.17-0.50). No unexpected safety signals were observed. The quality of life scores during the entire treatment period was not significantly different between the two arms. Circulating biomarker analyses showed emerging oncogenic alterations in RAS, BRAF, EGFR, HER2, and MET, which were more commonly detected after cetuximab than after regorafenib. Conclusions The therapeutic sequence of regorafenib followed by cetuximab suggests a longer OS than the current standard sequence.
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U2 - 10.1093/annonc/mdy526
DO - 10.1093/annonc/mdy526
M3 - Article
C2 - 30508156
AN - SCOPUS:85058857232
VL - 30
SP - 259
EP - 265
JO - Annals of Oncology
JF - Annals of Oncology
SN - 0923-7534
IS - 2
ER -