Reverce: A randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients

K. Shitara, T. Yamanaka, T. Denda, Y. Tsuji, K. Shinozaki, Y. Komatsu, Y. Kobayashi, J. Furuse, H. Okuda, M. Asayama, K. Akiyoshi, Y. Kagawa, T. Kato, E. Oki, T. Ando, Y. Hagiwara, Y. Ohashi, T. Yoshino

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Abstract

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.

Original languageEnglish
Pages (from-to)259-265
Number of pages7
JournalAnnals of Oncology
Volume30
Issue number2
DOIs
Publication statusPublished - Feb 1 2019

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irinotecan
Colorectal Neoplasms
oxaliplatin
Survival
Confidence Intervals
Safety
Therapeutics
Disease-Free Survival
Blood Proteins
Biomarkers
Quality of Life
Cetuximab
regorafenib
Exons
DNA
Neoplasms

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

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Reverce : A randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients. / Shitara, K.; Yamanaka, T.; Denda, T.; Tsuji, Y.; Shinozaki, K.; Komatsu, Y.; Kobayashi, Y.; Furuse, J.; Okuda, H.; Asayama, M.; Akiyoshi, K.; Kagawa, Y.; Kato, T.; Oki, E.; Ando, T.; Hagiwara, Y.; Ohashi, Y.; Yoshino, T.

In: Annals of Oncology, Vol. 30, No. 2, 01.02.2019, p. 259-265.

Research output: Contribution to journalArticle

Shitara, K, Yamanaka, T, Denda, T, Tsuji, Y, Shinozaki, K, Komatsu, Y, Kobayashi, Y, Furuse, J, Okuda, H, Asayama, M, Akiyoshi, K, Kagawa, Y, Kato, T, Oki, E, Ando, T, Hagiwara, Y, Ohashi, Y & Yoshino, T 2019, 'Reverce: A randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients', Annals of Oncology, vol. 30, no. 2, pp. 259-265. https://doi.org/10.1093/annonc/mdy526
Shitara, K. ; Yamanaka, T. ; Denda, T. ; Tsuji, Y. ; Shinozaki, K. ; Komatsu, Y. ; Kobayashi, Y. ; Furuse, J. ; Okuda, H. ; Asayama, M. ; Akiyoshi, K. ; Kagawa, Y. ; Kato, T. ; Oki, E. ; Ando, T. ; Hagiwara, Y. ; Ohashi, Y. ; Yoshino, T. / Reverce : A randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients. In: Annals of Oncology. 2019 ; Vol. 30, No. 2. pp. 259-265.
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abstract = "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.",
author = "K. Shitara and T. Yamanaka and T. Denda and Y. Tsuji and K. Shinozaki and Y. Komatsu and Y. Kobayashi and J. Furuse and H. Okuda and M. Asayama and K. Akiyoshi and Y. Kagawa and T. Kato and E. Oki and T. Ando and Y. Hagiwara and Y. Ohashi and T. Yoshino",
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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.

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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