K Shitara1, T Yamanaka2, T Denda3, Y Tsuji4, K Shinozaki5, Y Komatsu6, Y Kobayashi7, J Furuse8, H Okuda9, M Asayama10, K Akiyoshi11, Y Kagawa12, T Kato13, E Oki14, T Ando15, Y Hagiwara16, Y Ohashi17, T Yoshino18. 1. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. 2. Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan. 3. Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan. 4. Department of Medical Oncology, Tonan Hospital, Sapporo, Japan. 5. Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima, Japan. 6. Division of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, Japan. 7. Department of Medical Oncology, Kushiro Rosai Hospital, Kushiro, Japan. 8. Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan. 9. Department of Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan. 10. Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan. 11. Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan. 12. Department of Surgery, Kansai Rosa Hospital, Amagasaki, Japan. 13. Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan. 14. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 15. School of Medicine, University of Tsukuba, Tsukuba, Japan. 16. Department of Biostatistics, School of Public Health, The University of Tokyo, Tokyo, Japan. 17. Department of Integrated Science and Engineering for Sustainable Society, Faculty of Science and Engineering, Chuo University, Tokyo, Japan. 18. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: tyoshino@east.ncc.go.jp.
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 offluoropyrimidine, 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.
RCT Entities:
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 cancerpatients. 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.
Authors: Rachel P Riechelmann; Luiz S Leite; Giovanni M Bariani; Joao Glasberg; Thomas G Rivelli; Leonardo Gomes da Fonseca; Daniela R Nebuloni; Maria I Braghiroli; Marcelo A Queiroz; Alice M Isejima; Christian Kappeler; Luciana Kikuchi; Paulo M Hoff Journal: Oncologist Date: 2019-06-07
Authors: S Kopetz; A Grothey; E Van Cutsem; R Yaeger; H Wasan; T Yoshino; J Desai; F Ciardiello; F Loupakis; Y S Hong; N Steeghs; T K Guren; H-T Arkenau; P Garcia-Alfonso; A Belani; X Zhang; J Tabernero Journal: ESMO Open Date: 2022-05-30
Authors: Louise B Callesen; Julian Hamfjord; Anders K Boysen; Niels Pallisgaard; Tormod K Guren; Elin H Kure; Karen-Lise G Spindler Journal: Br J Cancer Date: 2022-04-19 Impact factor: 9.075