Modified FOLFOXIRI plus cetuximab versus bevacizumab in RAS wild-type metastatic colorectal cancer: a randomized phase II DEEPER trial

Manabu Shiozawa, Yu Sunakawa (), Takanori Watanabe, Hirofumi Ota, Hisateru Yasui, Taichi Yabuno, Mitsuyoshi Tei, Mitsugu Kochi, Dai Manaka, Hisatsugu Ohori, Tatsuro Yamaguchi, Tamotsu Sagawa, Masahito Kotaka, Yutaro Kubota, Takashi Sekikawa, Masato Nakamura, Masahiro Takeuchi, Wataru Ichikawa, Masashi Fujii and Akihito Tsuji
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Manabu Shiozawa: Kanagawa Cancer Center
Yu Sunakawa: St. Marianna University School of Medicine
Takanori Watanabe: Tokushima Municipal Hospital
Hirofumi Ota: Ikeda City Hospital
Hisateru Yasui: Kobe City Medical Center General Hospital
Taichi Yabuno: Yokohama Municipal Citizen’s Hospital
Mitsuyoshi Tei: Osaka Rosai Hospital
Mitsugu Kochi: School of Medicine
Dai Manaka: Kyoto Katsura Hospital
Hisatsugu Ohori: Ishinomaki Red Cross Hospital
Tatsuro Yamaguchi: Komagome Hospital
Tamotsu Sagawa: National Hospital Organization Hokkaido Cancer Center
Masahito Kotaka: Sano Hospital
Yutaro Kubota: Showa University Hospital
Takashi Sekikawa: Showa University Fujigaoka Hospital
Masato Nakamura: Aizawa Hospital
Masahiro Takeuchi: The University of Tokyo
Wataru Ichikawa: Showa University Fujigaoka Hospital
Masashi Fujii: Japan Clinical Cancer Research Organization
Akihito Tsuji: Kagawa University

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: Abstract The clinical significance of FOLFOXIRI (5-FU, leucovorin, oxaliplatin, and irinotecan) plus anti-EGFR monoclonal antibody using cetuximab for metastatic colorectal cancer (mCRC) remains controversial. We report results from a randomized phase 2 DEEPER trial (UMIN000018217, jRCTs061180022) to test the superiority of modified (m)-FOLFOXIRI plus weekly cetuximab over bevacizumab in patients with RAS wild-type (wt) mCRC. Primary endpoint was depth of response (DpR). Secondary endpoints included objective response rate (ORR), early tumor shrinkage (ETS) at week 8, progression-free survival (PFS), overall survival (OS), time to tumor growth (TTG), time to treatment failure (TTF), association between tumor shrinkage and prognosis, association between TTG and prognosis, R0 resection rate, and safety. In 359 enrolled patients with RAS wt mCRC, median DpR was significantly better in cetuximab (57.3% vs 46.0%, p = 0.0029); however, ORR, ETS, R0 resection rate, TTG, TTF, PFS and OS were similar between 2 treatments. There was a weak association between DpR and survival time in both treatments. The correlation between TTG and OS was slightly stronger in cetuximab. The post-hoc exploratory analysis showed that cetuximab produced greater PFS (15.3 vs 11.7 months; HR 0.68) and OS (53.6 vs 40.2 months; HR 0.54) in patients with left-sided and RAS/BRAF wt tumors. m-FOLFOXIRI plus cetuximab has clinical benefit for tumor shrinkage in RAS wt mCRC. The survival benefit for RAS/BRAF wt and left-sided mCRC needs further investigation.

Date: 2024
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DOI: 10.1038/s41467-024-54460-2

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