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

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.

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Publication Details

Journal
Nature Communications
Published
2024-11-25
DOI
https://doi.org/10.1038/s41467-024-54460-2
Citations
11
Primary Topic
Colorectal Cancer Treatments and Studies
Type
article
Field-Weighted Citation Impact
3.11

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article

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

Yutaro Kubota, Akihito Tsuji, Wataru Ichikawa, Yu Sunakawa et al.
11 citations
Nature Communications
Colorectal Cancer Treatments and Studies
3.11
article

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

Yutaro Kubota, Akihito Tsuji, Wataru Ichikawa, Yu Sunakawa, Hisatsugu Ohori, Takanori Watanabe, Dai Manaka, Masato Nakamura, Tatsuro Yamaguchi, Manabu Shiozawa, Mitsugu Kochi, Masahito Kotaka, Hisateru Yasui, Taichi Yabuno, Hirofumi Ota, Masahiro Takeuchi, Mitsuyoshi Tei, Masashi Fujii, Tamotsu Sagawa, Takashi Sekikawa
article en
11 citations

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.

Nature CommunicationsVol. 15(1)
St. Marianna University School of Medicine (JP), Kagawa University (JP), Kanagawa Prefectural Hospital Organization (JP), Tokyo Metropolitan Komagome Hospital (JP), Ikeda Municipal Hospital (JP), National Hospital Organization Hokkaido Medical Center (JP), Osaka Rosai Hospital (JP), Yokohama Municipal Citizen's Hospital (JP), Kyoto Katsura Hospital (JP), Japan Clinical Cancer Research Organization (JP), Aizawa Hospital (JP), SHOWA Medical University Fujigaoka Hospital (JP), SHOWA Medical University Hospital (JP), Tokushima Municipal Hospital (JP), Kobe City Medical Center General Hospital (JP), Sapporo National Hospital (JP), Kanagawa Cancer Center, The University of Tokyo (JP), International University of Health and Welfare (JP)
National Center for Child Health and Development, Merck KGaA
Good health and well-being
Openalex Percentile: Top 7%
Colorectal Cancer Treatments and Studies
3.11
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