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Phase I study of the anti-heparin-binding epidermal growth factor-like growth factor antibody U3-1565 with cetuximab in patients with cetuximab- or panitumumab-resistant metastatic colorectal cancer


KRAS wild-type colorectal cancers initially responsive to anti-endothelial growth factor receptor (EGFR) antibodies [cetuximab (Cetu)/panitumumab (Pani)] develop acquired resistance. Overexpression of EGFR ligands such as heparin-binding EGF-like growth factor (HB-EGF) may be one resistance mechanism. This phase I study of U3-1565, anti-HB-EGF antibody, and Cetu combination therapy enrolled patients with KRAS wild-type metastatic colorectal cancer who had received two ≤ regimens with fluoropyrimidine, oxaliplatin, irinotecan, and Cetu/Pani and had disease progression on Cetu/Pani. Recommended dose (RD) was determined in the 1st stage, followed by evaluation of efficacy at the RD level in the 2nd-stage. Cetu was given at a loading dose of 400 mg/m2 followed by weekly infusions of 250 mg/m2 in levels 1 and 0. U3-1565 was administered at a loading dose of 24 mg/m2 followed by biweekly infusions of 16 mg/m2 in level 1 and 16–12 mg/m2 in level 0. Twenty-two patients were enrolled. No dose-limiting toxicities were observed among three patients in level 1 in the first stage, which was determined as RD. Grade 3 or higher adverse events occurred in 59.1%; those in ≥5% of patients were anemia, γ-GTP elevation, and acneiform rash. Overall response rate was 0.0% [95% confidence interval (CI): 0.0%–15.4%] and disease control was achieved in 17 patients (77.3%, 95% CI: 54.6%–92.2%). Median progression-free survival time was 85.0 days (95% CI: 54.0–91.0) and median survival time was 196 days (95% CI: 113.0–306.0). RD was determined as level 1. The efficacy of this combination therapy after progression on Cetu/Pani was negligible. Trial Registration: UMIN000013006.

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This study was funded by Daiichi Sankyo Co., Ltd.

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Correspondence to Takako Eguchi Nakajima.

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Conflict of interest

Takako Eguchi Nakajima, Narikazu Boku and Yu Sunakawa received honoraria or consultation fees from Merck Serono. The other authors declare no potential conflicts of interests.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments, and the Japanese Good Clinical Practice guidelines.

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Informed consent was obtained from all individual participants included in the study.

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Nakajima, T.E., Boku, N., Doi, A. et al. Phase I study of the anti-heparin-binding epidermal growth factor-like growth factor antibody U3-1565 with cetuximab in patients with cetuximab- or panitumumab-resistant metastatic colorectal cancer. Invest New Drugs 38, 410–418 (2020).

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  • Anti-HB-EGF antibody
  • Cetuximab re-challenge
  • Colorectal cancer
  • Phase I
  • U3-1565