Phase II study of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as second-line treatment for metastatic colorectal cancer and exploratory analysis of associations between DNA methylation status and the efficacy of the anti-EGFR antibody: T-CORE1201

Shin Takahashi; Kota Ouchi; Yasuhiro Sakamoto; Takahiro Mori; Hideki Shimodaira; Masahiro Takahashi; Hisatsugu Ohori; Chieko Kudo; Yoshikazu Takahashi; Hiroo Imai; Shoko Akiyama; Masanobu Takahashi; Takeshi Suto; Yasuko Murakawa; Takayuki Oishi; Hideki Isobe; Yoshinari Okada; Sadayuki Kawai; Takashi Yoshioka; Toshihiko Sato; Yoshiaki Shindo; Shunsuke Sugiyama; Keigo Komine; Natsuko Chiba; Akira Okita; Takuhiro Yamaguchi; Chikashi Ishioka

doi:10.21037/jgo-22-862

Phase II study of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as second-line treatment for metastatic colorectal cancer and exploratory analysis of associations between DNA methylation status and the efficacy of the anti-EGFR antibody: T-CORE1201

J Gastrointest Oncol. 2023 Apr 29;14(2):676-691. doi: 10.21037/jgo-22-862. Epub 2023 Mar 27.

Authors

Shin Takahashi^{1

2}, Kota Ouchi^{1

2}, Yasuhiro Sakamoto³, Takahiro Mori^{1

2}, Hideki Shimodaira^{1

2}, Masahiro Takahashi^{1

2}, Hisatsugu Ohori⁴, Chieko Kudo⁵, Yoshikazu Takahashi³, Hiroo Imai^{1

2}, Shoko Akiyama^{1

2}, Masanobu Takahashi^{1

2}, Takeshi Suto⁶, Yasuko Murakawa⁷, Takayuki Oishi^{1

2}, Hideki Isobe⁸, Yoshinari Okada^{1

2}, Sadayuki Kawai^{1

2}, Takashi Yoshioka⁹, Toshihiko Sato⁶, Yoshiaki Shindo¹⁰, Shunsuke Sugiyama^{1

2}, Keigo Komine^{1

2}, Natsuko Chiba¹, Akira Okita^{1

2}, Takuhiro Yamaguchi¹¹, Chikashi Ishioka^{1

2}

Affiliations

¹ Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan.
² Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan.
³ Department of Medical Oncology, Osaki Citizen Hospital, Miyagi, Japan.
⁴ Department of Medical Oncology, Japanese Red Cross Ishinomaki Hospital, Miyagi, Japan.
⁵ Department of Medical Oncology, South Miyagi Medical Center, Miyagi, Japan.
⁶ Department of Surgery, Yamagata Prefectural Central Hospital, Yamagata, Japan.
⁷ Department of Medical Oncology, Miyagi Cancer Center, Miyagi, Japan.
⁸ Department of Surgery, Yamagata Saiesei Hospital, Yamagata, Japan.
⁹ Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata, Japan.
¹⁰ Department of Gastroenterological Surgery, Nakadori General Hospital, Akita, Japan.
¹¹ Division of Biostatistics, Tohoku University Graduate School of Medicine, Miyagi, Japan.

Abstract

Background: Little is known about the biweekly combined use of cetuximab and chemotherapy as second-line treatment of metastatic colorectal cancer (mCRC). Recently, DNA methylation status has been reported to be a new possible predictor of the efficacy from the anti-epidermal growth factor receptor (EGFR) antibody treatment. The purpose of this study was to examine the efficacy and safety of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as a second-line treatment for KRAS exon 2 wild-type mCRC. We also investigated the predictability of DNA methylation status on the efficacy of the EGFR antibody-containing treatment.

Methods: Patients who were refractory or intolerant to the first-line chemotherapy were enrolled and received biweekly cetuximab plus mFOLFOX6 or mFOLFIRI. The primary endpoint was progression-free survival (PFS). Tumor evaluations were performed every 2 months using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. DNA methylation status of colorectal cancer cells was defined by a modified MethyLight assay.

Results: Sixty-six cases were enrolled. The median PFS (mPFS) was 5.1 [95% confidence interval (CI), 3.8-7.6] months. The median overall survival (mOS) was 12.7 (95% CI, 7.5-15.3) months. Grade 3 or higher neutropenia occurred in 53.0% of patients, whereas skin disorders with a grade 3 or higher occurred in <15% of patients. In multivariate analysis, DNA methylation status could not be an independent predictor of PFS [hazard ratio (HR), 1.43; P=0.39] and OS (HR, 2.13; P=0.086). However, in RAS/BRAF wild-type patients, the mPFS and mOS in the low-methylated colorectal cancer (LMCC) group was numerically better than those in the highly-methylated colorectal cancer (HMCC) group, although the difference was not statistically significant [mPFS: 8.5 (95% CI, 6.1-10.9) vs. 3.3 (95% CI, 1.2-not reached) months, P=0.79; ΔmPFS, 5.2 months; mOS: 15.3 (95% CI, 11.9-23.5) vs. 6.5 (95% CI, 3.1-not reached) months, P=0.53; ΔmOS, 8.8 months].

Conclusions: Biweekly cetuximab plus mFOLFOX6 or mFOLFIRI is a useful second-line therapy for mCRC. DNA methylation status warrants further exploration as a predictive biomarker for anti-EGFR efficacy in mCRC.

Keywords: DNA methylation; FOLFIRI; FOLFOX; Metastatic colorectal cancer (mCRC); cetuximab.