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A phase I/II study of S-1 and irinotecan (IRIS) combined with cetuximab in patients with RAS wild-type metastatic colorectal cancer (KSCC1401)

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Abstract

Purpose

This study was designed to assess the tolerability, efficacy, and safety of tri-weekly irinotecan plus S-1 (IRIS) and weekly cetuximab in patients with metastatic colorectal cancer (mCRC).

Methods

The main eligibility criteria were RAS wild-type mCRC with no prior chemotherapy. S-1 was given orally at a dose of 40 mg/m2 (40–60 mg) twice for 2 weeks, followed by a 1-week rest. Irinotecan was given on day 1 of each cycle at a dose of 150 mg/m2. Cetuximab was administered on days 1 (400 mg/m2), 8 (250 mg/m2), and 15 (250 mg/m2), and then once weekly (250 mg/m2) thereafter. A standard 3 + 3 phase I dose de-escalation design was used to determine the maximum tolerated dose and the recommended dose (RD) of irinotecan. The primary end point of the Phase II study was overall response rate (ORR).

Results

Between December 2014 and September 2017, 4 and 54 patients were enrolled in phase I and phase II studies, respectively. No dose-limiting toxicity was observed in the phase I study, and the RD of irinotecan was 150 mg/m2. In the phase II study, the ORR was 56.9% (90% confidence interval 44.4%–68.7%). The safety profile revealed that the most common grade 3/4 adverse events were neutropenia (31.4%), appetite loss (27.5%), hypokalemia (11.8%), and diarrhea (11.8%). Grade 3/4 hand–foot skin syndrome occurred in nine patients (9.8%).

Conclusion

This study showed that the efficacy and safety of IRIS combined with cetuximab were comparable to those for other first-line treatments. This regimen is a good candidate for first-line treatment of RAS wild-type mCRC.

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Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We sincerely thank the participating patients and their families. We are indebted to the physicians and all other medical staff. We also thank Ms. Sakamoto and the staff at the KSCC (Kyushu Study Group of Clinical Cacner) and CReS Kyushu for their excellent data collection and management, secretarial assistance, and support. Finally, we thank James P. Mahaffey, PhD, from Edanz Group (https://en-author-services.edanzgroup.com/) for editing a draft of this manuscript. This work was supported by the CReS Kyushu with funding from Merck Biopharma Co., Ltd., an affiliate of Merck KGaA, Darmstadt, Germany under a research contract.

Funding

This work was supported by the CReS Kyushu with funding from Merck Serono Co., Ltd., an affiliate of Merck KGaA, Darmstadt, Germany under a research contract.

Author information

Authors and Affiliations

  1. Gastrointestinal Disease Center, Urazoe General Hospital, Okinawa, Japan

    Hironori Samura

  2. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Eiji Oki, Koji Ando & Masaki Mori

  3. Department of Surgery, Kagoshima Koseiren Hospital, Kagoshima, Japan

    Hiroshi Okumura

  4. Department of Surgery, Social Insurance Tagawa Hospital, Fukuoka, Japan

    Takefumi Yoshida

  5. Department of Surgery, Nakatsu Municipal Hospital, Oita, Japan

    Seiichiro Kai

  6. Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Kazuma Kobayashi

  7. Division of Digestive and General Surgery, University of the Ryukyu Faculty of Medicine, Okinawa, Japan

    Tatsuya Kinjo

  8. Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Shinichiro Mori

  9. Department of Surgery, Nakagami Hospital, Okinawa, Japan

    Tetsuo Tohyama

  10. Department of Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan

    Kippei Ohgaki & Yoshihiko Maehara

  11. Clinical Research Institute and Department of Surgery, National Hospital Organization Beppu Medical Center, Oita, Japan

    Hirofumi Kawanaka

  12. Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Fukuoka, Japan

    Akitaka Makiyama

  13. Cancer Center, Gifu University Hospital, Gifu, Japan

    Akitaka Makiyama

  14. Department of Medical Oncology, Saga-Ken Medical Center Koseikan, Saga, Japan

    Norio Ureshino

  15. Gastrointestinal Cancer Center, Sano Hospital, Hyogo, Japan

    Masahito Kotaka

  16. Clinical Research Support Center Kyushu, Fukuoka, Japan

    Takayuki Shimose

  17. Department of General Surgical Science Graduate School of Medicine, Gunma University, Gunma, Japan

    Hiroshi Saeki

  18. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Hideo Baba

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  1. Hironori Samura
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Correspondence to Eiji Oki.

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Conflict of interest

Eiji Oki received lecture fee from Merck Biopharma Co., Ltd., Bayer Yakuhin Japan, Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly, Yakult Honsha Co., Ltd., and Takeda Pharmaceutical Co., Ltd. Akitaka Makiyama reports personal fees from Lily, personal fees from Chugai, personal fees from Takeda, outside the submitted work. Masahito Kotaka reports lecturefee from Chugai Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Takeda Pharmaceutical Company Limited, Merck Biopharma Co., Ltd., and Taiho Pharmaceutical Co., Ltd., outside the submitted work. Hideo Baba reports grants, personal fees and non-financial support from Taiho Pharmaceutical Co., Ltd., grants and non-financial support from Merck Biopharma Co., Ltd., during the conduct of the study; grants, personal fees and non-financial support from Ono Pharmaceutical Co., Ltd., grants, personal fees and non-financial support from Eli Lilly Japan K.K., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants from Shionogi & Co., Ltd., grants from Covidien Japan Inc., grants and non-financial support from Yakult Honsha Co.,Ltd., grants from Shin Nippon Biomedical Laboratories, Ltd., grants from Novartis-pharma K.K., grants from Toyama Chemical Co., Ltd., grants and non-financial support from Johnson & Johnson K.K., outside the submitted work. Other authors have no conflict of interest.

Ethics approval (include appropriate approvals or waivers)

This study was conducted in accordance with the Declaration of Helsinki and Ethical Guidelines for Clinical Studies in Japan, and the protocol was approved by the institutional review boards of all participating medical institutions. This study was registered in the UMIN clinical trials registry. (UMIN-CTR number UMIN000023329).

Informed consent

The informed consent form stated that the results would be published after completion of the study. Consent of the family is not required at the time of article publication according to Japanese ethical guidelines.

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Samura, H., Oki, E., Okumura, H. et al. A phase I/II study of S-1 and irinotecan (IRIS) combined with cetuximab in patients with RAS wild-type metastatic colorectal cancer (KSCC1401). Cancer Chemother Pharmacol 86, 285–294 (2020). https://doi.org/10.1007/s00280-020-04108-x

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