Early Tumor Shrinkage and Depth of Response in the Second-Line Treatment for KRAS exon2 Wild-Type Metastatic Colorectal Cancer: An Exploratory Analysis of the Randomized Phase 2 Trial Comparing Panitumumab and Bevacizumab in Combination with FOLFIRI (WJOG6210G)

Targeted Oncology volume 15, pages623–633(2020)Cite this article

Abstract

Background

Predictive markers for the clinical outcomes of second-line treatment in patients with metastatic colorectal cancer (mCRC) remain unclear.

Objective

This retrospective biomarker study was conducted to explore predictive markers for patients with KRAS exon 2 wild-type mCRC who were treated with FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev) in the WJOG6210G trial.

Patients and methods

The associations of early tumor shrinkage (ETS), tumor location, and VEGF-D with progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox proportional hazards model. Spearman’s correlation coefficient was used to analyze the association of depth of response (DpR) with PFS and OS. Serum VEGF-D levels were measured in samples collected before treatment using magnetic bead panel Milliplex xMAP kits.

Results

In total, 101 patients (Pani, n = 49; Bev, n = 52) were enrolled in this study. Patients with ETS had longer PFS (Pani: hazard ratio (HR) 0.40, P = 0.009; Bev: HR 0.078, P = 0.0002) and OS (Pani: HR 0.49, P = 0.044; Bev: HR 0.35, P = 0.048) than patients without ETS. The DpR was moderately correlated with PFS and OS in Pani (rs = 0.75, P < 0.001; rs = 0.60, P < 0.001) and Bev groups (rs = 0.68, P < 0.001; rs = 0.44, P = 0.002). No significant differences were observed in PFS and OS between the two treatment groups even if in left-sided tumors. No significant interaction between VEGF-D levels and treatment was observed in PFS and OS.

Conclusions

ETS and DpR serve as surrogate markers of PFS and OS in the second-line treatment with FOLFIRI plus targeted agent for mCRC.

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Acknowledgments

This study was supported by the West Japan Oncology Group (WJOG), a non‐profit organization, and funded by WJOG Funds. We thank the data managers and other support staff of WJOG, especially Dr. Koji Takeda, Dr. Shinichiro Nakamura and Kaori Mori.

Author information

Affiliations

  1. Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan

    Naoki Izawa, Yu Sunakawa & Takako Eguchi Nakajima

  2. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Kohei Shitara & Takayuki Yoshino

  3. Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Japan

    Kimio Yonesaka

  4. Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan

    Takeharu Yamanaka

  5. Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan

    Toshiki Masuishi & Kei Muro

  6. Department of Gastroenterology, Chiba Cancer Center Hospital, Chiba, Japan

    Tadamichi Denda

  7. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shimonagakubo, Japan

    Kentaro Yamazaki

  8. Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Toshikazu Moriwaki & Ichinosuke Hyodo

  9. Department of Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan

    Hiroyuki Okuda

  10. Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan

    Chihiro Kondoh

  11. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan

    Tomohiro Nishina

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

    Akitaka Makiyama

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

    Akitaka Makiyama

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

    Hideo Baba

  15. Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan

    Hironori Yamaguchi

  16. Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Japan

    Masato Nakamura

  17. Kyoto Innovation Center for Next Generation Clinical Trials and iPS Cell Therapy (Ki-CONNECT), Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Takako Eguchi Nakajima

Authors
  1. Naoki Izawa
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  2. Kohei Shitara
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  3. Kimio Yonesaka
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  4. Takeharu Yamanaka
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  5. Takayuki Yoshino
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  6. Yu Sunakawa
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  7. Toshiki Masuishi
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  8. Tadamichi Denda
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  9. Kentaro Yamazaki
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  10. Toshikazu Moriwaki
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  11. Hiroyuki Okuda
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  12. Chihiro Kondoh
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  13. Tomohiro Nishina
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  14. Akitaka Makiyama
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  15. Hideo Baba
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  16. Hironori Yamaguchi
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  17. Masato Nakamura
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  18. Ichinosuke Hyodo
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  19. Kei Muro
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  20. Takako Eguchi Nakajima
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Corresponding author

Correspondence to Takako Eguchi Nakajima.

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Author contributions

Conception and design: Kohei Shitara, Kimio Yonesaka. Provision of study materials or patients: All authors. Collection and assembly of data: All authors. Data analysis and interpretation: Naoki Izawa, Takeharu Yamanaka. Manuscript writing: All authors. Final approval of manuscript: All authors.

Funding

This work was supported by the Japan Agency for Medical Research and Development (grant numbers 961928, 965308).

Disclosures

Author K.S. has received consulting or advisory roles for Astellas, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono, MSD, Taiho, Novartis, AbbVie, and GlaxoSmithKline; honoraria from Novartis, AbbVie, and Yakult; research funding from Astellas, Lilly, Ono, Sumoitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD and Medi Science. Author T.M. has received honoraria from Takeda, Chugai, Merck Serono, Taiho, Bayer, Lilly Japan, Yakult Honsha and Sanofi; research funding from MSD, Daiichi Sankyo, and Ono. Author Y.S. has received consulting fees from Takeda Pharmaceutical and Daiichi Sankyo; honoraria form Takeda Pharmaceutical Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha, Sanofi, Bayer Yakuhin, Bristol-Myers Squibb Japan, Merck Biopharma, Lilly Japan, Nippon Kayaku, and Kyowa Kirin. Author T.D. has received personal fees from SAWAI Pharmaceutical Co and Sysmex; grants from MSD and Ono Pharmaceutical. Author H.B. has received grants form Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., and MSD K.K; payment for lectures including service on speaker bureaus from Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd. Author T.Y. has received grants form Novartis Pharma K.K., MSD.K.K., Sumitomo Dainippon pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Sanofi K.K., Co., Ltd., and GlaxoSmithKline K.K. Author A.M. has received honoraria form Lilly, Chugai and Takeda Daiichi Sankyo Company, Limited, Parexel International Inc., Ono Pharmaceutical. Author I.H. has received grants and personal fees form Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., Eli Lilly Japan, Asahi Kasei Pharma Corp., and Takeda Pharmaceutical Co., Ltd. The other authors have declared no conflicts of interest.

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University St. Marianna University School of Medicine (29 March 2018, No. 3933).

Consent to participate

Informed consent was obtained from all individual participants included in WJOG6210G trial. We provided participating subjects with the opportunity to opt out on-line from the study.

Consent to Publication

Informed consent was obtained from all individual participants included in WJOG6210G trial. We provided participated patients with the opportunity to opt out on-line from the study.

Availability of Data and Material

Individual participant data were extracted from the database of the WJOG6210G trial.

Code availability

Not applicable.

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Izawa, N., Shitara, K., Yonesaka, K. et al. Early Tumor Shrinkage and Depth of Response in the Second-Line Treatment for KRAS exon2 Wild-Type Metastatic Colorectal Cancer: An Exploratory Analysis of the Randomized Phase 2 Trial Comparing Panitumumab and Bevacizumab in Combination with FOLFIRI (WJOG6210G). Targ Oncol 15, 623–633 (2020). https://doi.org/10.1007/s11523-020-00750-w

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