A Phase II Study of FOLFIRI Plus Ziv-Aflibercept After Trifluridine/Tipiracil Plus Bevacizumab in Patients with Metastatic Colorectal Cancer: WJOG 11018G.

Ichinosuke Hyodo, Takao Tsuduki, Kenro Hirata, Hirokazu Shoji, Toshihiko Matsumoto, Kenichi Yoshimura, Masahito Kotaka, Yoshiyuki Yamamoto, Naoki Takahashi, Kei Muro, Akitaka Makiyama, Takashi Ohta, Shuichi Hironaka, Masahiro Tsuda, Kentaro Yamazaki, Yasushi Tsuji, Narikazu Boku, Naoki Izawa, Yosuke Kito, Toshiki Masuishi, Hisateru Yasui, Satoshi Otsu

Journal: Targeted oncology 2024;19(2):181-190

PMID: 38427280

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Abstract

BACKGROUND

Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in the phase III TRUSTY study, and we conducted a phase II study of FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept (AFL) after FTD/TPI plus BEV. However, the TRUSTY study failed during the recruitment of our patients.

OBJECTIVE

We present the findings of a phase II study on the efficacy of FOLFIRI plus zib-aflibercept (AFL) after FTD/TPI plus BEV, including clinical results with plasma biomarker analyses.

METHODS

This was a multicenter, single-arm, phase II study in patients with metastatic colorectal cancer refractory or intolerant to oxaliplatin, fluoropyrimidine, BEV, and FTD/TPI. The primary endpoint was progression-free survival. Fifteen plasma angiogenesis-associated biomarkers were analyzed using a Luminex multiplex assay U-kit.

RESULTS

Between January 2020 and May 2022, 26 patients (median age, 68 years) from 15 sites were enrolled. The median progression-free survival was 4.9 months (85% confidence interval, 3.4 month-not estimated). The overall response and disease control rates were 8% and 62%, respectively. The median levels of vascular endothelial growth factor-A and placental growth factor, both targets of AFL, were below the measurable limit of 30 pg/mL and 16 pg/mL, respectively. Patients were divided into two groups at the median levels of baseline biomarkers. The progression-free survival did not differ between high and low expressers of placental growth factor (p = 0.7), while it tended to be shorter in those with high levels of osteopontin (p = 0.05), angiopoietin-2 (p = 0.07), and tissue inhibitor of matrix metalloproteinases-1 (p = 0.1).

CONCLUSIONS

This study did not meet the primary endpoint. Hence, FOLFIRI plus AFL should not be used after FTD/TPI plus BEV for metastatic colorectal cancer. Further studies are needed to determine factors not targeted by AFL that may affect the efficacy of the treatment.

CLINICAL TRIAL REGISTRATION

jRCTs041190100.

Address: Cancer Treatment Center, Kansai Medical University Hospital, 2-3-1, Shinmachi, Hirakata-shi, Osaka, 5731191, Japan. [email protected].; Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaragi, Japan.; Gastrointestinal Cancer Center, Sano Hospital, Kobe-shi, Hyogo, Japan.; Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya-shi, Aichi, Japan.; Department of Clinical Oncology, Tonan Hospital, Sapporo-shi, Hokkaido, Japan.; Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.; Department of Internal Medicine, Himeji Red Cross Hospital, Himeji-shi, Hyogo, Japan.; Cancer Center, Gifu University Hospital, Gifu-shi, Gifu, Japan.; Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan.; Department of Gastroenterology, Saitama Cancer Center Hospital, Kita-adachi-gun, Saitama, Japan.; Department of Gastroenterological Oncology, Hyogo Cancer Center, Akashi-shi, Hyogo, Japan.; Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe-shi, Hyogo, Japan.; Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki-shi, Hyogo, Japan.; Department of Medical Oncology, Ishikawa Prefectural Central Hospital, Kanazawa-shi, Ishikawa, Japan.; Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, Yufu-shi, Oita, Japan.; Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, Yufu-shi, Oita, Japan.; Department of Medical Oncology, Faculty of Medicine, Kyorin University, Mitaka-shi, Tokyo, Japan.; Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan.; Department of Oncology and General Medicine, Institute of Medical Science Hospital, University of Tokyo, Tokyo, Japan.; Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.; Medical Center for Translational and Clinical Research, Hiroshima University, Hiroshima-shi, Hiroshima, Japan.

DOI: 10.1007/s11523-024-01043-2