A multicenter randomized phase II trial comparing CAPOXIRI + bevacizumab with FOLFOXIRI + bevacizumab as first-line treatment in patients with metastatic colorectal cancer: Primary results of the QUATTRO-II study.

person Hideaki Bando Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan info_outline Hideaki Bando, Hironaga Satake, Daisuke Kotani, Tetsuya Hamaguchi, Manabu Shiozawa, Taro Ikumoto, Yoshihiro Okita, Toshiki Masuishi, Yoshinori Kagawa, Hisateru Yasui, Eiji Oki, Yoshito Komatsu, Hiroya Taniguchi, Kei Muro, Masahito Kotaka, Kentaro Yamazaki, Toshihiro Misumi, Takayuki Yoshino, Takeshi Kato, Akihito Tsuji

Authors person Hideaki Bando Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan info_outline Hideaki Bando, Hironaga Satake, Daisuke Kotani, Tetsuya Hamaguchi, Manabu Shiozawa, Taro Ikumoto, Yoshihiro Okita, Toshiki Masuishi, Yoshinori Kagawa, Hisateru Yasui, Eiji Oki, Yoshito Komatsu, Hiroya Taniguchi, Kei Muro, Masahito Kotaka, Kentaro Yamazaki, Toshihiro Misumi, Takayuki Yoshino, Takeshi Kato, Akihito Tsuji Organizations Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan, Department of Medical Oncology, Kochi Medical School, Nankoku-City, Japan, National Cancer Center Hospital East, Japan, Kashiwa-Shi, Japan, Department of Gastroenterological Oncology, Saitama Medical University International Medical Center, Saitama, Japan, Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan, Gastrointestinal Cancer Center, Sano Hospital, Kobe, Japan, Department of Medical Oncology, Kagawa University Hospital, Kagawa, Japan, Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan, Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, Japan, Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan, Department of Data Science, National Cancer Center Hospital East, Kashiwa, Japan, National Hospital Organization, Osaka National Hospital, Osaka, Japan, Department of Medical Oncology, Kagawa University Hospital, Takamatsu, Japan Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Chugai Pharmaceutical Background: FOLFOXIRI plus bevacizumab (Bev) is highly effective for treating patients (pts) with metastatic colorectal cancer (mCRC); however, high incidences of hematologic adverse events (AEs) and pump infusion of 5-FU q2wk can complicate treatment continuation. According to the safety lead-in (Step 1), CAPOXIRI plus Bev with 1600-mg/m 2 capecitabine (Cap), 130-mg/m 2 oxaliplatin (Ox), 200-mg/m 2 irinotecan (Iri), and 7.5-mg/kg Bev q3wk was the recommended phase 2 dose (Kotani D, et al., Invest New Drugs, 2021). Here, we report the results of the randomized phase II part (Step 2) of the QUATTRO-Ⅱ study, which examined the efficacy and safety of CAPOXIRI + Bev versus FOLFOXIRI + Bev. Methods: Enrolled pts were ECOG PS 0 or 1, and had chemotherapy-naïve mCRC with wild-type or single heterozygous UGT1A1 *6/*28 genetic polymorphism. Pts were randomly allocated to FOLFOXIRI + Bev (Arm A) or CAPOXIRI + Bev (Arm B) in a 1:1 ratio. The induction treatment in Arm A /B was continued for 8/6 cycles (12/8 cycles at maximum if feasible), and the maintenance treatment was either 5-FU + leucovorin + Bev or Cap + Bev at the discretion of the investigators. The primary endpoint was progression-free survival (PFS), with the two groups deemed equivalent if the hazard ratio (HR) of the point estimate was 0.8 < HR < 1.25. Secondary endpoints were overall survival (OS), overall response rate (ORR), early tumor shrinkage (ETS), depth of response (DpR), and safety. Results: From June 2020 to June 2021, 103 pts (Arm A/B, 51/52 pts) were randomly assigned. Baseline characteristics, including age (median 60 years in both arms) and ECOG PS 0 (90%/94%), were well balanced between arms. At a median follow-up of 23.7 months, the median PFS (Arm A/B) was 10.6 months (95% CI 7.7–13.3)/10.9 months (95% CI 9.3–14.3; HR 1.119, P = 0.639), and the primary endpoint was met (HR: 0.8 < 1.119 < 1.25). The 2-year OS rate (Arm A/B) was 65.5% (95% CI 49.5–77.6)/74.3% (95% CI 59.8–84.2), with the median OS not reached. Moreover, the ORR was 76.5% (95% CI 62.5–87.2)/84.6% (95% CI 71.9–93.1), ETS was achieved in 71.4%/82.0% of pts, and the median DpR was 43.0%/54.2%. Incidences of major grade ≥3 AEs (Arm A/B) were as follows: neutropenia (68.6%/40.4%), febrile neutropenia (9.8%/11.5%), diarrhea (7.8%/17.3%), and appetite loss (7.8%/17.3%). No treatment-related deaths occurred. Conclusions: The efficacy of CAPOXIRI + Bev was comparable to that of FOLFOXIRI + Bev. Although CAPOXIRI + Bev was associated with increased incidences of certain nonhematologic AEs, it was well tolerated, with a decreased incidence of neutropenia and no unexpected safety signal. Good survival and response results suggest that CAPOXIRI + Bev could become a new first-line treatment option in pts with mCRC. Clinical trial information: NCT04097444.