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A multicenter randomized phase II study comparing CAPOXIRI plus bevacizumab and FOLFOXIRI plus bevacizumab as the first-line treatment for metastatic colorectal cancer: A safety analysis of the QUATTRO-II study
Background
FOLFOXIRI plus bevacizumab (BEV) is the standard first-line treatment for metastatic colorectal cancer (mCRC) despite its association with a high incidence of neutropenia and diarrhea. In this study, capecitabine (CAP), oxaliplatin (OX), and irinotecan (IRI) (CAPOXIRI) plus BEV are hypothesized to be more feasible than FOLFOXIRI plus BEV, without compromising the efficacy. Here, results of safety analysis in the induction phase are reported in the randomized phase II QUATTRO-II study comparing CAPOXIRI plus BEV and FOLFOXIRI plus BEV as the first-line treatment for mCRC.
Methods
This multicenter, open-label, randomized phase II study enrolled patients with the ECOG performance status of 0 or 1, without previous chemotherapy in the metastatic setting, with adequate organ function, and with UGT1A1 *6/*28 gene polymorphisms of wild-type or single heterozygous. Patients were randomized in a 1:1 ratio to FOLFOXIRI plus BEV (arm A) or CAPOXIRI plus BEV (arm B). As we previously reported, the recommended phase II doses of CAPOXIRI plus BEV were determined as CAP, 1,600 mg/m2; OX, 130 mg/m2; IRI, 200 mg/m2; and BEV, 7.5 mg/kg every 3 weeks from the results of Safety Lead-In of this study. FOLFOXIRI plus BEV or CAPOXIRI plus BEV in the induction phase was continued until 8/6 (arm A/B) cycles (maximum, 12/8 cycles), followed by 5-FU/l-LV plus BEV or CAP plus BEV in the maintenance phase at the investigator’s discretion. The primary endpoint was progression-free survival, and secondary endpoints were overall response rate, overall survival, and safety. The completion of the induction phase was defined as meeting both of the following two criteria in all cycles: all drugs are administered (dose reduction was permitted); and the cycle was started within 28 days of the planned start date.
Results
A total of 103 patients (arm A/B, 51/52) were enrolled from June 2020 to June 2021. Baseline patient characteristics (arm A/B), including the median age (range), 60 (38–75)/60 (35–77) years; the ECOG performance status of 0, 46 (90%)/49 (94%); and UGT1A1 *6/*28 gene polymorphisms, wild-type 30 (59%)/29 (56%) were similar between the two treatment arms. At the data cutoff of December 17, 2021, the incidence of grade >3 major adverse events (AEs) in the induction phase was as follows (arm A/B): neutropenia (65%/39%), febrile neutropenia (10%/12%), diarrhea (8%/17%), and anorexia (8%/17%). No treatment-related deaths occurred. Among patients in arms A and B, 26 (51%) and 30 (58%) patients achieved the completion of the induction phase, respectively. The main reasons for incompletion of the induction phase (arm A/B) were treatment discontinuation due to resection (9/9), disease progression (2/5), and adverse events (5/1) and not meeting the definition of completion of the induction phase (6/6).
Conclusions
This safety analysis showed that both CAPOXIRI plus BEV and FOLFOXIRI plus BEV were safe and tolerable with differences in AE incidences and toxicity profiles. The QUATTRO-II study is still in the follow-up phase, and the efficacy data will be reported in next year’s scientific meeting.
Clinical trial identification
Trial registration: Clinicaltrials.gov NCT04097444.
Legal entity responsible for the study
The authors.
Funding
Chugai Pharmaceutical Co, Ltd.
Disclosures
T. Masuishi: Honoraria (self): Taiho, Lilly, Chugai, Yakult Honsha. H. Bando: Honoraria (self): Eli Lilly Japan, Taiho pharmaceutical, Ono pharmaceutical; Research grant / Funding (self): Ono pharmaceutical. H. Satake: Honoraria (self): Ono pharmaceutical co., ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan Co., Ltd., Merck Bio Pharma Co., Ltd., MSD Co., Ltd., Bayer Co., Ltd., Bristol-Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Sanofi Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Co., Ltd. and Yakult Honsha Co., Ltd.; Research grant / Funding (institution): Ono pharmaceutical co., ltd., Daiichi Sankyo, Takeda Pharmaceutical Co., Ltd., Sanofi, Taiho Pharmaceutical Co., Ltd.. D. Kotani: Honoraria (self): Takeda, Chugai. T. Hamaguchi: Honoraria (self): Chugai; Research grant / Funding (institution): Chugai. Y. Kagawa: Speaker Bureau / Expert testimony: Lilly, Taiho, Yakult, MSD, Bayer, Daiichisankyo, Sanofi, Chugai, Ono, Takeda, Merck. H. Yasui: Honoraria (self): Daiichi Sankyo, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb Japan, TERUMO, Eli Lilly Japan, Merk Biopharma, Yakult Honsha, Bayer Yakuhin, Takeda Pharmaceutical; Research grant / Funding (self): MSD, Ono Pharmaceutical, Daiichi Sankyo, Astellas Pharma. T. Moriwaki: Speaker Bureau / Expert testimony: Taiho Pharmaceutical, Chugai Pharma; Research grant / Funding (institution): Taiho Pharmaceutical, Chugai Pharma. H. Kawakami: Honoraria (self): Taiho Pharmaceutical Co. Ltd, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Daiichi-Sankyo Co. Ltd.; Advisory / Consultancy: Daiichi-Sankyo Co. Ltd.; Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd, Bristol-Myers Squibb Co. Ltd, Eisai Co. Ltd., Kobayashi Pharmaceutical. Co., Ltd.. Y. Komatsu: Speaker Bureau / Expert testimony: TAIHO Phamaceutical Co., Ltd., yakult; Research grant / Funding (institution): TAIHO Phamaceutical Co., Ltd., CHUGAI Phamaceutical Co., Ltd.. H. Taniguchi: Honoraria (self): Takeda, Taiho, Merck Biopharma; Research grant / Funding (institution): Daiichi-Sankyo, Sysmex, Takeda. K. Muro: Honoraria (self): Eli Lilly, Chugai, Takeda, Ono, Taiho, Sanofi, Bristol-Myers Squibb, and Bayer; Advisory / Consultancy: Amgen, AstraZeneca, Ono, and Chugai; Research grant / Funding (institution): Astellas, Amgen, Solasia Pharma, Sanofi, Daiichi Sankyo, Parexel International, Taiho, MSD, Merck Biopharma, Pfizer, Eisai, Novartis, and Ono . M. Kotaka: Honoraria (self): Chugai pharmaceutical, Lilly. K. Yamazaki: Honoraria (self): Chugai Pharma, Takeda, Taiho; Research grant / Funding (institution): Taiho Pharmaceutical. T. Yoshino: Honoraria (self): Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical and MSD; Research grant / Funding (institution): Ono Pharmaceutical, Sanofi, Daiichi Sankyo, PAREXEL International, Pfizer Japan, Taiho Pharmaceutical, MSD, Amgen, Genomedia, Sysmex, Chugai Pharmaceutical and Nippon Boehringer Ingelheim. T. Kato: Honoraria (self): CHUGAI PHARMACEUTICAL CO., LTD, ONO Pharmaceutical Co, Eli Lilly and Company; Honoraria (Institution): CHUGAI PHARMACEUTICAL CO., LTD,; Research grant / Funding (self): ONO Pharmaceutical Co; Research grant / Funding (institution): ONO Pharmaceutical Co. A. Tsuji: Speaker Bureau / Expert testimony: Taiho Pharmaceutical Co., Ltd. , Chugai Pharmaceutical Co., Ltd. , Eli Lilly Japan Co., ; Research grant / Funding (institution): Taiho Pharmaceutical Co., Ltd. , Sanofi Corporation, Ono Pharmaceutical Co.,. All other authors have declared no conflicts of interest.
