The TRIBE study showed that FOLFOXIRI plus bevacizumab (Bmab) significantly improved efficacy outcomes as first-line treatment in patients (pts) with metastatic colorectal cancer. A prospective single-arm, multicenter, phase II study investigated the efficacy and safety of Japanese pts.
Pts were treated with 12 cycles of FOLFOXIRI plus Bmab as induction therapy followed by maintenance with 5-FU plus Bmab until disease progression or unacceptable toxicities. Pts with the double heterozygous or homozygous genotype of the UGT1A1 *28 and *6 polymorphisms were excluded. Prophylactic uses of G-CSF were not permitted. The primary end point was progression-free survival (PFS) rate at 10 months by investigator, which was confirmed by central assessment.
Totally, 69 pts were enrolled. The median age was 60 years, and 42 pts were male. 39 pts with the UGT1A1 single heterozygous genotype and 30 pts with wild-type were enrolled. At a median follow-up time of 19.6 months, the PFS rate at 10 months by investigator and central assessment were 75.2% (95% CI, 63.8–86.6) and 69.0% (95% CI, 56.6-81.4), respectively. The median PFS was 13.3 months (95% CI, 11.5–19.4). The response rate and the rate of early tumor shrinkage were respectively 73.9% and 71.0%, achieving R0 resection rate of 24.6%. The major grade ≥3 adverse events were neutropenia (74%), hypertension (35%), and febrile neutropenia (FN; 22%). One treatment-related death occurred. During the first 2 cycles of induction therapy, grade 4 neutropenia and FN in UGT1A1 single heterozygous pts were 46% and 26%, while those in wild-type pts were 13% and 10% (P = 0.0044 and P = 0.127). However, no association in terms of efficacy between UGT1A1 single heterozygous and wild-type pts was indicated.
The efficacy of FOLFOXIRI plus Bmab in Japanese were consistent with those of previous phase II and III studies, with manageable but different toxicity profiles in terms of grade 4 neutropenia and FN between UGT1A1 single heterozygous and wild-type pts. Prophylactic use of G-CSF in UGT1A1 single heterozygous pts was suggested considering the high incidence of grade 4 neutropenia and FN.
Clinical trial identification
Legal entity responsible for the study
Chugai Pharma Pharmaceutical Co., Ltd.
T. Kato: Bayer Yakuhin, Ltd, Japan; Eli Lilly Japan K.K., Ltd.; Yakult Honsha Co., Ltd., Ltd.; Takeda Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd. K. Muro: Shionogi & Co., Ltd., MSD K.K., Daiichi Sankyo Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Gilead Sciences, Chugai Phramaceutical Co., Ltd, Takeda Pharmaceutical Company, Ltd., Eli Lilly Japan K.K., Merck Serono, Taiho, Yakult Honsha. K. Yamazaki: Honoraria: Bayer Yakuhin, Bristol-Myers Squibb Japan, Chugai Pharma, Daiichi Sankyo, Lilly Japan, Merck Serono, Takeda, Taiho Pharmaceutical, and Yakult Honsha. Research funding: Bristol-Myers Squibb Japan and Sanofi. E. Oki: Honoraria for lecturing from Bayer Yakuhin, Ltd, Japan, Eli Lilly Japan K.K, Taiho Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Merck Serono Co., Ltd., Takeda Pharmaceutical Co., Ltd., Johnson & Johnson K.K. and Chugai Pharmaceutical Co., Ltd. A. Tsuji: Honoraria Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, Merck Serono, Takeda Pharmaceutical, Bristol-Myers Squibb Japan. Speakers\' Bureau Chugai Pharma, Taiho Pharmaceutical, Takeda, Merck Serono. Y. Emi: Honoraria for lecturing from Chugai Pharmaceutical Co., Ltd. M. Kotaka: Chugai Pharmaceutical Co., Ltd. T. Yamanaka: Honoraria: Takeda, Chugai, Merck-Serono, Boehringer-Ingelheim, Taiho Pharmaceutical. All other authors have declared no conflicts of interest.