TAS-102 demonstrated significant improvement in overall survival (OS) over placebo in patients (pts) with metastatic colorectal cancer (mCRC). Nintedanib is a triple angiokinase inhibitor of VEGFR (1, 2, 3), PDGFR (a, β), and FGFR (1, 2, 3). In preclinical models, the combination of TAS-102 plus nintedanib demonstrated enhanced activity against CRC compared with either drug alone. This study was conducted to determine the recommended phase II dose (RP2D) and evaluate the efficacy and safety in pts with mCRC refractory to standard therapies. RP2D was determined nintedanib 200mg BID every day adding to standard-dose of TAS-102 in the phase I part (Nishina T, et al. ESMO 2016). We present here on the efficacy and safety data from the ongoing study.
The key eligibility criteria were pts with mCRC refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-angiogenesis inhibitor and anti-EGFR antibody (if wild-type RAS) and without prior regorafenib. Primary endpoint was investigator-assessed progression-free survival (PFS) rate at 16 weeks in pts treated with RP2D. Using a single stage binomial design, this study required 52 pts, with the PFS rate at 16 weeks of 40% deemed promising and 25% unacceptable (alpha=0.1; beta=0.2).
From August 2015 to August 2016, 55 pts were enrolled. Among them, 52 pts received the RP2D as full analysis set. The PFS rate at 16 weeks was 38.5% (80% confidence interval: 29.3–48.3%). Four pts (7.7%) achieved a partial response, median PFS and disease control rate were 3.7 months and 69.2%, respectively. Median OS was 9.2 months. The median number of treatment cycles was 4 (range 1 - 14). The most common grade 3 or worse treatment-associated adverse events were neutropenia (59.6%), anemia (17.3%), thrombocytopenia (11.5%) and increased liver enzymes (AST: 9.6%, ALT: 7.7%; asymptomatic reversible elevation without any bilirubin elevation). Febrile neutropenia occurred in two (3.8%) pts. There was no treatment-related death.
Standard-dose of TAS-102 with nintedanib 200 mg BID showed promising antitumor activity with acceptable toxicity for mCRC pts.
Clinical trial identification
Legal entity responsible for the study
Exploratory Oncology Research & Clinical Trial Center
Taiho Pharmaceutical and Boehringer Ingelheim
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. Y. Kuboki: Corporate-sponsored research: Takeda; Other Substantive Relationships (Taiho Pharmaceutical, Bayer: (Honoraria)) E. Shinozaki: Other Substantive Relationships (Taiho, Merck Serono, Takeda, Ono, Chugai, Yakult, Bayer (Honoraria)) H. Hara: Advisory Board Ono, Chugai Corporate-sponsored-research AstraZeneca, Chugai, Merck Serono, MSD, Ono, Taiho, Takeda, Boehringer Ingelheim, Dainippon Sumitomo, Daiichi Sankyo, Lilly Other Chugai, Taiho, Merck Serono, Yakult Honsha, Lilly(Honoraria) Y. Komatsu: Corporate-sponsored-research (Taiho Chugai Pharma Novartis MSD Ono Pharmaceutical Bayer Yakult Lilly) Other Substantive Relationships (Novartis, Pfizer, Bayer(Honoraria)) (Taiho Chugai Lilly Novartis Merck Pfizer, Bayer (Speaker bureau)) K. Yamaguchi: Corporate-sponsored-research (Taiho MSD daiichi-sankyo Ono Merck Bristol Dainipponn-sumitomo Beringer Yakurut Honsha) Other Substantive Relationships (Taiho Takeda Chugai Merck Yakurut-Honsha Lilly(Speaker bureau)) M. Asayama: Corporate-sponsored research (Takeda) T. Tsushima: Other Substantive Relationships (Chugai Pharmaceutical, Takeda Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical(Honoraria)) S. Nomura: Other Substantive Relationships Asahi-Kasei pharma (immediately family member; employment) A. Sato: Corporate-sponsored-research (Taiho Dainippon Sumitomo Pharma Novartis Ono Pharmaceutical Boehringer Ingelheim Bayer) T. Doi: Advisory Board(Lilly, Chugai, Kyowa Hakko Kirin, Novartis, MSD, Daiichi Sankyo, Amgen) Corporate-sponsored-research (Taiho, Merck, Astellas, Janssen, Takeda, Pfizer, Lilly, Sumitomo Group, Bayer, Chugai, Kyowa Hakko Kirin, Boehringer, Novartis, MSD, Daiichi Sankyo, Celgene) A. Ohtsu: Corporate-sponsored-research BMS Other Substantive Relationships Celgene (immediately family member; employment) T. Yoshino: Corporate-sponsored-research GlaxoSmithKline K.K.Boehringer Ingelheim GmbH All other authors have declared no conflicts of interest.