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Bevacizumab, irinotecan and biweekly trifluridine/tipiracil for pretreated metastatic colorectal cancer: MODURATE, a phase Ib study
Background
Treatment of refractory metastatic colorectal cancer (mCRC) with trifluridine/tipiracil yields some survival benefits. Trifluridine/tipiracil combined with bevacizumab or irinotecan suggested enhanced therapeutic effects in preclinical models. A phase Ib study combining standard trifluridine/tipiracil regimens with irinotecan resulted in better antitumor activity, accompanied by a high degree of febrile neutropenia.
Methods
This phase Ib study of trifluridine/tipiracil, irinotecan, and bevacizumab in previously treated mCRC was conducted at two centers, Shizuoka Cancer Center and Aichi Cancer Center in Japan, and consisted of dose escalation (3+3 design) and expansion cohorts. Key eligibility criteria included histologically confirmed colorectal adenocarcinoma, failure or intolerant to fluoropyrimidine and oxaliplatin, no prior therapy with trifluridine/tipiracil and irinotecan, age of 20–75 years, and ECOG PS of 0–1. Patients received trifluridine/tipiracil (25–35 mg/m2 twice daily on days 1–5), irinotecan (150–180 mg/m2; day 1), and bevacizumab (5 mg/kg; day 1) every 2 weeks. The recommended phase II dose (RPTD) in the dose escalation cohort was administered to at least 15 patients in both cohorts.
Results
A total of 28 patients from two centers were enrolled between August 2016 and January 2020, comprising 18 in dose escalation cohort and 10 additional patients in expansion cohort. Five dose-limiting toxicities were observed in dose escalation cohort. RPTD was defined as trifluridine/tipiracil 35 mg/m2, irinotecan 150 mg/m2, and bevacizumab 5 mg/kg. Of the 16 patients who received RPTD, patients characteristics were as follows; median age (range), 64 (38-73) years; male/female, 11/5; PS 0/1, 13/3; right-/left-sided tumor, 1/15; median number of metastatic site (range), 2 (1-5); RAS mutant/wild-type, 9/7; uridine diphosphate glucuronosyltransferase 1A1 genotype wild/single hetero/double hetero or homo, 7/8/1; prior history of bevacizumab/anti-EGFR antibody, 6/4. The most common grade 3/4 adverse events were neutropenia (86%) and leukopenia (63%) without febrile neutropenia. No treatment-related death was observed. Dose reduction, delay, and discontinuation occurred in 94%, 94%, and 6% of patients, respectively. At a median follow-up time (range) of 417 (346–611) days, the overall response rate was 19%, with 3 patients achieving a partial response. The disease control rate was 75%, with an additional 9 patients exhibiting stable disease for >4 months duration in 5 patients. The median progression-free survival and overall survival were 7.1 (95% confidence interval [CI], 3.7–not reached [NR]) months and 21.7 (95% CI, 11.3–NR) months, respectively.
Conclusions
Biweekly administration of trifluridine/tipiracil, irinotecan, plus bevacizumab may decrease febrile neutropenia with moderate antitumor activity in previously treated mCRC patients. Further investigation of this combination therapy is required.
Clinical trial identification
UMIN000019828 jRCTs041180028.
Legal entity responsible for the study
The author.
Funding
This study was funded by Taiho Pharmaceutical Co., Ltd. This study was supported by the Fuji Pharma Valley Center, a nonprofit organization.
Disclosures
K. Yamazaki: Honoraria (self): Chugai Pharma, Takeda, Taiho; Research grant / Funding (institution): Taiho Pharmaceutical. H. Taniguchi: Honoraria (self): Takeda, Taiho, Merck Biopharma; Research grant / Funding (institution): Daiichi-Sankyo, Sysmex, Takeda. T. Masuishi: Honoraria (self): Taiho, Lilly, Chugai, Yakult Honsha. T. Kawakami: Honoraria (self): Taiho Pharmaceutical, Ono pharmaceutical, Bristol-Myers Squibb, Bayer. T. Tsushima: Honoraria (self): Taiho pharmaceutical. 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. All other authors have declared no conflicts of interest.
