Phase II trial of trifluridine/tipiracil (TAS-102) in patients with advanced refractory biliary tract cancer (BTC)

Abstract Background Advanced BTC is an aggressive neoplasm with median overall survival (OS) of less than a year with current therapy. There is no approved second line therapy. TAS-102, a combination of the thymidine analog trifluridine, and tipiracil an inhibitor of trifluridine degradation, has shown activity in both fluoropyrimidine sensitive and resistant tumours. We conducted a single arm phase 2 trial to evaluate safety and efficacy of TAS-102 in pts with advanced, refractory BTC. Methods Pts of advanced BTC with ECOG PS 0-1 and adequate major organ function, who had progressed on at least one gemcitabine based chemotherapy, were enrolled and treated with TAS-102 at a dose of 35 mg/m2 BID on days 1-5 and 8-12 of a 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint was 16-week progression-free survival (PFS) rate, defined as number of pts who are progression-free and alive at 16 weeks since registration (success) divided by the number of evaluable pts. Using a single stage binomial design, this study required 25 evaluable pts to compare a PFS rate at 16 weeks of 10% (null) versus 30% (alternative) with one-sided alpha of 0.05 and 80% power. Among the first 25 evaluable pts, 6 or more successes were needed for the regimen to be considered for further investigation. Secondary objectives included assessment of safety and tolerability, OS, response rate, and PFS. Results From 10/2017 to 8/2018, 28 pts were enrolled, of which 53.6 % pts were male and median age was 61.5 years (range: 46-77). 27 pts were evaluable for endpoint (1 patient did not start any treatment). PFS rate at 16 weeks was 9/27 [33.3%; 95% confidence interval (95% CI): 16.5-54.0 %]. Median (95% CI) PFS and OS were 3.9 (2.0 – 6.7) and 6.8 (5.8 – 12.3) months, respectively. The median number of treatment cycles was 3 (range: 1-8). Best response seen in this cohort was stable disease (13/27 pts). The most common grade 3 or worse adverse events were neutrophil count decreased (44.4%), anemia (22.2%), alkaline phosphate increased (22.2%), blood bilirubin increased (18.5%), and white blood cell decreased (18.5%) without any unexpected safety signals. Conclusions Treatment of advanced refractory BTC pts with TAS-102 demonstrated antitumor activity with acceptable toxicity. Clinical trial identification NCT03278106. Legal entity responsible for the study Amit Mahipal. Funding Eisai. Disclosure All authors have declared no conflicts of interest.