Randomized study evaluating trifluridine/tipiracil (TAS-102) versus + trifluridine/tipiracil + bevacizumab as last-line therapy in patients with chemorefractory unresectable metastatic colorectal cancer (mCRC).

637Background: Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) is approved for the use in patients with chemorefractory mCRC. Inspired by the encouraging results of a small phase I/II study, C-TASK FORCE, evaluating the combination of FTD/TPI and bevacizumab in chemorefractory mCRC patients (Kuboki et al, 2017), we designed the present randomized trial. Methods: This randomized study enrolled as planned 80 mCRC patients. The main inclusion criteria were: histologically confirmed and chemorefractory mCRC; PD during or after therapy with fluoropyrimidine, irinotecan, oxaliplatin, EGFR-inhibitor (RAS wildtype), and bevacizumab was optional; PS 0-1. In arm A, FTD/TPI was administered orally at the dose of 35 mg/m²/dose bid from day 1 to day 5 and from day 8 to day 12 and in arm B the same dose of FTD/TPI was combined with bevacizumab at a dose of 5 mg/kg on day 1 and on day 15 of a 28-day treatment cycle. The primary endpoint was to increase progression-free survival (PFS) from 1.8 months to 3.8 months. Secondary objectives included overall survival (OS) and safety. Results: Eighty patients with chemorefractory mCRC were randomized from September 2017 to August 2018. The median PFS was significantly improved from 2.6 months (arm A) to 5.9 months (arm B) with a hazard ratio (HR) 0.51 (95% CI, 0.28 to 0.92; P <0.03) and median OS was significantly improved from 7.3 months (arm A) to 10.3 months (arm B) with HR 0.42 (95% CI, 0.18 to 0.99; P <0.05). After median follow-up for OS of 5.6 months, 57 patients were alive at September 7th, 2018. Therapy was well tolerated with adverse events as expected, patients receiving FTD/TPI + bevacizumab had more grade 3-4 neutropenia (56% in arm B vs 30% in arm A, p = 0.03) and three patients in arm B (vs zero in arm A ) developed febrile neutropenia. SAEs were observed in 13 (arm A) and 11 patients (arm B), respectively. Conclusions: In patients with chemorefractory mCRC, FTD/TPI + bevacizumab, as compared with FTD/TPI monotherapy, was associated with a significant and clinical relevant improvement in PFS and OS with tolerable toxicity. Clinical trial information: 2016-005241-23.