Bevacizumab improves efficacy of trifluridine/tipiracil (TAS-102) in patients with chemorefractory metastatic colorectal cancer: a Danish randomized trial

Introduction: Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) prolongs survival in patients with chemorefractory metastatic colorectal cancer (mCRC). Inspired by the promising results of C-TASK FORCE (Kuboki et al, 2017), we designed the present investigator-initiated randomized trial. Methods: This randomized study enrolled 93 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 days 1-5 and 8-12 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. Eighty patients were needed to show an increase in progression-free survival (PFS) from 1.8 months to 3.8 months. A planned safety analysis performed once 40 patients had received 2 cycles of therapy showed no toxicity issues, but PFS was slightly longer than expected in arm A. An amended protocol aiming for a total of 124 patients was approved by the Ethical Committee but this was later rejected by the Danish Health Authorities because Lonsurf was not approved in Denmark. Here we report efficacy and safety data of all 93 patients (intention-to-treat population) that were randomized. Results: A total of 93 patients with chemorefractory mCRC were randomized from September 2017 to October 2018. The median PFS was significantly improved from 2.6 months (arm A) to 4.6 months (arm B) with a hazard ratio (HR) of 0.45 (95% CI, 0.29 to 0.72; P = .001). Median OS was significantly prolonged from 6.7 months (arm A) to 9.4 months (arm B) with HR 0.55 (95% CI, 0.32 to 0.94; P = .03). After a median follow-up for OS of 11 months, 37 patients were alive as of February 15th, 2019. Therapy was well tolerated with adverse events as expected. Patients receiving FTD/TPI + bevacizumab had more grade 3-4 neutropenia (67% in arm B vs 38% in arm A, P < .05) and three patients in arm B (vs one in arm A) developed febrile neutropenia. SAEs were observed in 21 (arm A) and 19 patients (arm B), respectively. Conclusion: In patients with chemorefractory mCRC, FTD/TPI + bevacizumab demonstrated a significant and clinically relevant improvement in PFS and OS compared with FTD/TPI monotherapy, with a favorable safety profile.