Multicenter phase Ib/II study of biweekly trifluridine/tipiracil with bevacizumab combination for patients with metastatic colorectal cancer refractory to standard therapies (BiTS study)

647 Background: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (Bmab) combination therapy has shown a promising activity with manageable safety profile in patients (pts) with heavily pretreated metastatic colorectal cancer (mCRC). The aim of this multicenter, phase Ib/II study was to assess the activity and safety of biweekly FTD/TPI with Bmab combination for pts with mCRC who were refractory or intolerant to standard therapies. Methods: Inclusion criteria were ≥ 20 years; histologically confirmed unresectable mCRC; refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type RAS); ECOG PS 0 or 1; evaluable lesion according to the RECIST version 1.1. Phase Ib part is designed to determine the recommended phase II dose (RP2D), and pts received the RP2D in phase Ib part were included in efficacy and safety populations. The primary endpoint in phase II part was an investigator assessed progression-free survival rate at 16 weeks (16w-PFS) with a hypothesis of 15% considered unacceptable and 38.7% deemed promising. Given a one-sided α of 0.025 and statistical power of 90%, a minimum of 40 pts were required for phase II part. Results: From October 2017 to January 2018, totally 46 pts were enrolled (6 pts in phase Ib and 40 pts in phase II). The RP2D was determined to be 5 mg/kg for Bmab and 30 mg/m2 for FTD/TPI in phase Ib. Of the 44 eligible pts (median age, 69; male, 55%; PS 0, 57%; right-sided primary, 29.5%), 16w-PFS rate was 40.9 % (95% CI: 26.3 to 56.8 %) and the null hypothesis of 16w-PFS rate ≤ 15% was rejected (p < 0.0001). Response rate and disease control rate were 0 % (95 %CI: 0 to 6.6 %) and 59.1 % (95%CI: 43.3 to 73.7 %), respectively. With a median follow up of 5.86 months (range, 1.53-9.79), median PFS was 4.25 months (95% CI: 2.54 to 5.57). Grade 3 or higher adverse events were hypertension (40.9%), neutropenia (11.4 %), leucopenia (11.4 %), anemia (9.1 %), anorexia (9.1 %), nausea (6.8 %), hyperbilirubinemia (6.8 %) and proteinuria (6.8 %). Conclusions: Bi-weekly FTD/TPI plus Bmab showed promising anti-tumor effect with acceptable toxicities. Clinical trial information: UMIN000029198.