First report of the randomized phase III study of bi-weekly trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) vs. FTD/TPI monotherapy for chemorefractory metastatic colorectal cancer (mCRC): JCOG2014 (ROBiTS).
Authors: Hironaga Satake, Kentaro Yamazaki, Yusuke Suwa, Takahiro Tsushima, Yasunobu Ishizuka, Shogen Boku, Atsuo Takashima, Toshifumi Yamaguchi, Masako Asayama, Mitsuru Yokota, Koji Numata, Takashi Ohta, Hisateru Yasui, Yosuke Kito, Yasumasa Takii, Ryo Kitabayashi, Yusuke Sano, Haruhiko Fukuda, Tetsuya Hamaguchi, Yukihide Kanemitsu
Journal: Journal of Clinical Oncology (2024)

118 Background: FTD/TPI has been widely used as one of the standard therapies in the late-line treatment for patients with mCRC, and the efficacy of FTD/TPI plus BEV combination was also recently reported in the SUNLIGHT trial. However, the combination of FTD/TPI plus BEV increased the frequency of hematologic toxicity. On the other hand, several phase II studies suggested that modifying the FTD/TPI schedule in combination with BEV from 4-week intervals (2 weeks-on, 2 weeks-off) to bi-weekly dosing (1 week-on, 1 week-off) reduced hematologic toxicities without reducing efficacy. Therefore, we commenced a phase III study to confirm the superiority of bi-weekly FTD/TPI plus BEV to 4-week intervals FTD/TPI monotherapy. Methods: This study is an open-label, multicenter, phase III trial conducted in Colorectal Cancer Study Group of Japan Clinical Oncology Group. We randomly assigned, in a 1:1 ratio, patients who were refractory or intolerant to fluoropyrimidine, oxaliplatin, irinotecan, angiogenesis inhibitor, anti-EGFR antibody (if RAS-wild type), BRAF inhibitor and anti-EGFR antibody (if BRAF V600E -mutant), and immune check point inhibitor (if dMMR/MSI-H) to the treatment of mCRC to receive 4-week intervals FTD/TPI 70mg/m 2 /day monotherapy (arm A) or bi-weekly FTD/TPI plus bevacizumab 5mg/kg (arm B). The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), response rate (RR), disease control rate (DCR), and safety. Results: In consideration of the results of the SUNLIGHT trial, this study was prematurely terminated. Between January 2022 and February 2023, a total of 152 patients were randomized (75 in the arm A and 77 in the arm B). Patient backgrounds between the two arms were well balanced. At the data cut-off date, all enrolled patients discontinued protocol treatment due to disease progression (69.3% vs. 59.7%) and treatment-related adverse events (6.7% vs. 2.6%). With a median follow-up of 8.3 months for surviving patients (OS events, 45% vs. 40%), the median OS was 12.2 vs. 11.8 months (hazard ratio [HR], 0.905; 95% confidence interval [CI], 0.556 to 1.473) and the median PFS was 2.4 vs. 4.0 months (HR, 0.607; 95% CI, 0.426 to 0.865). RR was 1.3% vs. 5.3% and DCR was 45.3% vs. 53.3%. The most common Grade 3 or higher adverse events in each group were neutropenia (46.6% vs. 24.0%), anemia (15.1% vs. 4.0%), fatigue (2.7% vs. 8.0%), anorexia (5.5% vs. 5.3%), nausea (5.5% vs. 5.3%) and febrile neutropenia (4.1% vs. 0%). Conclusions: Although this study was terminated early, the bi-weekly FTD/TPI plus BEV combination in late-line chemotherapy for patients with mCRC resulted in prolonged PFS and reduced hematologic toxicity compared to 4-week intervals FTD/TPI monotherapy. Long-term results including OS are currently under follow-up. Clinical trial information: jRCTs031210544 .