Colon to Rectum
Lancet Gastroenterol Hepatol. 2023;8(2):133–44
Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): A randomized, open-label phase 3 study
Background: Trifluridine-tipiracil plus bevacizumab has shown efficacy in previous phase 2 studies including patients with unresectable metastatic colorectal cancer (CRC). The authors aimed to investigate first-line trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab in patients with unresectable metastatic colorectal cancer ineligible for intensive treatment.
Methods: In this open-label, randomized, phase 3 study, the authors enrolled patients aged 18 years and older with histologically confirmed metastatic CRC, ineligible for full-dose doublet or triplet chemotherapy and curative resection across 25 countries and regions. Participants were randomly allocated (1:1) to trifluridine-tipiracil plus bevacizumab or capecitabine plus bevacizumab until disease progression or unacceptable toxicity using an interactive web response system, stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1 vs. 2), primary tumor location (right vs. left colon), and the main reason for not being a candidate for intensive therapy (clinical condition vs. non-clinical condition). The primary end point was investigator-assessed progression-free survival (PFS), defined as the time from randomization to radiological progression or death from any cause, in the intention-to-treat (ITT) population. Safety was assessed in all patients having taken at least 1 dose of the study drug. The trial is ongoing, findings presented here are those of the primary analysis of PFS, conducted after 629 events had occurred.
Findings: Between March 21, 2019, and September 14, 2020, 856 patients (54% male, 46% female) were randomly assigned to trifluridine-tipiracil plus bevacizumab (n = 426) or capecitabine plus bevacizumab (n = 430). After a median follow-up of 16.6 months (95% confidence interval [CI]: 16.5–17.1), the hazard ratio for PFS for trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab was 0.87 (95% CI: 0.75–1.02; p = 0.0464; protocol-defined significance level of p = 0.021 not met). Investigator-assessed median PFS was 9.4 months (95% CI: 9.1–10.9) with trifluridine-tipiracil plus bevacizumab versus 9.3 months (95% CI: 8.9–9.8) with capecitabine plus bevacizumab. The most common grade 3 and higher treatment-emergent adverse events were neutropenia (220 [52%] of 423 patients in the trifluridine-tipiracil plus bevacizumab group vs. 6 [1%] of 427 in the capecitabine plus bevacizumab group), decreased neutrophil count (78 [18%] vs. 4 [< 1%]), anemia (60 [14%] vs. 16 [4%]), and hand-foot syndrome (0 vs. 61 [15%]). Nine deaths (5 in the trifluridine-tipiracil plus bevacizumab group and 4 in the capecitabine plus bevacizumab group) were treatment related.
Interpretation: First-line trifluridine-tipiracil plus bevacizumab was not superior to capecitabine plus bevacizumab in this population. As expected, the safety profile differed between the 2 treatments, but there were no new safety concerns. Trifluridine-tipiracil plus bevacizumab represents a feasible alternative to capecitabine plus bevacizumab in this population.