VP11-2021: Trifluridine/tipiracil plus bevacizumab vs capecitabine plus bevacizumab as first line treatment for patients with metastatic colorectal cancer (mCRC) ineligible for intensive therapy: The phase III randomized SOLSTICE study

Based on the results of the phase 2 TASCO1 trial, this study was conducted in patients with previously untreated unresectable mCRC not eligible to receive standard doublet regimens with oxaliplatin or irinotecan due to age, performance status, comorbidities or non-clinical reasons (low tumour burden, patient's choice, others). The aim was to demonstrate the superiority of the combination trifluridine/tipiracil plus bevacizumab (TT-B) over capecitabine plus bevacizumab (C-B) in terms of progression-free survival (PFS). From 21 Mar 2019 to 14 Sep 2020, 856 patients were randomized (1:1) to receive either oral TT-B, or oral C-B. Stratification factors were: ECOG performance status (0 vs 1 vs 2), reason for non-eligibility for intensive therapy (clinical condition vs non-clinical condition) and primary tumor localization (right vs left). The primary endpoint was PFS based on investigator assessment according to RECIST 1.1 criteria. Secondary endpoints included overall survival (not mature yet), overall response rate, disease control rate, quality of life and safety. The primary efficacy analysis was performed after 629 PFS events occurred. In total, 426 patients were randomly assigned to the TT-B arm and 430 to the C-B arm. The HR for PFS based on investigator assessment was 0.87 (95% CI: 0.75-1.02; p=0.09). Median PFS was 9.4 months (95%CI: 9.1-10.9) in TT-B arm vs 9.3 months (95%CI: 8.9-9.8) for C-B arm. TT-B arm had more grade ≥3 neutropenia (66.4% vs 2.3%) and C-B arm had more grade ≥3 hand-foot syndrome (14.5% vs 0%) consistent with the known safety profiles of TT and C. In the subgroup analysis, three subsets were identified to have a better outcome with TT-B treatment: RAS wildtype, males and Neutrophil Lymphocyte Ratio <5. T-B treatment was not superior to C-B in terms of PFS based on investigator assessment in the studied population. Safety data were in line with known safety profiles. Solstice is the first large-scale trial exploring this population who are not candidates for intensive therapy including fit, unfit and oncogeriatric patients.