Efficacy and Safety of Trifluridine/Tipiracil-Containing Combinations in Colorectal Cancer and Other Advanced Solid Tumors: A Systematic Review

Abstract

We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common grade ≥ 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, grade ≥ 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation.

Keywords: antineoplastic agents; antineoplastic drugs; colorectal neoplasms; review literature; tipiracil; trifluridine.

Figure 1.

Selection process for studies included in the systematic literature review (PRISMA diagram). *Studies in second-line or later settings were included for qualitative synthesis. Studies based on frontline treatment or where line of treatment was not explicitly reported were summarized separately. Abbreviations: 1L, first line; 2L, second line; GC, gastric cancer; GEJC, gastro-oesophageal junction carcinoma; mCRC, metastatic colorectal cancer; NET, neuroendocrine tumors; NR, not reported; TiAb, title/abstract; Tx, treatment.

Figure 2.

Median OS with FTD/TPI-containing combination regimens in patients with metastatic colorectal cancer in second- or third-line settings. *Data pertains to patients who received FTD/TPI ± BEV. Abbreviations: 2L, second line; 3L, third line; BEV, bevacizumab; chemo, chemotherapy; FTD/TPI, trifluridine/tipiracil; IRI, irinotecan; NA, not applicable; NIN, nintedanib; NIVO, nivolumab; OS, overall survival; OXA, oxaliplatin; PAN, panitumumab.

Figure 3.

Median PFS with FTD/TPI-containing combination regimens in patients with metastatic colorectal cancer in second- or third-line settings. *Median PFS was 3.7 by central assessment and 5.6 months by investigator assessment. **Data pertain to patients receiving FTD/TPI ± BEV. ^†Median PFS was 2.2 months per immune-related response criteria and 2.8 months per response evaluation criteria in solid tumors (RECIST). Abbreviations: 2L, second line; 3L, third line; BEV, bevacizumab; chemo, chemotherapy; FTD/TPI, trifluridine/tipiracil; IRI, irinotecan; NA, not applicable; NIN, nintedanib; NIVO, nivolumab; OXA, oxaliplatin; PAN, panitumumab; PFS, progression-free survival; REG, regorafenib.