On August 2, 2023, the fixed combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor, was approved for use with bevacizumab for metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF biological therapy; and, if the disease is RAS wild-type, an anti-EGFR therapy.1 Trifluridine/tipiracil (Lonsurf) was originally approved in this setting as monotherapy in September 2015.
Supporting Efficacy Data
Approval was based on findings in the open-label multicenter SUNLIGHT trial (ClinicalTrials.gov identifier NCT04737187), in which 492 patients who had received a maximum of two prior chemotherapy regimens and demonstrated progressive disease or intolerance to the last regimen were randomly assigned to receive trifluridine/tipiracil with (n = 246) or without (n = 246) bevacizumab. Treatment consisted of trifluridine/tipiracil at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle with or without bevacizumab at 5 mg/kg every 2 weeks (days 1 and 15) of each cycle until disease progression or unacceptable toxicity.
The median overall survival rate was 10.8 months (95% confidence interval [CI] = 9.4–11.8 months) in the combination group vs 7.5 months (95% CI = 6.3–8.6 months) in the control group (hazard ratio [HR] = 0.61, 95% CI = 0.49–0.77, P < .001). The median progression-free survival rate was 5.6 months (95% CI = 4.5–5.9 months) in the combination group vs 2.4 months (95% CI = 2.1–3.2 months) in the control group (HR = 0.44, 95% CI = 0.36–0.54, P < .001).
The recommended trifluridine/tipiracil dose when given with bevacizumab in this indication is 35 mg/m2 (based on the trifluridine component) twice daily on days 1 to 5 and days 8 to 12 of each 28-day cycle. The agent should not be initiated in patients with baseline moderate or severe hepatic impairment and should be given at a reduced dose in patients with severe renal impairment.
In SUNLIGHT, the most common adverse events of any grade in the trifluridine and tipiracil plus bevacizumab group were fatigue (45% vs 37% in the trifluridine and tipiracil group), nausea (37% vs 27%), diarrhea (21% vs 19%), abdominal pain (20% vs 18%), and decreased appetite (20% vs 15%). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (52%), decreased hemoglobin (5%), and decreased platelets (4%).
Trifluridine/tipiracil carries warnings/precautions for severe myelosuppression and embryofetal toxicity.
Serious adverse events occurred in 25% of patients in the combination group, most commonly intestinal obstruction (2.8%) and COVID-19 infection (2%). Adverse events led to discontinuation of treatment in 13% of patients, most commonly (≥ 2%) fatigue. Adverse events led to death in 1.2% of patients.
Trifluridine/tipiracil carries warnings/precautions for severe myelosuppression and embryofetal toxicity. Patients should be advised not to breastfeed while receiving trifluridine/tipiracil.
1. Lonsurf (trifluridine and tipiracil) tablets prescribing information, Taiho Pharmaceutical Co, Ltd, August 2023. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/207981s012lbl.pdf. Accessed August 10, 2023.