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.
Safety Profile
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%).
OF NOTE
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.
REFERENCE
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.
