September 22, 2015
The U. S. Food and Drug Administration approved trifluridine/tipiracil (LONSURF, Taiho Oncology, Inc.) for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- , and irinotecan-based chemotherapy, an anti-VEGF biologic product, and an anti-EGFR monoclonal antibody, if RAS wild-type.
LONSURF is a combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor, indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy
Trifluridine, an antineoplastic thymidine-based nucleoside analogue, is described chemically as 2’-deoxy-5-(trifluoromethyl) uridine, and has the following structural formula:
Tipiracil hydrochloride, a thymidine phosphorylase inhibitor, is described chemically as 5 chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione monohydrochloride or 2,4(1H,3H)-Pyrimidinedione, 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-, hydrochloride (1:1), and has the following structural formula:
Mechanism of Action
LONSURF consists of a thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil, at a molar ratio 1:0.5 (weight ratio, 1:0.471). Inclusion of tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase. Following uptake into cancer cells, trifluridine is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation. Trifluridine/tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice.
Efficacy and Safety
The efficacy and safety of Lonsurf were evaluated in an international, randomized, double-blind study involving 800 patients with previously treated metastatic colorectal cancer.
Study participants received Lonsurf plus best supportive care, or placebo plus best supportive care until their disease worsened or side effects became intolerable. The primary endpoint of the study was overall survival and the secondary endpoint was progression-free survival. Patients treated with Lonsurf lived an average of 7.1 months compared to 5.3 months for those treated with placebo. On average, the time to disease progression was two months for patients on Lonsurf compared to 1.7 months for patients receiving placebo.
DOSAGE AND ADMINISTRATION
• Recommended dose: 35 mg/m2 /dose orally twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. • Take LONSURF within 1 hour after completion of morning and evening meals.
WARNINGS AND PRECAUTIONS
• Severe Myelosuppression: Obtain complete blood counts prior to and on Day 15 of each cycle. Reduce dose and/or hold LONSURF as clinically indicated.
• Embryo-Fetal Toxicity: Fetal harm can occur. Advise women of potential risk to a fetus.
The most common adverse reaction (≥10%) are anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.