Trifluridine/tipiracil: Third-line 
oral agent for resistant metastatic colorectal cancer

New Drug

FDA recently approved a combination medication, trifluridine/tipiracil (Lonsurf—Taiho Oncology), for patients with refractory colorectal cancer. The new agent brings another option to patients with colorectal cancer who have experienced treatment failure with chemotherapy (fluoropyrimidine, oxaliplatin, and irinotecan based), anti–vascular endothelial growth factor (VEGF) biological therapy, and anti–epidermal growth factor receptor (EGFR) therapy (if carrying the KRAS wild-type gene).

“Trifluridine/tipiracil is reserved for patients with colorectal cancer who have already been treated with several lines of therapy but who are also healthy and active aside from their colorectal cancer,” Tracy Krause, PharmD, BCOP, oncology clinical pharmacy specialist at the Hospital of the University of Pennsylvania, told Pharmacy Today.

Efficacy in clinical trials

Researchers conducted an international, randomized, double-blind, placebo-controlled study in patients with resistant metastatic colorectal cancer who experienced treatment failure with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. They randomized 800 patients 2:1 to receive either trifluridine/tipiracil 35 mg/m2 on days 1 to 5 and days 8 to 12 of a 28-day cycle (N = 534) or to placebo (N = 266) and best supportive care. 

Participants had the KRAS wild-type gene (49%) or KRAS mutation (51%), had received at least two prior regimens, had Eastern Cooperative Oncology Group performance scores of 0 to 1, and were a median age of 63 years. The efficacy outcome measures were overall survival (OS) and progression-free survival (PFS).

Trial results showed a statistically significant improvement in both median OS (7.1 mo vs. 5.3 mo; hazard ratio [HR] 0.68 [95% CI 0.58–0.81, P <0.001) and PFS (2 mo vs 1.7 mo; HR 0.47 [95% CI 0.40–0.55], P <0.001) in patients who received trifluridine/tipiracil compared with those who received placebo.

Safety of trifluridine/tipiracil

The most common adverse reactions (≥10%) with trifluridine/tipiracil are anemia, neutropenia, asthenia/fatigue, thrombocytopenia, pyrexia, and gastrointestinal symptoms (e.g., decreased appetite, nausea, vomiting, diarrhea, abdominal pain). Grade 3 or 4 neutropenia and thrombocytopenia and grade 3 anemia have been reported more commonly in patients aged 65 years or older.

Clinical pearls

Trifluridine/tipiracil can cause severe thrombocytopenia and neutropenia. Patients require baseline blood counts and blood counts regularly throughout treatment. The manufacturer, Taiho Oncology, offers financial support to eligible patients; Oncology Patient Support at 844-TAIHO-4U (824-4648) or for more information. 

Patient counseling

Advise patients to their primary care provider if symptoms of infection or persistent gastrointestinal effects occur. Patients should take trifluridine/tipiracil within 1 hour of a meal. Trifluridine/tipiracil requires special handling and disposal and should not be handled by others without gloves. Women should not breastfeed or become pregnant while on trifluridine/tipiracil. Men with partners of childbearing age should use condoms while taking trifluridine/tipiracil and for 3 months after completing therapy.

Trifluridine/tipiracil (Lonsurf)

Manufacturer: Taiho Oncology

Drug class: Antineoplastic agent (thymidine-based nucleic acid analogue and thymidine phosphorylate inhibitor)

Indication: For the treatment of colorectal cancer in patients refractory to fluropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; anti-VEGF biological therapy; and anti-EGFR therapy (if KRAS wild type).

Dosage: Start at 35 mg/m2 (based on trifluridine component) up to a maximum of 80 mg per dose orally twice daily (rounded to the nearest 5 mg), to be taken within 1 hour after morning and evening meals (days 1–5 and 8–12) in a 28-day cycle. Repeat until disease progression or intolerable adverse effects. 

Of note: Complete blood cell counts are needed before day 15 of cycle and on day 15. The prescribing information details dose modifications or disruption based on absolute neutrophil count, platelet count, presence of febrile neutropenia, or serious (grade 3 or 4) nonhematological adverse reactions. Patients with moderate renal impairment who develop trifluridine/tipiracil toxicity may require a dose reduction.