FDA approves trifluridine/tipiracil for colorectal cancer

Camden Svec

Lisa HolleOn September 22, 2015, FDA approved trifluridine/tipiracil (Lonsurf; Taiho Oncology), a new, orally administered cytotoxic drug for the treatment of patients with metastatic colorectal cancer (CRC). CRC is the third most commonly diagnosed cancer in men and second most common cancer in women worldwide. Unless it is caught early with preliminary screening, this cancer usually is diagnosed at an advanced stage.

In patients with stage IV CRC, the cancer has spread to outside organs; therefore, surgical resection is not so useful and combination chemotherapy is the main treatment option.

Treatment regimens typically include active drugs, either in combination or as single agents, such as fluoropyrimidines (capecitabine, fluorouracil/leucovorin); oxaliplatin, irinotecan, anti-vascular endothelial growth (VEGF) biologic therapy (bevacizumab, ramucirumab, ziv-aflibercept); multikinase inhibitors (regorafenib) and/or an anti-EGFR monoclonal antibody, if the tumor is KRAS wild-type (cetuximab, panitumumab).

Patients often will receive an initial chemotherapy regimen until their disease progresses, at which time they’ll go on to receive a second regimen that contains one or more of the other active drugs. This process usually continues until the patient has received all the active drugs. Trifluridine/tipiracil is now an option for patients who were previously treated with the available agents fluoropyrimidine, oxaliplatin, irinotecan-based chemotherapy, and anti-VEGF biologic product; and an anti-EGFR monoclonal antibody, if KRAS wild-type.

Efficacy

Trifluridine/tipiracil’s efficacy was demonstrated in a multicenter, double-blind, placebo-controlled, intention-to-treat study known as the RECOURSE trial, which included 800 patients previously treated for metastatic CRC. Patients were randomized (2:1) to receive trifluridine/tipiracil (N=534) or matching placebo (N=266). At baseline all patients in both study arms had received previous chemotherapy regimens containing fluoropyrimidine, oxaliplatin, and irinotecan. All patients except one in the placebo group had received bevacizumab. All but two patients (one in each study group) with KRAS wild-type tumors had received cetuximab or panitumumab. Regorafenib, an oral multikinase inhibitor, was used in 17% of the trifluridine/tipiracil group and 20% of the placebo group. Patients received 35 mg/m² trifluridine/tipiracil or placebo twice daily after morning and evening meals on days 1–5 and 8–12 followed by a 14-day rest period. The regimen was repeated until disease progression or unacceptable toxicity occurred.

Treatment resulted in an improvement in overall survival, progression-free survival (PFS), and performance status scores. The median overall survival was 7.1 and 5.3 months in the trifluridine/tipiracil and placebo groups respectively (HR 0.68 [95% CI: 0.58, 0.81], P<0.001). Increased PFS was also improved in patients receiving trifluridine/tipiracil (2 months) vs. placebo (1.7 months; [HR 0.47 (95% CI: 0.40, 0.55), P<0.001]). The Eastern Cooperative Oncology Group (ECOG) performance score, a commonly used performance status measure in cancer patients, was also significantly improved in the trifluridine/tipiracil group vs. placebo group [HR 0.66 (95% CI: 0.56, 0.78), P<0.001]. The median time to an ECOG performance status of 2 or higher was 5.7 months and 4.0 months in the trifluridine/tipiracil and placebo groups, respectively.

Safety

Adverse effects and abnormal laboratory values were more common with trifluridine/tipiracil than with placebo, and included anemia (77%), neutropenia (67%), nausea (48%), decreased appetite (39%), diarrhea (32%), vomiting (28%), abdominal pain (21%), fatigue (52%), and pyrexia (19%).

This regimen is considered to have a moderate-to-high emesis risk and should be pretreated with an oral daily dose of a serotonin (5-HT3) antagonist such as ondansetron, granisetron, or dolasetron to reduce nausea and vomiting. If breakthrough emesis occurs, one agent from a different drug class can be added to the current regimen as needed (olanzapine, lorazepam, dronabinol, prochlorperazine, metoclopramide, etc).

The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, asthenia, and diarrhea. However, no clinically meaningful differences were observed with respect to hepatic or renal dysfunction, anorexia, stomatitis, hand-foot syndrome, or cardiac events.

Management of adverse effects is necessary to minimize morbidity. Monitoring includes collecting a complete blood count (CBC), differential and absolute neutrophil count (ANC) prior to therapy initiation, prior to day 15 of each cycle, on day 15 of each cycle, and more frequently if needed. If severe myelosuppression occurs, dose should be reduced or held as clinically indicated.

Animal studies indicate trifluridine/tipiracil can cause fetal harm and should not be given to pregnant women. Women should not breastfeed while using this medication or for one day following the final dose. Grades 3 or 4 neutropenia and thrombocytopenia and grade 3 anemia occurred more commonly in patients 65 years or older. Patients who have moderate renal impairment may require dose modifications for increased toxicity.

Dosing

The recommended dose of trifluridine/tipiracil is 35mg/m²/dose (based on trifluridine component) orally twice daily on days 1 through 5 and days 8 through 12 of each 28-day cycle. Each dose should be rounded to the nearest 5-mg increment. Trifluridine/tipiracil comes in an oral combination tablet in 15-mg/ 6.14-mg and 20-mg/8.19-mg strengths.

Patients should be advised to take this medication within one hour after morning and evening meals. Patients should not take additional doses to make up for missed or held doses and should not split this tablet. No pharmacokinetic drug-drug interaction studies have been conducted with trifluridine/tipiracil.

Do not initiate the cycle of trifluridine/tipiracil until the absolute neutrophil count (ANC) is ≥1,500/mm³ or febrile neutropenia is resolved, platelets are ≥75,000/mm³, or grades 3 or 4 nonhematological adverse reactions are resolved to grades 0 or 1.

Patients should withhold trifluridine/tipiracil if during a treatment cycle the ANC is less than 500/mm³, febrile neutropenia develops, platelets are less than 50,000/mm³, or if grade 3/4 nonhematological adverse reactions occur. After recovery of febrile neutropenia, thrombocytopenia, or nonhematologic grades 3 or 4 adverse reactions, dosing should be reduced by 5 mg/m²/dose from the previous dose level before restarting. 

Camden E. Svec  is a 2016 PharmD graduate from University of Connecticut School of Pharmacy, Storrs, Conn. Lisa M. Holle is an assistant clinical professor at University of Connecticut School of Pharmacy, Storrs, Conn.