In the Clinic provides overviews of novel hematology and oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On February 22, trifluridine/tipiracil tablets were approved for the treatment of adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2-targeted therapy.^1,2 The drug is a fixed combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor.

Supporting Efficacy Data

Approval was based on findings in the international double-blind phase III TAGS trial (ClinicalTrials.gov identifier NCT02500043).^2,3 In the trial, 507 patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy were randomly assigned 2:1 to receive trifluridine/tipiracil at 35 mg/m² orally twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle with best supportive care (n = 337) or placebo with best supportive care (n = 170) until disease progression or unacceptable toxicity.

Patients had a median age of 63 years; 73% were male; 70% were white and 16% Asian; 38% had an Eastern Cooperative Oncology Group performance status of 0; 71% had gastric tumors, 29% had gastroesophageal junction tumors, and two patients had gastric/gastroesophageal junction tumors. All patients received platinum-based chemotherapy, 99% received fluoropyrimidine-based therapy, 91% received a taxane, 55% received irinotecan, and 33% received ramucirumab.

HER2 status was negative in 62%, positive in 19%, and unknown in 20% of patients. Among the 94 patients with HER2-positive tumors, 89% had received anti-HER2 therapy.

The median overall survival was 5.7 months in the trifluridine/tipiracil group vs 3.6 months in the placebo group (hazard ratio [HR] = 0.69, P = .0006). Progression-free survival events occurred in 85% vs 92% of patients (HR = 0.56, P < .0001).

How It Works

The agent consists of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil (molar ratio = 1:0.5; weight ratio = 1:0.471). Tipiracil acts to increase trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase.

After uptake into cancer cells, trifluridine is incorporated into DNA, interfering with DNA synthesis and inhibiting cell proliferation. Trifluridine/tipiracil exhibited antitumor activity against KRAS wild-type and mutant colorectal cancer xenografts in mice.

How It Is Used

The recommended dosage of trifluridine/tipiracil is 35 mg/m² up to a maximum of 80 mg per dose (based on the trifluridine component) orally twice daily on days 1 to 5 and days 8 to 12 of each 28-day cycle until disease progression or unacceptable toxicity. Doses should be rounded to the nearest 5-mg increment. Treatment should not be started in patients with baseline moderate or severe hepatic impairment.

Complete blood cell counts should be obtained prior to and on day 15 of each cycle. A cycle of treatment should not be initiated until absolute neutrophil count (ANC) is ≥ 1,500/mm³ or febrile neutropenia is resolved; platelets are ≥ 75,000/mm³; and grade 3 or 4 nonhematologic adverse reactions are resolved to grade 0 or 1.

Within a treatment cycle, treatment should be withheld for the following: ANC < 500/mm³ or febrile neutropenia; platelets < 50,000/mm³; and grade 3 or 4 nonhematologic adverse reactions. After recovery, treatment can be resumed after reducing the dose by 5 mg/m² per dose from the previous dose level if the following occur: febrile neutropenia; uncomplicated grade 4 neutropenia (which has recovered to ≥ 1,500/mm³) or thrombocytopenia (which has recovered to ≥ 75,000/mm³) that results in more than a 1-week delay in the start of the next cycle; nonhematologic grade 3 or grade 4 adverse reactions except for grade 3 nausea or vomiting controlled by antiemetic therapy; or grade 3 diarrhea responsive to antidiarrheal medication.

A maximum of three dose reductions are permitted. Treatment should be permanently discontinued in patients unable to tolerate a dose of 20 mg/m² twice daily. Dosage should not be escalated after it has been reduced.

Safety Profile

The most common adverse events or laboratory abnormalities (≥ 10%) observed in clinical trials of trifluridine/tipiracil have been anemia, neutropenia, fatigue/asthenia, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, and pyrexia.

In the TAGS trial, the most common adverse events or laboratory abnormalities of any grade (≥ 10% incidence) in patients receiving trifluridine/tipiracil occurring at a higher incidence vs the placebo group were neutropenia (66% vs 4%), anemia (63% vs 38%), nausea (37% vs 32%), decreased appetite (34% vs 31%), thrombocytopenia (34% vs 9%), vomiting (25% vs 20%), and diarrhea (23% vs 14%). Infection of any grade occurred in 23% vs 16%.

The most common grade 3 or 4 adverse events in the trifluridine-tipiracil group included neutropenia (38% vs 0%), anemia (19% vs 7%), decreased appetite (9% vs 7%), and thrombocytopenia (6% vs 0%). Pulmonary emboli occurred in 3.1% vs 1.8% of patients. Adverse events led to trifluridine/tipiracil dose reduction in 11% of patients (most commonly due to neutropenia, anemia, febrile neutropenia, and diarrhea) and discontinuation in 13%.

Interstitial lung disease has been reported in 15 patients (0.2%), including 3 fatal cases, among approximately 7,000 patients exposed to trifluridine/tipiracil in clinical studies and clinical practice settings in Asia.

Trifluridine/tipiracil carries warnings/precautions for severe myelosuppression and embryofetal toxicity. Patients should be advised not to breastfeed during trifluridine/tipiracil therapy. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves Lonsurf for recurrent, metastatic gastric and gastroesophageal junction adenocarcinoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm632032.htm. Accessed June 28, 2019.

2. Lonsurf (trifluridine and tipiracil) tablets prescribing information, Taiho Pharmaceutical Co, Ltd, February 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/207981s008lbl.pdf. Accessed June 28, 2019.

3. Shitara K, Doi T, Dvorkin M, et al: Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 19:1437-1448, 2018.