Lonsurf (trifluridine and tipiracil) is an oral anti-cancer drug indicated for the treatment of patients with advanced metastatic colorectal cancer (mCRC) who are unresponsive to other therapies such as chemotherapy and biological therapy.
The drug is manufactured by Taiho Oncology, a subsidiary of Taiho Pharmaceutical (Japan). Taiho Pharmaceuticals and Servier signed an exclusive licence agreement for co-developing and commercialising Lonsurf in Europe and other countries outside the US, Canada, Mexico, and Asia.
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Lonsurf is available in 15mg trifluridine/6.14mg tipiracil dosage strength as white round, film-coated tablets and 20mg trifluridine/8.19mg tipiracil dosage strength as pale red, biconvex, round, film-coated tablets.
Regulatory approvals for Lonsurf
Lonsurf was approved by the US Food and Drug Administration (FDA) for the treatment of advanced mCRC in September 2014.
The drug was also approved in Japan for the treatment of recurrent colorectal cancer in March 2014.
In 2019, the FDA approved the drug for the treatment of adults with previously treated advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Lonsurf received approval from the FDA in August 2023 as a single agent or in combination with bevacizumab for the treatment of patients with mCRC who were formerly treated with fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab and anti-Epidermal Growth Factor Receptor (EGFR) antibodies and are diagnosed with RAS wild-type mCRC.
The approval was based on data from the Phase III SUNLIGHT clinical trial.
Metastatic colorectal cancer
Colorectal cancer affects the parts of the large intestine such as the colon and rectum. It often begins as a small growth, called a polyp, which eventually turns cancerous. Identifying and removing polyps could prevent colorectal cancer.
Colorectal cancer, according to the American Cancer Society, is the third most common type of cancer and is the second leading cause of cancer-related deaths in the US.
In 2014, an estimated 136,830 cases of either colon or rectum cancer were diagnosed of which, the cancer had spread to another part of the body in more than 20% of cases.
Lonsurf’s mechanism of action
Lonsurf is composed of two active components which are trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor, at a molar ratio of 1:0.5.
Tipiracil, which is a thymidine phosphorylase inhibitor, curbs the metabolism of trifluridine and increases its exposure. Once trifluridine enters the cancer cells, it is incorporated into the DNA, interferes with its synthesis, and reduces cell proliferation.
Clinical trials on Lonsurf
The FDA approval of Lonsurf was based on results from a Phase III clinical trial, known as Recourse, which was conducted to determine the safety and efficacy of the drug.
Recourse is a global, randomised, double-blind study, which enrolled 800 patients that had been treated for mCRC with at least two lines of standard chemotherapy. Key eligibility also included an absence of brain metastasis and ascites.
During the study, subjects were randomised in a 2:1 ratio and treated with either Lonsurf along with best supportive care (BSC), or placebo with BSC.
Subjects in one arm received 35mg/m² Lonsurf while those in the other received a matching placebo orally twice a day after meals until their disease progressed or side effects became intolerable.
The primary endpoint of the study was overall survival (OS) while the secondary endpoint was progression-free survival (PFS). Results showed there was statistically significant improvement in both OS and PFS in patients treated with Lonsurf and BSC, compared to those treated with placebo and BSC. The drug reduced the risk of death by 32% compared to a placebo.
The most common adverse reactions recorded during the trials were anaemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhoea, vomiting, abdominal pain, and pyrexia.
Dose reduction resulted in certain adverse reactions including neutropenia, anaemia, febrile neutropenia, fatigue, and diarrhoea.
Clinical trials on Lonsurf for GEJ adenocarcinoma indication
The FDA approval of Lonsurf for GEJ adenocarcinoma was based on data from the multinational, double-blind, randomised, placebo-controlled Phase III TAGS clinical trial.
The study evaluated the efficacy and safety of Lonsurf in 507 patients suffering from non-resectable, metastatic gastric adenocarcinoma who had received at least two previous chemotherapy regimens and had experienced radiological disease progression.
The participants were randomised to receive (2:1) either 35mg oral trifluridine/tipiracil twice daily plus best supportive care or placebo plus best supportive care.
The trial met its primary and secondary endpoints exhibiting prolonged OS with Lonsurf versus placebo and a safety profile consistent with earlier experience with this drug. The median OS rate in the trifluridine/tipiracil group was 5.7 months compared to 3.6 months in the placebo group.
The most common severe effects reported during the trial were fatigue, nausea, decreased appetite, vomiting, infection, and diarrhoea.
SUNLIGHT clinical trial details
The multinational, randomised, active-controlled, open-label, two-arm Phase III SUNLIGHT clinical trial enrolled 492 patients with mCRC who have undergone two chemotherapy programmes. The patients were randomised in a 1:1 ratio to receive Lonsurf in combination with bevacizumab or Lonsurf as a monotherapy.
The study met both the primary and secondary endpoints, with the median OS being 10.8 months in the Lonsurf plus bevacizumab arm versus 7.5 months in the Lonsurf arm.
The most common severe effects reported during the trials were neutropenia and anaemia.
