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Trifluridine/tipiracil approved in Europe and US for metastatic colorectal cancer

Trifluridine/tipiracil (Lonsurf) has received approval for use in combination with bevacizumab from the European Commission and the FDA for the treatment of adult patients with metastatic colorectal cancer.

Eligible patients will have received two prior anti-cancer treatments including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

The approval in both markets is based on the findings of the phase 3 SUNLIGHT trial, conducted by Servier and Taiho Oncology, and published in the New England Journal of Medicine in May 2023.

Marwan Fakih, lead US investigator for the trial and professor, medical oncology and therapeutics research at City of Hope, Duarte, California, said: ‘The FDA approval of this combination provides patients with metastatic colorectal cancer an important new treatment option, one that has been shown to extend life in addition to other benefits and which I believe will change the treatment landscape for this patient population.

‘Notably, the use of Lonsurf plus bevacizumab in these patients did not result in an increase in potentially intolerable side effects that might limit the utility of this combination.‘

In the US, the approval also includes use of trifluridine/tipiracil as a single agent.

Trifluridine/tipiracil and overall survival

The Phase 3 SUNLIGHT trial was undertaken in patients with histologically confirmed, unresectable adenocarcinoma of the colon or rectum. The primary endpoint was overall survival, and the secondary endpoints included progression-free survival and safety.

A total of 246 patients were randomised in a ratio of 1:1 to receive trifluridine/tipiracil and bevacizumab or trifluridine/tipiracil alone.

The median overall survival was 10.7 months for trifluridine/tipiracil with bevacizumab compared to 7.5 months for trifluridine/tipiracil alone, which represents a 39% improvement in the median overall survival (Hazard ratio for death, HR = 0.61, 95% CI 0.49 to 0.77, p < 0.001).

In addition, the median progression free survival 5.6 months in the trifluridine/tipiracil with bevacizumab group compared to 2.4 months in the trifluridine/tipiracil group (HR = 0.44, 95% CI 0.36 to 0.54, p < 0.001).

The most frequent severe treatment emergent adverse events for trifluridine/tipiracil with bevacizumab compared to trifluridine/tipiracil alone were neutropenia (43.1% vs 32.1%) and anaemia (6.1% vs 11.0%), respectively.

Colorectal cancer is the third most common cancer globally, and nearly a third of patients are only diagnosed after the disease has undergone metastases. A previous study found higher levels of advanced colorectal cancer were detected during the Covid-19 pandemic.

Lonsurf is an oral nucleoside anti-tumour agent discovered and developed by Taiho Pharmaceutical. It consists of a thymidine-based nucleoside analog, trifluridine and the thymidine phosphorylase (TP) inhibitor tipiracil, which increases trifluridine exposure by inhibiting its metabolism by TP. Trifluridine is incorporated into DNA, resulting in DNA dysfunction and inhibition of cell proliferation.

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