Lonsurf (Trifluridine/Tipiracil) Approved by European Commission for Metastatic Gastric Cancer Following Prior Therapies

French pharmaceutical company Servier and its partner Taiho Pharmaceutical recently announced that the European Commission (EC) has approved Lonsurf (trifluridine/tipiracil) for the treatment of adult patients with metastatic gastric cancer (mGC, including metastatic gastroesophageal junction adenocarcinoma [mGEJC]) whose advanced disease was previously controlled by at least two systemic therapy regimens.

Gastric cancer is a disease characterized by the formation of malignant cells within the gastric mucosa. It is the fifth most common cancer worldwide, second only to lung cancer andLiver Cancerthe third leading cause of death, with an estimated 723,000 gastric cancer-related deaths annually. Over the past two decades, the proportion of patients with metastatic gastric cancer has risen to over 40%. Standard chemotherapy regimens for advanced gastric cancer include fluoropyrimidines, platinum derivatives, and either taxanes or irinotecan. The addition of trastuzumab to chemotherapy is the standard of care for patients with HER2-neu-positive advanced gastric cancer. However, standard third-line treatment options are limited after failure of first- and second-line therapies.

Lonsurf (also known as TAS-102) is a novel antimetabolite combination drug, consisting of anti-TumorIt consists of the nucleoside analog FTD (trifluridine) and the thymidine phosphorylase inhibitor TPI (tipiracil). FTD can directly incorporate into the DNA double strand by replacing thymine during DNA replication, leading to DNA dysfunction and interfering with cancer cell DNA synthesis; TPI inhibits thymidine phosphorylase, which is involved in FTD degradation, thereby reducing FTD breakdown and maintaining its plasma concentration.

The approval of Lonsurf was based on data from the global Phase III clinical study TAGS (TAS-102 Gastric Study). This was a randomized, double-blind study conducted in patients with metastatic gastric cancer refractory to standard therapies, evaluating the efficacy and safety of Lonsurf combined with best supportive care (BSC) versus placebo combined with BSC.

The study enrolled patients with unresectable metastatic gastric cancer who had previously received at least two lines of chemotherapy and undergone radiotherapy. In the Lonsurf group, treatment was administered in 28-day cycles, with oral Lonsurf given twice daily on days 1–5 and 8–12 at a single dose of 35 mg/m²; the control group received placebo.

Study Results: Lonsurf vs. Placebo

Median overall survival (OS): 5.7 months vs. 2.1 months;

Median Progression-Free Survival (PFS): 2.0 months vs. 1.8 months;

Objective Response Rate (ORR): 4% vs. 2%;

Disease Control Rate (DCR): 44% vs. 14%;

Median time to worsening to an ECOG performance status score of ≥2: 4.3 months vs. 2.3 months.

Grade 3 or higherAdverse ReactionsIncidence: 43% vs. 42%, no difference.

Based on this study, the 2019 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Gastric Cancer listed Lonsurf as a standard regimen for later-line treatment of metastatic gastric cancer.

In addition to gastric cancer,FDAApproval of Lonsurf for the Treatment of Colorectal Cancer

September 22, 2015, based on a Phase IIIClinical Trial，FDAApproval of Lonsurf for the treatment of patients with RAS wild-type metastatic colorectal cancer who have progressed after fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

This trial enrolled 800 patients with refractory advanced colorectal cancer who had failed first- and second-line standard therapies. Participants were randomized in a 2:1 ratio, with 534 patients receiving Lonsurf and 266 patients receiving placebo. The results demonstrated that the Lonsurf group achieved a significantly higher disease control rate (44% vs. 16%) and longer overall survival (7.1 months vs. 5.3 months), with a 32% reduction in the risk of death. Regarding adverse events, the main side effects in the Lonsurf group were bone marrow suppression (with an incidence of neutropenia at 38%), fatigue, nausea, and elevated liver enzymes.

As of July 2019, Lonsurf had been approved in 68 countries worldwide for the treatment of patients with metastatic colorectal cancer (mCRC), specifically adult patients with mCRC who had previously been treated with, or were not candidates for, available therapies (including fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy, anti-VEGF agents, and anti-EGFR agents). In February 2019, Lonsurf received approval in the United States for a new indication: the treatment of adult patients with metastatic gastric cancer (mGC) or metastatic gastroesophageal junction adenocarcinoma (mGEJC).

Lonsurf was discovered and developed by Taiho Pharmaceutical. In June 2015, Servier and Taiho Pharmaceutical entered into an exclusive licensing agreement to jointly develop and commercialize Lonsurf in Europe, the United States, Canada, Mexico, and other countries outside Asia. (BioValleyBioon.com）

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