Trifluridine/tipiracil Significantly Improved Overall Survival versus Placebo in Gastric Cancer

The safety and efficacy of trifluridine/tipiracil (Lonsurf?; Taiho Oncology/Taiho Pharmaceutical and Servier) in patients who had undergone gastrectomy, the surgical removal of a part or the whole of the stomach, as part of their treatment for metastatic gastric cancer (mGC), are consistent with the overall study results published in The Lancet Oncology.[1]

Lonsurf? consists of a thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil, at a molar ratio 1:0.5 (weight ratio, 1:0.471). Inclusion of tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase. Following uptake into cancer cells, trifluridine is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation. Trifluridine/tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice.

Colorectal cancer
Colorectal cancer is the fourth most commonly diagnosed cancer in the United States (U.S.).[2] In 2018, there were an estimated 140,250 new cases and 50,630 deaths in the U.S.[2][3] Approximately 21% of U.S. patients with colorectal cancer are diagnosed at the distant or metastasized stage, and between 50% and 60% of patients develop metastases.[2] Metastatic colorectal cancer (mCRC) is associated with poor prognosis with a five-year survival rate of approximately 14%.[2]

Over the last decade, clinical outcomes for patients with mCRC have improved considerably due to the advent of novel treatment agents, predictive biomarkers, and a more strategic approach to the delivery of systemic therapies. Currently, the median overall survival for patients with mCRC being treated both in phase III trials and in large observational series or registries is 30 months ? more than double that of 20 years ago.[4][5][6]

Trial results
The results show that trifluridine/tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer, a disease which represent a high unmet medical need.

Now updated result from the global Phase III TAGS trial, presented during the ASCO 2019 Gastrointestinal Cancers Symposium (ASCO GI), being held in San Francisco, CA, January 17 – 19, 2019, being highlighted on Thursday, January 17 during an oral and poster presentation, show similar results.

Additional data with trifluridine/tipiracil in metastatic colorectal cancer (mCRC) patients will be presented during a poster session on Saturday, January 19.

Trifluridine/tipiracil is indicated in the United States for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy and, if RAS wild-type, an anti-EGFR therapy

TAGS trial
TAGS (TAS-102 Gastric Study) is a Taiho-sponsored pivotal Phase III, multinational, randomized, double-blind study evaluating trifluridine/tipiracil, also known as TAS-102, plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic gastric cancer, including gastroesophageal junction cancer, refractory to standard treatments. The primary endpoint in the TAGS trial is overall survival (OS), and the main secondary endpoint measures include progression-free survival (PFS), and safety and tolerability, as well as quality of life.

In the TAGS trial, 221 (44%) of the 507 randomized mGC patients had undergone prior gastrectomy (147 trifluridine/tipiracil, 74 placebo), which is reflective of the real-world patient population diagnosed with mGC. The results confirmed that LONSURF prolonged survival versus placebo regardless of prior gastrectomy.

“We are pleased to present this subgroup analysis from TAGS in patients with metastatic gastric cancer who had undergone gastrectomy, which further support LONSURF as safe and effective for patients with this life-threatening condition for which treatment options are limited,” noted Martin J. Birkhofer, MD, senior vice president and Chief Medical Officer, Taiho Oncology.

“These data further add to the existing body of evidence that already support the benefit of Lonsurf for people living with metastatic colorectal cancer.”

During the 2019 ASCO GI meeting, additional posters will be presented on Saturday, January 19, 2019.? These posters will present results from exploratory analysis of the effect of trifluridine/tipiracil and regorafenib in patients with metastatic colorectal cancer (mCRC):

Presentations at ASCO GI will also include data about the health-related Quality of Life (hrQoL) in the early-access phase IIIb study of trifluridine/tipiracil in pretreated metastatic colorectal cancer (mCRC), a validation of cost-effectiveness of trifluridine/tipiracil versus best supportive care and regorafenib for previously treated metastatic colorectal cancer, and hrQoL of trifluridine/tipiracil-bevacizumab and capecitabine-bevacizumab as first-line treatments in metastatic colorectal cancer patients not eligible for intensive chemotherapy

References
[1] Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini 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. 2018 Nov;19(11):1437-1448. doi: 10.1016/S1470-2045(18)30739-3.
[2] National Cancer Institute Surveillance Epidemiology and End Results Program. Cancer Stat Facts: Colon and Rectum Cancer. https://seer.cancer.gov/statfacts/html/colorect.html. Accessed May 17, 2018.
[3] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians. 2018;68(1):7-30. https://onlinelibrary.wiley.com/doi/full/10.3322/caac.21442. Accessed December 2018.
[4] Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383(9927):1490-1502.
[5] Price TJ, Segelov E, Burge M, et al. Current opinion on optimal systemic treatment for metastatic colorectal cancer: outcome of the ACTG/AGITG expert meeting ECCO 2013. Expert review of anticancer therapy. 2014;14(12):1477-1493.
[6] Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386-1422.

Last Editorial Review: January 17, 2019

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