News Releases

Taiho Pharmaceutical Co., Ltd. of Tokyo announced on April 28 that the European Commission (EC) has granted marketing authorization for LONSURF^® (trifluridine/tipiracil), formerly known as TAS-102, in the European Union (EU) for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents. LONSURF was originally developed by Taiho Pharmaceutical, and Servier will co-develop and commercialize LONSURF in EU countries under a license agreement with Taiho Pharmaceutical.
“Data from the pivotal RECOURSE study provides evidence that LONSURF may offer patients with refractory metastatic colorectal cancer extended survival as well as a reduction in risk of death compared to placebo,” said Professor Eric Van Cutsem, MD, PhD, Digestive Oncology, University Hospitals Leuven in Belgium. “The combination of trifluridine and tipiracil in LONSURF works by directly attacking the DNA of the tumor cells which reduces the growth of cancer cells. This approach fights the cancer differently to other previously given treatments, allowing us to delay cancer progression rather than cycling back through therapies that have already been used.”
The decision from the EC follows the positive opinion issued by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommending the approval of LONSURF in February 2016.¹ Both the CHMP opinion and the EC decision were based on data from the international, double-blind, placebo-controlled Phase III RECOURSE study, which investigated the efficacy and safety of LONSURF with best supportive care (BSC) compared to placebo with BSC in 800 patients with previously treated mCRC. The study met the primary endpoint of statistically significant improvement in overall survival (OS).^2,3,4

RECOURSE is an international, double-blind, placebo-controlled Phase III study, which investigated the efficacy and safety of LONSURF with BSC compared to placebo with BSC in 800 patients with previously treated mCRC, among which 403 were treated in Europe.⁵ The study met the primary endpoint of statistically significant improvement in OS. Results demonstrated a 32% reduction in the risk of death compared to BSC (HR=0.68; 95% CI: 0.58 to 0.81 p<0.001). An updated OS analysis in 89% of events, presented at ASCO GI 2016, confirmed the clinically meaningful and statistically significant survival benefit of LONSURF with BSC compared to placebo with BSC. This translates into a 31% relative reduction in the risk of death (HR=0.69; 95% CI: 0.59 to 0.81; p<0.0001) and an improvement of 2 months in the median OS. The median OS was 7.2 months for LONSURF with BSC vs 5.2 months for placebo with BSC, and this translated into 1-year survival rates of 27.1% and 16.6%, respectively.^2,3,4
The most frequently observed side effects (≥ 30%) in patients receiving LONSURF were neutropenia, nausea, decreased appetite, diarrhea, fatigue, anemia, thrombocytopenia, increase in total bilirubin, alkaline phosphatase and ASAT levels, and leucopenia.^2,4

There remains a high unmet need in the treatment of colorectal cancer (CRC), which was the second leading cause of cancer-related deaths in Europe in 2012, responsible for 215,000 deaths.⁶ Approximately 25% of patients with CRC present with metastases at initial diagnosis and almost 50% of patients with CRC will develop metastases.⁷ This contributes to the high mortality rates reported for CRC; the 5-year survival rate of patients diagnosed with stage IV mCRC is about 11%.⁸

LONSURF is currently available in Japan for the treatment of unresectable advanced or recurrent CRC and in the United States for the treatment of patients with mCRC 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.^9,10,11 LONSURF is marketed by Taiho Pharmaceutical in Japan and by Taiho Oncology, Inc. a subsidiary of Taiho Pharmaceutical, in the U.S. LONSURF is an oral anticancer drug, comprising the combination of trifluridine (FTD) and tipiracil (TPI), whose dual mechanism of action is designed to maintain clinical activity and differs from fluoropyrimidines. FTD is an antineoplastic nucleoside analog, which is incorporated directly into DNA, thereby interfering with the function of DNA. The blood concentration of FTD is maintained via TPI, which is an inhibitor of the FTD-degrading enzyme, thymidine phosphorylase.^2,4,12
In June 2015, Taiho Pharmaceutican and Servier entered into an exclusive license agreement for the co-development and commercialization of LONSURF. Under the terms of the agreement, Servier has the right to co-develop and commercialize LONSURF in Europe and other countries outside of the United States, Canada, Mexico and Asia. Taiho Pharmaceutical retains the right to develop and commercialize LONSURF in the United States, Canada, Mexico, and Japan/Asia and to manufacture and supply the product.

Servier is an independent research-based pharmaceutical company headquartered in France. With a strong international presence in 148 countries and 92% of its medicines being prescribed outside of France, Servier employs more than 21,200 people worldwide. In 2015, the company recorded a turnover of 3.9 billion euros of which 24% was reinvested in research and development. Currently, there are nine new molecular entities in clinical development for oncology respectively in breast, lung and other solids tumors as well as various leukemias and lymphomas.
This portfolio of innovative cancer treatments is being developed with various partners worldwide, and covers different hallmarks of cancer including cytotoxics, proapoptotic, targeted, immune and cellular therapies.

1 Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 22-25 February 2016. Available at:http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/02/news_detail_002474.jsp&mid=WC0b01ac058004d5c1 Accessed April 2016

2 LONSURF Summary of Product Characteristics

3 TAS-102 versus placebo plus best supportive care in patients with metastatic colorectal cancer refractory to standard therapies: Final survival results of the phase III RECOURSE trial. J Clin Oncol 34, 2016 (suppl 4S; abstr 634) Available at: http://meetinglibrary.asco.org/content/159397-173 Accessed April 2016

4 Mayer R, Van Cutsem E, et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. N Engl J Med 2015; 372:1909-19.
5 Ohtsu A, Yoshino T, Wabha M, et al. Phase 3 RECOURSE Trial of TAS-102 Versus Placebo With Best Supportive Care in Patients With Metastatic Colorectal Cancer: Geographic Subgroups. J Clin Oncol 33, 2015 (suppl; abstr 3564).

6 Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49: 1374–1403.

7 Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol (2014) 25 (suppl 3): iii1-iii9.

8 American Cancer Society. Colorectal Cancer. Available at: http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-survival-rates Accessed April 2016

9 FDA News Release. FDA approves new oral medication to treat patients with advanced colorectal cancer. 22 September 2015. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm463650.htm Accessed April 2016

10 Taiho Pharma. Taiho's Lonsurf® (trifluridine and tipiracil hydrochloride) Tablets Approved in Japan for Treatment in Advanced Metastatic Colorectal Cancer. Available at: http://www.taiho.co.jp/english/news/20140324.html Accessed April 2016

11 Taiho Pharma. Lonsurf® Combination Tablet for the Treatment of Unresectable Advanced or Recurrent Colorectal Cancer Receives Approval in Japan for Partial Change in Indications. Available at: http://www.taiho.co.jp/english/news/20150320.html Accessed April 2016

12 Emura T et al. A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells Int J Mol Med 2004;13:545-49.