LONSURF demonstrated 2-month improvement in median overall survival (OS) compared to placebo in patients with advanced metastatic colorectal cancer (mCRC) (*1, *2), an important benefit in a disease with a 5-year survival rate of only 11% at diagnosis (*3).

Taiho Pharmaceutical Co., Ltd. of Tokyo announced on April 28, 2016, that the European Commission (EC) has granted marketing authorization for LONSURF (R) (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 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. 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.

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 (*4). 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) (*1, *2, *5).

About RECOURSE

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 (*6). 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 less than 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 less than 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 (*1, *2, *5).

The most frequently observed side effects (greater than or equal to 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.(*1, *5)

About Metastatic Colorectal Cancer

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 (*7). Approximately 25% of patients with CRC present with metastases at initial diagnosis and almost 50% of patients with CRC will develop metastases (*8). 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% (*3).

About LONSURF

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. FTD is an antineoplastic nucleoside analog, which is incorporated directly into DNA, thereby interfering with DNA synthesis and inhibits cell proliferation. The blood concentration of FTD is maintained via TPI, which is an inhibitor of the FTD-degrading enzyme, thymidine phosphorylase (*1, *5, *12).  

In June 2015, Taiho Pharmaceutical 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 LONSURF globally and commercialize LONSURF in Europe and other countries excluding the United States, Canada, Mexico, Japan and Asia, where Taiho Pharmaceutical retains the right to develop and commercialize LONSURF. Taiho Pharmaceutical also manufactures and supplies the product globally.  

Important Safety Information (U.S.) (*1)

WARNINGS AND PRECAUTIONS

Severe Myelosuppression: In Study 1, LONSURF caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%), and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF-treated patients received granulocyte-colony stimulating factors.

Obtain complete blood counts prior to and on Day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/mm3. Upon recovery, resume LONSURF at a reduced dose.

Embryo-Fetal Toxicity: LONSURF can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF.  

USE IN SPECIFIC POPULATIONS

Lactation: It is not known whether LONSURF or its metabolites are present in human milk. There are no data to assess the effects of LONSURF or its metabolites on the breastfed infant or the effects on milk production. Because of the potential for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with LONSURF and for one day following the final dose.

Male Contraception: Advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose.

Geriatric Use: Grade 3 or 4 neutropenia and thrombocytopenia and Grade 3 anemia occurred more commonly in patients 65 years old or older who received LONSURF.  

Renal Impairment: Patients with moderate renal impairment may require dose modifications for increased toxicity. No patients with severe renal impairment were enrolled in Study 1.

Hepatic Impairment: Patients with moderate or severe hepatic impairment were not enrolled in Study 1.

ADVERSE REACTIONS

Most Common Adverse Drug Reactions in Patients Treated with LONSURF (Greater than or equal to 5%): The most common adverse drug reactions in LONSURF-treated patients vs placebo-treated patients with refractory mCRC, respectively, were: asthenia/fatigue (52% vs 35%), nausea (48% vs 24%), decreased appetite (39% vs 29%), diarrhea (32% vs 12%), vomiting (28% vs 14%), abdominal pain (21% vs 18%), pyrexia (19% vs 14%), stomatitis (8% vs 6%), dysgeusia (7% vs 2%), and alopecia (7% vs 1%).

Additional Important Adverse Drug Reactions: The following occurred more frequently in LONSURF-treated patients compared to placebo: infections (27% vs 15%), and pulmonary emboli (2% vs 0%).

Interstitial lung disease (0.2%), including fatalities, has been reported in clinical studies and clinical practice settings in Asia.

Laboratory Test Abnormalities in Patients Treated with LONSURF: Laboratory test abnormalities in LONSURF-treated patients vs placebo-treated patients with refractory mCRC, respectively, were: anemia (77% vs 33%), neutropenia (67% vs 1%), and thrombocytopenia (42% vs 8%).

Please see Full U.S. Prescribing Information.

https://www.taihooncology.com/us/prescribing-information.pdf

About Taiho Pharmaceutical Co., Ltd. (Japan)

Taiho Pharmaceutical, a subsidiary of Otsuka Holdings Co., Ltd., is an R&D-driven specialty pharma focusing on the three fields of oncology, allergies and immunology, and urology. Its corporate philosophy takes the form of a pledge: "We strive to improve human health and contribute to a society enriched by smiles." In the field of oncology in particular, Taiho Pharmaceutical is known as a leading company in Japan for developing innovative medicines for the treatment of cancer. In areas other than oncology, as well, the company creates quality products that effectively treat medical conditions. Always putting customers first, Taiho Pharmaceutical also aims to offer over-the-counter medicinal products that support people's efforts to lead fulfilling and rewarding lives.

For more information about Taiho Pharmaceutical, please visit: http://www.taiho.co.jp/english/.

For more information about Taiho Oncology, please visit: https://www.taihooncology.com

About Servier

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)  LONSURF Summary of Product Characteristics

(*2)  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

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

(*4) 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

(*5)  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.

(*6) 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).

(*7)  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.

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

(*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 (R) (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 (R) 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.