Open access Editorial Extension of the European Medicines Agency (EMA) approval of trifluridine/ tipiracil for gastric cancer Maria Alsina ‍ ‍ ,1,2 Elizabeth C Smyth3 To cite: Alsina M, Smyth EC. The European Medicines Agency’s (EMA) with antitumor activity based primarily via the Extension of the European Committee for Medicinal Products for Human trifluridine incorporation into replicating Medicines Agency (EMA) approval of trifluridine/tipiracil Use has recommended an extension to the DNA strands, resulting in the inhibition of for gastric cancer. ESMO Open indication of trifluridine/tipiracil. Previously, cell proliferation and tumour growth. Triflu- 2019;4:e000591. doi:10.1136/ trifluridine/tipiracil had been approved as ridine also inhibits thymidine synthetase (TS) esmoopen-2019-000591 a later line treatment in colorectal cancer which is necessary for DNA synthesis, but this (CRC). Now, a positive opinion for the use of is believed to play a minor role in its antitumor Received 9 September 2019 trifluridine/tipiracil as monotherapy for the effects. Tipiracil is an inhibitor of the TP, Revised 16 September 2019 treatment of adult patients with metastatic which inhibits trifluridine degradation and Accepted 18 September 2019 gastric cancer including adenocarcinoma of consequently increases its availability. Trifluri- the gastro-oesophageal junction, who have dine/tipiracil had been previously approved Published online 1 October 2019 been previously treated with at least two prior for patients with refractory CRC, based on systemic treatment regimens for advanced the results of the phase III RECOURSE trial,4 disease, has been given on 25 July 2019 with and had demonstrated preliminary efficacy in full EMA approval on 6 September 2019. Japanese patients with GC (EPOC1201 trial).5 Gastric and gastro-oesophageal junction Fluoropyrimidines (fluorouracil (5-FU), cancer (GC) represents a significant world- capecitabine and S-1, a prodrug of 5-FU) wide problem, being the sixth most common are the most extensively used chemothera- malignancy and the fifth most common peutic agents in gastrointestinal (GI) cancers. cause of cancer death.1 Due to its critical Indeed, they constitute the backbone of the location, patients with GC normally present combination therapies for these cancers, with symptoms which can impact on their being recommended for first-line and second- performance status. This fact, linked with the line treatment of metastatic CRC6 7 and first- inherent aggressiveness of this tumour, makes line metastatic GC, as well as perioperative GC as one of the most difficult neoplasias to and adjuvant therapy.2 The cytotoxic mech- manage. In the metastatic setting, first-line anism of action of the fluoropyrimidines is and second-line chemotherapy treatment primarily mediated via the inhibition of TS by improve survival and quality of life (QoL) one of its metabolites thereby impeding DNA © Author (s) (or their of patients with GC.2 Only two targeted synthesis. Antitumor activity is also achieved employer(s)) 2019. Re-use permitted under CC BY-NC. No agents have demonstrated its efficacy in through the misincorporation of 5-FU metab- commercial re-use. Published GC; trastuzumab in the first-line setting for olites into DNA and RNA. The primary by BMJ on behalf of the patients with human epidermal growth factor difference in the mechanism of action of European Society for Medical Oncology. receptor-2 (HER-2)-positive GC tumours, trifluridine compared with fluoropyrimidines 1 and ramucirumab in the second-line setting. enables trifluridine/tipiracil to overcome Medical Oncology, University Hospital Vall d'Hebron, The lack of an adequate biomarker selection, acquired resistance to these standard thera- Universitat Autònoma de together with the intrinsic heterogeneity of pies. Preclinical data demonstrating activity Barcelona, Barcelona, Spain GC, has challenged the development of many of trifluridine/tipiracil in 5-FU-resistant and 2 Medical Oncolgy, Vall d'Hebron other targeted agents that have been tested in other fluoropyrimidine-resistant cell lines Institute of Oncology, Barcelona, Spain phase III clinical trials.2 3 and in fluoropyrimidine-refractory patients 3 Medical Oncology, Cambridge Trifluridine/tipiracil is an orally active have been validated in clinical trials including University Hospitals NHS chemotherapy agent which comprises a nucle- in chemorefractory CRC where it is a stan- Foundation Trust, Cambridge, UK oside analogue consisting of a thymidine base dard of care.4 8 Correspondence to (trifluridine) and a thymidine phosphory- The approval for trifluridine/tipiracil in Dr Maria Alsina; lase (TP) inhibitor (tipiracil). Trifluridine/ GC is based on the results of the Trifluridine/ ​malsina@​vhio.​net tipiracil has a unique mechanism of action Tipiracil vs Placebo in Patients with Advanced Alsina M, Smyth EC. ESMO Open 2019;4:e000591. doi:10.1136/esmoopen-2019-000591 1 Open access Gastric Cancer Trial,8 a randomised phase III trial which compound into earlier lines of therapy will continue to randomised in a 2:1 ratio 507 patients with GC refractory improve survival for patients with GC. to at least two lines of chemotherapy to receive either best In conclusion, in a chemorefractory patient population supportive care (BSC) plus trifluridine/tipiracil (35 mg/ affected by GC, trifluridine/tipiracil has demonstrated to m2 twice daily on days 1–5 and days 8–12 every 28 days) offer a clinically meaningful and statistically significant or BSC plus placebo. Randomisation was stratified by improvement in the median OS with an increase of 2.1 region (Japan vs rest of the world), Eastern Cooperative months compared with placebo,8 with a good tolerability Oncology Group (ECOG) performance status (0 vs 1) and a trend towards patient QoL improvement. Thus, the and previous treatment with ramucirumab (yes vs no). benefit of trifluridine/tipiracil to overcome fluoropyrim- Both patients and investigators were masked to treatment idine resistance has been clearly established. Ongoing allocation, and the primary endpoint was the median research evaluating different combinations with triflu- overall survival (OS) in the intention-to-treat population. ridine/tipiracil will determine its potential role as the Median OS was 5.7 months in the trifluridine/tipiracil chemotherapeutic backbone for the continuum of care group and 3.6 months in the placebo group (HR 0.69, for GC in the future. 95% CI 0.56 to 0.85; p<0.001). The efficacy of trifluri- Funding The authors have not declared a specific grant for this research from any dine/tipiracil was maintained after adjusting for prog- funding agency in the public, commercial or not-for-profit sectors. nostic factors (ECOG performance status, age, number of Competing interests MA declares scientific consultancy and/or speaking previous chemotherapy regiments, number of metastatic honoraria from Amgen, BMS, Lilly, MSD, Roche and Servier. ECS declares honoraria sites and HER-2 status). Trifluridine/tipiracil offered a from Astellas, BMS, Celgene, Five Prime Therapeutics, Servier and Gritstone relatively low objective response rate (ORR), although Oncology. with a good disease control rate (DCR) (ORR and DCR Patient consent for publication Not required. of 4% and 44%, respectively, in patients receiving triflu- Provenance and peer review Not commissioned; externally peer reviewed. ridine/tipiracil, vs 2% and 14% in the placebo group). Open access This is an open access article distributed in accordance with the Although a higher number of adverse events (AE) were Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which observed in trifluridine/tipiracil-treated patients (grade permits others to distribute, remix, adapt, build upon this work non-commercially, ≥3 events in 80% of the patients in the trifluridine/ and license their derivative works on different terms, provided the original work is properly cited, any changes made are indicated, and the use is non-commercial. tipiracil group vs 58% in the placebo group), most of AEs See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. were mainly non-complicated haematological AEs. The tolerability of trifluridine/tipiracil is demonstrated by the ORCID iD Maria Alsina http://​orcid.​org/​0000-​0003-​4835-​7159 low rate of treatment discontinuation due to AEs (11% in the trifluridine/tipiracil group vs 13% in the placebo group). Notably, patient QoL remained stable for most functional and symptom scales in both arms, and a posi- References 1 Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: tive trend towards a lower risk of the QoL deterioration GLOBOCAN estimates of incidence and mortality worldwide for 36 was reported for the patients receiving trifluridine/ cancers in 185 countries. CA Cancer J Clin 2018;68): :394–424. 2 Smyth EC, Verheij M, Allum W, et al. Gastric cancer: ESMO clinical tipiracil.9 practice guidelines for diagnosis, treatment and follow-up†. Ann Use of combination regimens of fluoropyrimidines Oncol 2016;27(suppl_5):v38–49. 3 Alsina M, Miquel JM, Diez M, et al. How I treat gastric with other chemotherapeutic agents (ie, 5-FU, leucov- adenocarcinoma. ESMO Open 2019;4(Suppl 2):e000521. orin and oxaliplatin) and/or molecularly targeted 4 Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. 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