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Published online: 2024-02-05

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Trifluridine/tipiracil (FTD/TPI) in metastatic colorectal cancer treatment

Patryk S. Michel1, Marek Jankowski1, Dawid Sigorski2, Tomasz Kubiatowski3

Abstract

Metastatic colorectal cancer (mCRC) remains a formidable health challenge that needs novel therapeutic approaches. Trifluridine/tipiracil (FTD/TPI), an oral cytostatic antimetabolite drug, has emerged as a promising option in mCRC management. Trifluridine/tipiracil’s mechanism involves incorporating trifluridine into DNA, impeding cell proliferation, and inhibiting thymidine synthase. Clinical investigations underscore its efficacy as both monotherapy and polytherapy. Phase II trials in Japan and a significant multicenter phase III trial (RECOURSE) globally established FTD/TPI’s superiority in terms of overall survival (OS) and progression-free survival (PFS) compared to placebo in heavily pretreated mCRC patients. White blood cells, platelet count, lactate dehydrogenase, alkaline phosphatase, carcinoembryonic antigen, chemotherapy-induced neutropenia, and multiple metastatic sites were determined as potential prognostic factors in FTD/TPI treatment. Intriguingly, recent studies demonstrated that specific KRAS mutations (G12 vs. G13) may potentially guide personalized treatment strategies for achieving better therapeutic outcomes and decreasing drug toxicity. Thanks to clinical trials and real-world studies, the role of FTD/TPI in personalized treatment approaches continues to evolve, with ongoing research poised to unlock further its therapeutic potential.

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References

  1. Didkowska J, Wojciechowska U, Olasek P, et al. CANCER IN POLAND IN 2019. http://onkologia.zalecenia.med.pl/pdf/zalecenia_PTOK_tom1_04_1_Wytyczne_postepowania_diagnostyczno-terapeutycznego_u_chorych_na_raka_okreznicy_i_zagiecia_esiczo-odbytniczego_20200716.pdf.
  2. Cervantes A, Adam R, Roselló S, et al. ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023; 34(1): 10–32.
  3. 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.
  4. Temmink OH, Emura T, de Bruin M, et al. Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies. Cancer Sci. 2007; 98(6): 779–789.
  5. Uboha N, Hochster HS. TAS-102: a novel antimetabolite for the 21st century. Future Oncol. 2016; 12(2): 153–163.
  6. Bendell JC, Rosen LS, Mayer RJ, et al. Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer. Cancer Chemother Pharmacol. 2015; 76(5): 925–932.
  7. Yoshino T, Mizunuma N, Yamazaki K, et al. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012; 13(10): 993–1001.
  8. Van Cutsem E, Mayer RJ, Laurent S, et al. RECOURSE Study Group. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018; 90: 63–72.
  9. Mayer RJ, Van Cutsem E, Falcone A, et al. RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015; 372(20): 1909–1919.
  10. van de Haar J, Ma X, Ooft SN, et al. Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer. Nat Med. 2023; 29(3): 605–614.
  11. Kasi PM, Grothey A. Should we optimize cytotoxic therapy by dosing to neutropenia? Lessons from TAS-102. Ann Oncol. 2020; 31(1): 15–16.
  12. Kasi PM, Kotani D, Cecchini M, et al. Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study. BMC Cancer. 2016; 16: 467.
  13. Hamauchi S, Yamazaki K, Masuishi T, et al. Neutropenia as a Predictive Factor in Metastatic Colorectal Cancer Treated With TAS-102. Clin Colorectal Cancer. 2017; 16(1): 51–57.
  14. Giuliani J, Bonetti A. The Onset of Grade ≥3 Neutropenia Is Associated With Longer Overall Survival in Metastatic Colorectal Cancer Patients Treated With Trifluridine/Tipiracil. Anticancer Res. 2019; 39(7): 3967–3969.
  15. Takahashi M, Sakamoto Y, Ohori H, et al. Phase II study of trifluridine/tipiracil (TAS-102) therapy in elderly patients with colorectal cancer (T-CORE1401): geriatric assessment tools and plasma drug concentrations as possible predictive biomarkers. Cancer Chemother Pharmacol. 2021; 88(3): 393–402.
  16. Fernandez Montes A, Vazquez Rivera F, Martinez Lago N, et al. Efficacy and safety of trifluridine/tipiracil in third-line and beyond for the treatment of patients with metastatic colorectal cancer in routine clinical practice: patterns of use and prognostic nomogram. Clin Transl Oncol. 2020; 22(3): 351–359.
  17. Fernández Montes A, Carmona-Bayonas A, Jimenez-Fonseca P, et al. Prediction of survival in patients with advanced, refractory colorectal cancer in treatment with trifluridine/tipiracil: real-world vs clinical trial data. Sci Rep. 2021; 11(1): 14321.
  18. Nakajima H, Fukuoka S, Masuishi T, et al. Clinical Impact of Primary Tumor Location in Metastatic Colorectal Cancer Patients Under Later-Line Regorafenib or Trifluridine/Tipiracil Treatment. Front Oncol. 2021; 11: 688709.
  19. Kuboki Y, Nishina T, Shinozaki E, et al. TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study. Lancet Oncol. 2017; 18(9): 1172–1181.
  20. Pfeiffer P, Yilmaz M, Möller S, et al. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020; 21(3): 412–420.
  21. Yoshida Y, Yamada T, Kamiyama H, et al. TAS CC3 Study Group.. Combination of TAS-102 and bevacizumab as third-line treatment for metastatic colorectal cancer: TAS-CC3 study. Int J Clin Oncol. 2021; 26(1): 111–117.
  22. Yoshida Y, Yamada T, Matsuoka H, et al. A Trial Protocol of Biweekly TAS-102 and Bevacizumab as Third-Line Chemotherapy for Advanced/Recurrent Colorectal Cancer: A Phase II Multicenter Clinical Trial (The TAS-CC4 Study). J Anus Rectum Colon. 2019; 3(3): 136–141.
  23. Van Cutsem E, Danielewicz I, Saunders MP, et al. Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study. Ann Oncol. 2020; 31(9): 1160–1168.
  24. André T, Falcone A, Shparyk Y, et al. VP11-2021: Trifluridine/tipiracil plus bevacizumab vs capecitabine plus bevacizumab as first line treatment for patients with metastatic colorectal cancer (mCRC) ineligible for intensive therapy: The phase III randomized SOLSTICE study. Ann Oncol. 2022; 33(2): 229–230.
  25. Tabernero J, Prager G, Fakih M, et al. Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study. J Clin Oncol. 2023; 41(4_suppl): 4–4.
  26. Patel MR, Falchook GS, Hamada K, et al. A phase 2 trial of trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite-stable metastatic colorectal cancer. Cancer Med. 2021; 10(4): 1183–1190.
  27. Chuang J, Gong J, Li SM, et al. A Phase I Clinical Trial of Trametinib in Combination with TAS-102 in Patients with Chemotherapy-Resistant RAS-Mutated (PIK3CA/PTEN-Wild Type) Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2022; 21(3): 252–258.
  28. Moehler M, Michel M, Stein A, et al. A Phase I dose-escalation study of third-line regorafenib with trifluridine/tipiracil in metastatic colorectal cancer. Future Oncol. 2021; 17(25): 3309–3319.
  29. Li Q, Zhang X, Fan B, et al. Anlotinib combined with TAS-102 as the third-line treatment for a patient with metastatic colon cancer: A case report. Front Oncol. 2022; 12: 978005.
  30. Sommerhäuser G, Kurreck A, Stintzing S, et al. Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer. BMC Cancer. 2022; 22(1): 820.
  31. Samawi HH, Brezden-Masley C, Afzal AR, et al. Real-world use of trifluridine/tipiracil for patients with metastatic colorectal cancer in Canada. Curr Oncol. 2019; 26(5): 319–329.
  32. Kwakman JJM, Vink G, Vestjens JH, et al. Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands. Int J Clin Oncol. 2018; 23(3): 482–489.
  33. Jalali A, Gard G, Banks S, et al. Initial experience of TAS-102 chemotherapy in Australian patients with Chemo-refractory metastatic colorectal cancer. Curr Probl Cancer. 2022; 46(2): 100793.
  34. Fernandez Montes A, Vazquez Rivera F, Martinez Lago N, et al. Efficacy and safety of trifluridine/tipiracil in third-line and beyond for the treatment of patients with metastatic colorectal cancer in routine clinical practice: patterns of use and prognostic nomogram. Clin Transl Oncol. 2020; 22(3): 351–359.
  35. Weiss L, Karthaus M, Riera-Knorrenschild J, et al. TALLISUR study group. Efficacy, safety and quality-of-life data from patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: results of the TALLISUR trial. ESMO Open. 2022; 7(1): 100391.
  36. Vitale P, Zanaletti N, Famiglietti V, et al. Retrospective Study of Regorafenib Versus TAS-102 Efficacy and Safety in Chemorefractory Metastatic Colorectal Cancer (mCRC) Patients: A Multi-institution Real Life Clinical Data. Clin Colorectal Cancer. 2021; 20(3): 227–235.
  37. Signorelli C, Gemma D, Grande R, et al. Regorafenib-to-trifluridine/tipiracil Versus the Reverse Sequence for Refractory Metastatic Colorectal Cancer Patients: A Multicenter Retrospective Real-life Experience. Anticancer Res. 2021; 41(5): 2553–2561.
  38. Malik M, Michalak M, Radecka B, et al. Prognostic Value of Sarcopenia in Metastatic Colorectal Cancer Patients Treated with Trifluridine/Tipiracil. J Clin Med. 2021; 10(21).
  39. Cicero G, Addeo R, De Luca R, et al. TAS-102 in metastatic colorectal cancer (mCRC): efficacy, tolerability, and quality of life in heavily pretreated elderly patients: a real-life study. Drugs Context. 2020; 9.
  40. Nukatsuka M, Fujioka A, Nagase H, et al. Evaluation of a Novel Combination Therapy, Based on Trifluridine/Tipiracil and Fruquintinib, against Colorectal Cancer. Chemotherapy. 2023; 68(2): 102–110.
  41. Fidelman N, Atreya CE, Griffith M, et al. Phase I prospective trial of TAS-102 (trifluridine and tipiracil) and radioembolization with Y resin microspheres for chemo-refractory colorectal liver metastases. BMC Cancer. 2022; 22(1): 1307.