TAS-102 improved the overall survival of metastatic colorectal cancer (CRC) patients with a median progression-free survival (PFS) in the RECOURSE trial. Subsequently, the combination of TAS-102 and bevacizumab was shown to extend the median PFS (C-TASK FORCE study). However, the study included patients who received second- and third-line treatment. Our study exclusively examined patients receiving this combination as a third-line treatment to investigate the clinical impact beyond cytotoxic doublets.
This investigator-initiated, open-label, single-arm, multi-centered phase II study was conducted in Japan. Eligible CRC patients were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin in first- and second-line therapy. TAS-102 (35 mg/m2) was given orally twice daily on days 1–5 and 8–12 in a 4-week cycle, and bevacizumab (5 mg/kg) was administered by intravenous infusion every 2 weeks. The primary endpoint was PFS and the secondary endpoints were time-to-treatment failure, response rate, overall survival (OS), and safety.
Between June 2016 and August 2017, 32 patients were enrolled. All patients previously received bevacizumab. The median PFS was 4.5 months; the median overall survival was 9.3 months. Partial response was observed in two patients. The most common adverse events above grade 3 were neutropenia followed by thrombocytopenia. There were no non-hematological adverse events above grade 3 and no treatment-related deaths occurred.
This study met its primary endpoint of PFS, which is comparable to the results of the C-TASK FORCE study. The TAS-102 and bevacizumab combination has the potential to be a therapeutic option for third-line treatment of metastatic CRC.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Bray F et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424
Nielsen DL et al (2014) A systematic review of salvage therapy to patients with metastatic colorectal cancer previously treated with fluorouracil, oxaliplatin and irinotecan+/− targeted therapy. Cancer Treat Rev 40(6):701–715
Emura T et al (2004) A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells. Int J Mol Med 13(4):545–549
Chen J, Han M, Saif MW (2016) TAS-102 an emerging oral fluoropyrimidine. Anticancer Res 36(1):21–26
Kuboki Y et al (2017) 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 18(9):1172–1181
Pfeiffer P et al (2020) TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol S1470–2045(19):30827–30837
Kotani D et al (2019) Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer. BMC cancer 19(1):1253–1253
Fujii H et al (2020) Bevacizumab in combination with TAS-102 improves clinical outcomes in patients with refractory metastatic colorectal cancer: a retrospective study. Oncologist 25(3):e469–e476. https://doi.org/10.1634/theoncologist.2019-0541
Matsuhashi N et al (2019) Combination chemotherapy with TAS-102 plus bevacizumab in salvage-line treatment of metastatic colorectal cancer: a single-center, retrospective study examining the prognostic value of the modified Glasgow prognostic score in salvage-line therapy of metastatic colorectal cancer. Mol Clin Oncol 11(4):390–396
Yoshida Y et al (2018) Biweekly administration of TAS-102 for neutropenia prevention in patients with colorectal cancer. Anticancer Res 38(7):4367–4373
Van Cutsem E et al (2016) ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol Off J Eur Soc Med Oncol 27(8):1386–1422
Mayer RJ et al (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372(20):1909–1919
Xu J et al (2018) Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study. J Clin Oncol 36(4):350–358. https://doi.org/10.1200/JCO.2017.74.3245
Grothey A et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312
Loree JM, Kopetz S (2017) Recent developments in the treatment of metastatic colorectal cancer. Therap Adv Med Oncol 9(8):551–564
Takeda M et al (2016) Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (West Japan oncology group 5910L): an open-label, randomized, phase 2 trial. Cancer 122(7):1050–1059
Shoji T et al (2019) A New therapeutic strategy for recurrent ovarian cancer-bevacizumab beyond progressive disease. Healthcare (Basel) 7:3
Overman MJ et al (2018) The addition of bevacizumab to oxaliplatin-based chemotherapy: impact upon hepatic sinusoidal injury and thrombocytopenia. J Natl Cancer Inst 110(8):888–894
Grothey A et al (2008) Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol 26(33):5326–5334
Bennouna J et al (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 14(1):29–37
Grothey A et al (2014) Bevacizumab exposure beyond first disease progression in patients with metastatic colorectal cancer: analyses of the ARIES observational cohort study. Pharmacoepidemiol Drug Saf 23(7):726–734
Becherirat S et al (2018) Discontinuous schedule of bevacizumab in colorectal cancer induces accelerated tumor growth and phenotypic changes. Trans Oncol 11(2):406–415
Yoshida Y et al (2019) 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 Rect Colon 3(3):136–141
We thank all patients and co-workers for their participation and cooperation in the TAS-CC3 study. We also thank H. Nikki March, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of interest
Keiichiro Ishibashi has received research funding from Taiho and Chugai. Hideyuki Ishida has received research funding from Taiho and Chugai. Suguru Hasegawa has received research funding from Taiho and Takeda. The other authors declare that they have no competing interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Yoshida, Y., Yamada, T., Kamiyama, H. et al. Combination of TAS-102 and bevacizumab as third-line treatment for metastatic colorectal cancer: TAS-CC3 study. Int J Clin Oncol 26, 111–117 (2021). https://doi.org/10.1007/s10147-020-01794-8