First phase II/III trial to verify the efficacy and safety of trifluridine/tipiracil plus bevacizumab as second-line treatment for patients with metastatic colorectal cancer

Contributors: Yasutoshi Kuboki and Takayuki Yoshino; Department of Experimental Therapeutics and Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
Published in Cancer
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Background

The combination of fluoropyrimidines (e.g. 5-fluorouracil, S-1), l-leucovorin and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) or both (FOLFOXIRI), along with targeted biological agents such as bevacizumab (an anti-angiogenic agent), are recommended as first- or second-line treatment options for unresectable advanced or metastatic colorectal cancer (mCRC) [1]. Irinotecan-based regimens, commonly used as second-line treatment for mCRC, can cause toxicities such as diarrhoea and alopecia in some patients [1, 2], which may affect treatment compliance.

 Trifluridine/tipiracil (FTD/TPI) is an orally administered anti-metabolite comprising trifluridine (a thymidine-based nucleoside analogue) and tipiracil (a potent thymidine phosphorylase inhibitor) [3]. Several studies showed clinically relevant improvements in progression-free survival (PFS) in patients with mCRC treated with FTD/TPI plus bevacizumab, and evidence for the use of FTD/TPI plus bevacizumab as third- or later-line treatment for mCRC is accumulating [4-8]. FTD/TPI plus bevacizumab also showed satisfactory PFS in patients ineligible for intensive therapy and in elderly patients when used as first-line treatment [9, 10]. According to the 2023 National Comprehensive Cancer Network clinical practice guidelines for colorectal cancer, FTD/TPI with or without bevacizumab can be considered a treatment option for patients with mCRC who have progressed through standard therapies [1].

The treatment goals for second-line systemic treatment in mCRC are durable disease control, tumour response if needed, prolonging survival and/or maintaining quality of life (QoL) [11].

Compared with irinotecan-based regimens, FTD/TPI plus bevacizumab is expected to reduce the incidence of adverse events (AEs) with subjective symptoms and maintain QoL. Therefore, the phase II/III TRiflUridine/tipiracil in Second-line sTudY (TRUSTY) aimed to demonstrate the non-inferiority (in terms of overall survival [OS]) of FTD/TPI plus bevacizumab vs. FOLFIRI plus bevacizumab or S-1 and irinotecan plus bevacizumab as second-line treatment in Japanese patients with mCRC.

Methods

Patients with histologically confirmed mCRC who failed first-line chemotherapy, including fluoropyrimidine plus oxaliplatin with either bevacizumab or an anti-epidermal growth factor receptor (EGFR) antibody, were eligible. Patients were randomised to receive either FTD/TPI plus bevacizumab or either FOLFIRI or S-1 and irinotecan plus bevacizumab (control). The primary endpoint was OS. The non-inferiority margin of the hazard ratio (HR) was set to 1.33.

Results and Discussion

Based on the results of the interim analysis for futility, the study was terminated in July 2020, and 397 patients were enrolled at 65 institutions. The baseline characteristics of the patients were similar between the two groups. Median follow-up duration was 13.2 months. Median OS was 14.8 months in the FTD/TPI plus bevacizumab group and 18.1 months in the control group (HR 1.38; 95% confidence interval [CI] 0.99–1.93; upper limit of the HR above the non-inferiority margin of 1.33, P=0.592 for non-inferiority); the non-inferiority of FTD/TPI plus bevacizumab was not demonstrated. Median PFS was 4.5 months in the FTD/TPI plus bevacizumab group and 6.0 months in the control group. We assumed that irinotecan would be used as third-line treatment in the FTD/TPI plus bevacizumab group and that the use of irinotecan as second- or third-line treatment would result in equivalent OS in both arms; however, this was not true. Differences in PFS could not be recovered by the post-study treatment period. Thus, the importance of the efficacy of second-line treatment for mCRC was reaffirmed.

However, the FTD/TPI plus bevacizumab regimen remains a promising treatment option because the findings suggest its use as third- or later-line treatment. In the confirmatory phase III, SUNLIGHT study, the FTD/TPI plus bevacizumab regimen as third‑line treatment for patients with mCRC resulted in significantly longer OS and PFS vs. FTD/TPI monotherapy (median OS: 10.8 months vs. 7.5 months; HR 0.61, median PFS: 5.6 months vs. 2.4 months; HR 0.44) [12]. Based on the results of the SUNLIGHT study, we hope that FTD/TPI plus bevacizumab will be recommended as the standard third- or later-line treatment for refractory mCRC in the clinical practice guidelines.

In a post hoc analysis based on the baseline sum of the diameter of target lesions (STL), adjusted median OS in patients with an STL of ≥60 mm was 10.9 months in the FTD/TPI plus bevacizumab group and 16.2 months in the control group (HR 2.32; 95% CI 1.42–3.79). Conversely, the adjusted median OS in patients with an STL of <60 mm was 21.4 months in the FTD/TPI plus bevacizumab group and 20.7 months in the control group (HR 0.92; 95% CI 0.55–1.55). In the SOLSTICE and TASCO1 studies, approximately 10%–20% of patients with mCRC were ineligible to receive standard intensive treatment (e.g. full-dose doublet regimens with oxaliplatin or irinotecan) because of their low tumour burden [9, 13]. In the SOLSTICE study, FTD/TPI plus bevacizumab did not show significant superiority in terms of PFS when compared with capecitabine plus bevacizumab; the median PFS was 9.4 months vs. 9.3 months (HR 0.87) [13]. However, FTD/TPI plus bevacizumab was clinically satisfactory in patients with mCRC who had a low tumour burden in terms of PFS (HR 0.68) [13]. Thus, patients with a low tumour burden may benefit from treatment with FTD/TPI plus bevacizumab; however, as there is no consensus on the definition of a low tumour burden, it is important to consider tumour size, number of metastatic lesions, and metastasis site when administering treatment.

The most common grade ≥3 AEs in the FTD/TPI plus bevacizumab and control groups were neutropenia, leukopenia and anaemia. The safety profile of FTD/TPI plus bevacizumab in this study was consistent with those reported in other studies [6, 7, 9]. Haematological toxicities occurred more frequently in the FTD/TPI plus bevacizumab group than in the control group, whereas some nonhematological toxicities (e.g. stomatitis, diarrhoea, and alopecia) occurred more frequently in the control group vs. the FTD plus bevacizumab group. Serious adverse drug reactions occurred more frequently in the control group. Thus, FTD/TPI plus bevacizumab can be an alternative to irinotecan for oncologists to treat patients who cannot tolerate irinotecan-containing regimens because of non-haematological toxicities.

Conclusion

We concluded that FTD/TPI plus bevacizumab did not demonstrate non-inferiority to fluoropyrimidine and irinotecan plus bevacizumab in the second-line setting. Based on the evidence established till date, fluoropyrimidine and irinotecan plus bevacizumab remains the standard front-line treatment option for patients with mCRC, and the standard option of third- or late-stage treatment is FTD/TPI plus bevacizumab. Further investigations are warranted to explore more appropriate second-line treatments for patients with a low tumour burden.

Our paper is published in the British Journal of Cancer here: https://www.nature.com/articles/s41416-023-02212-2

Acknowledgement

Medical writing support was provided by Sarayu Pai, PhD, CMPP, of Cactus Life Sciences (part of Cactus Communications) and funded by Taiho Pharmaceutical Co., Ltd.

References

  1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Colon Cancer Version 3. 2022-January 25, 2023. Available at nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed March 3, 2023.
  2. Marsh, S., Hoskins, J.M. Irinotecan pharmacogenomics. Pharmacogenomics 11, 1003–1010 (2010).
  3. Burness, C.B., Duggan, S.T. Trifluridine/tipiracil: a review in metastatic colorectal cancer. Drugs 76, 1393–1402 (2016).
  4. Kuboki, Y., Nishina, T., Shinozaki, E., Yamazaki, K., Shitara, K., Okamoto, W., 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 18, 1172–1181 (2017).
  5. Satake, H., Kato, T., Oba, K., Kotaka, M., Kagawa, Y., Yasui, H., et al. Phase Ib/II study of biweekly TAS-102 in combination with bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (BiTS Study). Oncologist 25, e1855–e1863 (2020).
  6. Pfeiffer, P., Yilmaz, M., Möller, S., Zitnjak, D., Krogh, M., Petersen, L.N., 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 21, 412–420 (2020).
  7. Yoshida, Y., Yamada, T., Kamiyama, H., Kosugi, C., Ishibashi, K., Yoshida, 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).
  8. Takahashi, T., Yamazaki, K., Oki, E., Shiozawa, M., Mitsugi, K., Makiyama, A., et al. Phase II study of trifluridine/tipiracil plus bevacizumab by RAS mutation status in patients with metastatic colorectal cancer refractory to standard therapies: JFMC51-1702-C7. ESMO Open 6, 100093 (2021).
  9. Van Cutsem, E., Danielewicz, I., Saunders, M.P., Pfeiffer, P., Argilés, G., Borg, C., et al. Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study. Ann Oncol 31, 1160–1168 (2020).
  10. Oki, E., Makiyama, A., Miyamoto, Y., Kotaka, M., Kawanaka, H., Miwa, K., et al. Trifluridine/tipiracil plus bevacizumab as a first-line treatment for elderly patients with metastatic colorectal cancer (KSCC1602): a multicenter phase II trial. Cancer Med 10, 454–461 (2021).
  11. Argiles, G., Arnold, D., Prager, G., Sobrero, A.F., Van Cutsem, E. Maximising clinical benefit with adequate patient management beyond the second line in mCRC. ESMO Open 4, e000495 (2019).
  12. Tabernero, J., Prager, G.W., Fakih, M., Ciardiello, F., Van Cutsem, E., Elez, E., et al. Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: the phase 3 randomized SUNLIGHT study. J Clin Oncol 41, 4–4 (2023).
  13. André, T., Falcone, A., Shparyk, Y., Moiseenko, F., Polo-Marques, E., Csöszi, T., et al. Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study. Lancet Gastroenterol Hepatol 8, 133–144 (2023).

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A blog for our paper recently published in British Journal of Cancer: Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial

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