First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study

E Van Cutsem, I Danielewicz, M P Saunders, P Pfeiffer, G Argilés, C Borg, R Glynne-Jones, C J A Punt, A J Van de Wouw, M Fedyanin, D Stroyakovskiy, H Kroening, P Garcia-Alfonso, H Wasan, A Falcone, R Fougeray, A Egorov, N Amellal, V Moiseyenko, E Van Cutsem, I Danielewicz, M P Saunders, P Pfeiffer, G Argilés, C Borg, R Glynne-Jones, C J A Punt, A J Van de Wouw, M Fedyanin, D Stroyakovskiy, H Kroening, P Garcia-Alfonso, H Wasan, A Falcone, R Fougeray, A Egorov, N Amellal, V Moiseyenko

Abstract

Background: Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results.

Methods: TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1-5 and 8-12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1-14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS.

Results: At 1 September 2020, median OS was 22.3 months (95% CI: 18.0-23.7) with TT-B and 17.7 months (95% CI: 12.6-19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55-1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings.

Conclusions: TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy.

Clinical trial information: NCT02743221 (clinicaltrials.gov).

Conflict of interest statement

EVC has received research funding from Amgen, Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck KGaA, MSD, Novartis, Roche, Sanofi, and Servier and has attended advisory boards for Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GS, Incyte, Ipsen, Lilly, Merck KGaA, MSD, Novartis, Pierre-Fabre, Roche, Servier and Taiho. ID has received research funding from AstraZeneca Pharma (Poland), Bayer, Bristol-Myers Squibb, Celgene, Eli Lilly, Immutep, Janssen-Cilag, Merck, MorphoSys, Novartis, Regeneron Pharmaceuticals, Roche, Servier and Tesaro. MPS has attended advisory boards and chaired meetings for Roche, Merck KGaA, Servier, Amgen, Sanofi and Eisai. PP has received research funding from Amgen, Celgene, Lilly, Merck KGaA, Roche, Taiho, Nordic Drugs and Servier. GA has received research funding from Servier and Bayer; has attended advisory boards for Servier, Bayer, Amgen, Sanofi, Merck Serono, Bristol-Myers Squibb and Roche and has received travel expenses and accommodation from Servier, Bayer, Amgen and Roche. CB has attended advisory boards for Roche, Servier and Sanofi and has received a research grant from Roche. RG-J has received research funding from Servier. CJAP has acted in an advisory role for Servier. AJVdW, MF, DS and HK have received research funding from Servier. PG-A has attended advisory boards and chaired meetings for Roche, Merck KGaA, Amgen, Sanofi, Lilly and Servier. HW has received honoraria, attended advisory boards and received travel grants and/or speaker fees from Bayer, Bristol-Myers Squibb, Lilly, Roche, Pfizer, Biotheranostics, Servier, Merck KGaA, Sirtex Medical, Sanofi-Aventis, Celgene and Array; has received research funding from Sirtex Medical, Merck Serono, Pfizer and Merck & Co (MSD) and has received charitable funds/grants from Cancer Research UK, Medical Research Council, National Institute for Health Research (NIHR) and the CUP Foundation. AF has received compensation for participation in advisory boards and research grants to his institution from Amgen, Bayer, Merck KGaA, MSD, Roche, Lilly, Servier and Bristol-Myers Squibb. AE, RF and NA are employees of Servier. V.M. has received research funding from Servier, BMS, MSD, Roche, Biocade, Sanofi and AstraZeneca.

© 2022. The Author(s).

Figures

Fig. 1. Design of the TASCO1 trial.
Fig. 1. Design of the TASCO1 trial.
BID twice daily, d days, ECOG Eastern Cooperative Oncology Group, IV intravenous, mCRC metastatic colorectal cancer, p.o. orally, PS performance status, qxd every x days, R randomisation.
Fig. 2. Kaplan–Meier estimates of overall survival…
Fig. 2. Kaplan–Meier estimates of overall survival probability (final analysis) for first-line trifluridine/tipiracil plus bevacizumab (TT-B; n = 77) and capecitabine plus bevacizumab (C-B; n = 76) in patients with metastatic colorectal cancer who were ineligible for intensive chemotherapy.
CI confidence interval, HR hazard ratio.
Fig. 3. Forest plot of overall survival…
Fig. 3. Forest plot of overall survival (OS) by subgroup.
C-B capecitabine plus bevacizumab, CI confidence interval, ECOG PS Eastern Cooperative Oncology Group performance status, HR hazard ratio, TT-B trifluridine/tipiracil plus bevacizumab.

References

    1. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386–422. doi: 10.1093/annonc/mdw235.
    1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Colon cancer. Version 2.2021. 2021. . Accessed 31 January 2021.
    1. Cremolini C, Antoniotti C, Stein A, Bendell J, Gruenberger T, Rossini D, et al. Individual patient data meta-analysis of FOLFOXIRI plus bevacizumab versus doublets plus bevacizumab as initial therapy of unresectable metastatic colorectal cancer. J Clin Oncol. 2020;38:3314–24. doi: 10.1200/JCO.20.01225.
    1. Cremolini C. When to use triplet chemotherapy as first-line treatment in metastatic colorectal cancer. Clin Adv Hematol Oncol. 2019;17:433–5.
    1. Bossé D, Vickers M, Lemay F, Beaudoin A. Palliative chemotherapy for patients 70 years of age and older with metastatic colorectal cancer: a single-centre experience. Curr Oncol. 2015;22:e349–356. doi: 10.3747/co.22.2337.
    1. Bruera G, Russo A, Galvano A, Rizzo S, Ricevuto E. Clinical parameters to guide decision-making in elderly metastatic colorectal cancer patients treated with intensive cytotoxic and anti-angiogenic therapy. Oncotarget. 2017;8:37875–83. doi: 10.18632/oncotarget.14333.
    1. Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14:1077–85. doi: 10.1016/S1470-2045(13)70154-2.
    1. Dagher M, Sabido M, Zollner Y. Effect of age on the effectiveness of the first-line standard of care treatment in patients with metastatic colorectal cancer: systematic review of observational studies. J Cancer Res Clin Oncol. 2019;145:2105–14. doi: 10.1007/s00432-019-02948-6.
    1. Pinto C, Antonuzzo L, Porcu L, Aprile G, Maiello E, Masi G, et al. Efficacy and safety of bevacizumab combined with fluoropyrimidine monotherapy for unfit or older patients with metastatic colorectal cancer: a systematic review and meta-analysis. Clin Colorectal Cancer. 2017;16:e61–e72. doi: 10.1016/j.clcc.2016.08.006.
    1. Tapia Rico G, Price T, Tebbutt N, Hardingham J, Lee C, Buizen L, et al. Right or left primary site of colorectal cancer: outcomes from the molecular analysis of the AGITG MAX trial. Clin Colorectal Cancer. 2019;18:141–8. doi: 10.1016/j.clcc.2018.12.002.
    1. Kwakman JJM, Simkens LHJ, van Rooijen JM, van de Wouw AJ, Ten Tije AJ, Creemers GJM, et al. Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol. 2017;28:1288–93. doi: 10.1093/annonc/mdx122.
    1. European Medicines Agency. Lonsurf Summary of Product Characteristics. 2016. . Accessed 31 January 2021.
    1. Lenz HJ, Stintzing S, Loupakis F. TAS-102, a novel antitumor agent: a review of the mechanism of action. Cancer Treat Rev. 2015;41:777–83. doi: 10.1016/j.ctrv.2015.06.001.
    1. Tsukihara H, Nakagawa F, Sakamoto K, Ishida K, Tanaka N, Okabe H, et al. Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts. Oncol Rep. 2015;33:2135–42.
    1. 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. 2017;18:1172–81. doi: 10.1016/S1470-2045(17)30425-4.
    1. André T, Saunders M, Kanehisa A, Gandossi E, Fougeray R, Amellal NC, et al. First-line trifluridine/tipiracil plus bevacizumab for unresectable metastatic colorectal cancer: SOLSTICE study design. Future Oncol. 2020;16:21–29. doi: 10.2217/fon-2019-0786.
    1. Van Cutsem E, Danielewicz I, Saunders MP, Pfeiffer P, Argiles 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. 2020;31:1160–8. doi: 10.1016/j.annonc.2020.05.024.
    1. U.S. Deparment of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. 2010. . Accessed 31 March 2021.
    1. Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9. doi: 10.1200/JCO.2007.14.9930.
    1. Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008;26:2006–12. doi: 10.1200/JCO.2007.14.9898.
    1. Ducreux M, Bennouna J, Hebbar M, Ychou M, Lledo G, Conroy T, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2011;128:682–90. doi: 10.1002/ijc.25369.
    1. Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008;26:689–90. doi: 10.1200/JCO.2007.15.5390.
    1. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Kaiser F, Al-Batran SE, et al. FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial. Br J Cancer. 2021;124:587–94. doi: 10.1038/s41416-020-01140-9.
    1. Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015;16:1306–15. doi: 10.1016/S1470-2045(15)00122-9.
    1. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065–75. doi: 10.1016/S1470-2045(14)70330-4.
    1. Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23:3697–705. doi: 10.1200/JCO.2005.05.112.
    1. Kwakman JJM, van Werkhoven E, Simkens LHJ, van Rooijen JM, van de Wouw YAJ, Tije AJT, et al. Updated survival analysis of the randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer by the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2019;18:e229–e230. doi: 10.1016/j.clcc.2019.01.002.
    1. Pfeiffer P, Yilmaz M, Möller S, Zitnjak D, Krogh M, Petersen LN, 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;21:412–20. doi: 10.1016/S1470-2045(19)30827-7.
    1. Tabernero J, Taieb J, Prager GW, Ciardiello F, Fakih M, Leger C, et al. Trifluridine/tipiracil plus bevacizumab for third-line management of metastatic colorectal cancer: SUNLIGHT study design. Future Oncol. 2021;17:1977–85. doi: 10.2217/fon-2020-1238.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する