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Efficacy and Safety of Regorafenib in Combination with Chemotherapy as Second-Line Treatment in Patients with Metastatic Colorectal Cancer: A Network Meta-Analysis and Systematic Literature Review

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Abstract

Introduction

Although various therapies are available for the treatment of metastatic colorectal cancer (mCRC), there is lack of head-to-head evidence. Recent studies have demonstrated the efficacy of chemotherapy in combination with different biological agents including regorafenib in second-line therapy in patients with mCRC. We conducted a network meta-analysis (NMA) to estimate the relative efficacy and safety of regorafenib in combination with chemotherapy compared to other biological agents with chemotherapy combinations.

Methods

A literature search was conducted in PubMed, Embase, and Cochrane databases to identify all randomized controlled trials (RCTs) evaluating the efficacy and safety of bevacizumab, regorafenib, panitumumab, cetuximab, ramucirumab, conatumumab, ganitumab, and aflibercept in combination with chemotherapy against chemotherapy alone as second-line setting from inception to 7 February 2019 in patients with mCRC. The survival outcomes were analyzed by the frequentist statistical approach (R software, netmeta package) while the level of individual treatment arms was assessed using the Bayesian method (R software, gemtc package).

Results

We identified 12 articles involving eight RCTs studies analyzing 6805 patients. The studies compared bevacizumab (3), regorafenib (1), panitumumab (2), cetuximab (3), ramucirumab (1), conatumumab (1), ganitumab (1), and aflibercept (1) against chemotherapy alone as comparator. The progression-free survival (PFS) revealed that regorafenib performed better than aflibercept (HR 0.9631, 95% CI 0.6785–1.367), ganitumab (HR 0.7228, 95% CI 0.3985–1.3109), panitumumab (HR 0.9653, 95% CI 0.6781–1.3742), and ramucirumab (HR 0.9206, 95% CI 0.6504–1.303). Regorafenib performed better than bevacizumab (OR 0.797, 95% CI 0.328–1.88) in terms of tumor response. Safety analysis showed that regorafenib performed better in reducing grade ≥ 3 adverse events (AE) than cetuximab and conatumumab, neutropenia than conatumumab, and fatigue than cetuximab.

Conclusions

Regorafenib combined with chemotherapy might be a potential alternative to conventional therapeutic options in second-line treatment of patients with metastatic colorectal cancer and could be considered as the best option for treating patients with KRAS and BRAF mutated mCRC. However future RCTs are needed to confirm these results.

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References

  1. International Agency for Research on Cancer. Colorectal cancer fact sheet. https://gco.iarc.fr/today/data/factsheets/cancers/10_8_9-Colorectum-fact-sheet.pdf. Accessed Dec 26, 2019.

  2. Cremolini C, Loupakis F, Antoniotti C, 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.

    Article  CAS  Google Scholar 

  3. Venook AP, Niedzwiecki D, Lenz H-J, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA. 2017;317:2392–401.

    Article  CAS  Google Scholar 

  4. Heinemann V, von Weikersthal LF, Decker T, 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.

    Article  CAS  Google Scholar 

  5. Symonds LK, Cohen SA. Use of perioperative chemotherapy in colorectal cancer metastatic to the liver. Gastroenterol Rep (Oxf). 2019;7:301–11.

    Article  Google Scholar 

  6. Ades S. Adjuvant chemotherapy for colon cancer in the elderly: moving from evidence to practice. Oncology (Williston Park). 2009;23:162–7.

    Google Scholar 

  7. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–422.

    Article  CAS  Google Scholar 

  8. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.

    Article  CAS  Google Scholar 

  9. Herbst RS, Kurzrock R, Hong DS, et al. A first-in-human study of conatumumab in adult patients with advanced solid tumors. Clin Cancer Res. 2010;16:5883–911.

    Article  CAS  Google Scholar 

  10. Takahari D, Yamada Y, Okita NT, et al. Relationships of insulin-like growth factor-1 receptor and epidermal growth factor receptor expression to clinical outcomes in patients with colorectal cancer. Oncology. 2009;76:42–8.

    Article  CAS  Google Scholar 

  11. Metastatic Colorectal Cancer—ESMO. https://www.esmo.org/guidelines/gastrointestinal-cancers/metastatic-colorectal-cancer. Accessed Jun 18, 2020.

  12. STIVARGA (regorafenib) tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204369lbl.pdf. Accessed 2020 Jun 18, 2020.

  13. Dhillon S. Regorafenib: a review in metastatic colorectal cancer. Drugs. 2018;78:1133–44.

    Article  CAS  Google Scholar 

  14. Majithia N, Grothey A. Regorafenib in the treatment of colorectal cancer. Expert Opin Pharmacother. 2016;17:137–45.

    Article  CAS  Google Scholar 

  15. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–12.

    Article  CAS  Google Scholar 

  16. Li J, Qin S, Xu R, Yau TCC, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16:619–29.

    Article  CAS  Google Scholar 

  17. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14:29–37.

    Article  CAS  Google Scholar 

  18. Cao R, Zhang S, Ma D, Hu L. A multi-center randomized phase II clinical study of bevacizumab plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) compared with FOLFIRI alone as second-line treatment for Chinese patients with metastatic colorectal cancer. Med Oncol. 2015;32:325.

    Article  Google Scholar 

  19. Masi G, Salvatore L, Boni L, et al. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015;26:724–30.

    Article  CAS  Google Scholar 

  20. Sanoff HK, Goldberg RM, Ivanova A, et al. Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer. Cancer. 2018;124:3118–266.

    Article  CAS  Google Scholar 

  21. Peeters M, Oliner KS, Price TJ, et al. Analysis of KRAS/NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin Cancer Res. 2015;21:5469–79.

    Article  CAS  Google Scholar 

  22. Seymour MT, Brown SR, Middleton G, et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013;14:749–59.

    Article  CAS  Google Scholar 

  23. Passardi A, Scarpi E, Gelsomino F, et al. Impact of second-line cetuximab-containing therapy in patients with KRAS wild-type metastatic colorectal cancer: results from the ITACa randomized clinical trial. Sci Rep. 2017;7:10426.

    Article  Google Scholar 

  24. Ciardiello F, Normanno N, Martinelli E, et al. Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): a randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX. Ann Oncol. 2016;27:1055–61.

    Article  CAS  Google Scholar 

  25. Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:2311–9.

    Article  CAS  Google Scholar 

  26. Tabernero J, Lenz H-J, Siena S, et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol. 2015;16:937–48.

    Article  CAS  Google Scholar 

  27. Cohn AL, Tabernero J, Maurel J, et al. A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer. Ann Oncol. 2013;24:1777–855.

    Article  CAS  Google Scholar 

  28. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499–506.

    Article  Google Scholar 

  29. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706–13.

    Article  CAS  Google Scholar 

  30. Chu E. An update on the current and emerging targeted agents in metastatic colorectal cancer. Clin Colorectal Cancer. 2012;11:1–13.

    Article  CAS  Google Scholar 

  31. Pei X, Liu Y, Sun L, et al. Outcome of molecular targeted agents plus chemotherapy for second-line therapy of metastatic colorectal cancer: a meta-analysis of randomized trials. Clin Colorectal Cancer. 2016;15:e149–e156156.

    Article  Google Scholar 

  32. Chan DLH, Segelov E, Wong RS, et al. Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer. Cochrane Database Syst Rev. 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481896/. Accessed Dec 31, 2019.

  33. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539–44.

    Article  CAS  Google Scholar 

  34. Horita Y, Yamada Y, Kato K, et al. Phase II clinical trial of second-line FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: AVASIRI trial. Int J Clin Oncol. 2012;17:604–9.

    Article  CAS  Google Scholar 

  35. Alahmari AK, Almalki ZS, Alahmari AK, Guo JJ. Thromboembolic events associated with bevacizumab plus chemotherapy for patients with colorectal cancer: a meta-analysis of randomized controlled trials. Am Health Drug Benefits. 2016;9:221–32.

    PubMed  PubMed Central  Google Scholar 

  36. Schultheis B, Folprecht G, Kuhlmann J, et al. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol. 2013;24:1560–7.

    Article  CAS  Google Scholar 

  37. Jing Z, Rui Z, Binglan Z. A comparison of regorafenib and fruquintinib for metastatic colorectal cancer: a systematic review and network meta-analysis. J Cancer Res Clin Oncol. 2019;145:2313–23.

    Article  Google Scholar 

  38. Chen J, Wang J, Lin H, Peng Y. Comparison of regorafenib, fruquintinib, and TAS-102 in previously treated patients with metastatic colorectal cancer: a systematic review and network meta-analysis of five clinical trials. Med Sci Monit. 2019;25:9179–91.

    Article  Google Scholar 

  39. Abrahao ABK, Ko Y-J, Berry S, Chan KKW. A comparison of regorafenib and TAS-102 for metastatic colorectal cancer: a systematic review and network meta-analysis. Clin Colorectal Cancer. 2018;17:113–20.

    Article  Google Scholar 

  40. Sonbol MB, Benkhadra R, Wang Z, et al. A systematic review and network meta-analysis of regorafenib and TAS-102 in refractory metastatic colorectal cancer. Oncologist. 2019;24:1174–9.

    Article  CAS  Google Scholar 

  41. Xue W-S, Men S-Y, Liu W, Liu R-H. A meta-analysis of safety and efficacy of regorafenib for refractory metastatic colorectal cancer. Medicine (Baltimore). 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200445/. Accessed Jul 8, 2020.

  42. Røed Skårderud M, Polk A, Kjeldgaard Vistisen K, Larsen FO, Nielsen DL. Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: a systematic review. Cancer Treat Rev. 2018;62:61–73.

    Article  Google Scholar 

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Acknowledgements

Funding

The study was supported by Science and Technology Program of Guangzhou NO. 201803010073 and National Key Clinical Discipline. The journal’s Rapid Service Fee was funded by the authors.

Medical Writing Assistance

Medical writing and analysis support in preparation of this article was provided by Anwesha Mandal, Dr. G. Kaushik Subramanian and Dr. Amit Bhat of Indegene Pvt. Ltd, India, under the guidance of and funded by the authors.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Xiaoyu Xie, Jianwei Zhang, Huabin Hu, Yue Cai, Zehua Wu, Jiayu Ling, Weiwei Li and Yanhong Deng have nothing to disclose.

Compliance with Ethics Guidelines

The network meta-analysis (CRD42018099548) was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Authors had permission to access all data used in this study.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China

    Xiaoyu Xie, Jianwei Zhang, Huabin Hu, Yue Cai, Zehua Wu, Jiayu Ling, Weiwei Li & Yanhong Deng

  2. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China

    Yanhong Deng

  3. Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, People’s Republic of China

    Yanhong Deng

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  1. Xiaoyu Xie
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Correspondence to Yanhong Deng.

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Xie, X., Zhang, J., Hu, H. et al. Efficacy and Safety of Regorafenib in Combination with Chemotherapy as Second-Line Treatment in Patients with Metastatic Colorectal Cancer: A Network Meta-Analysis and Systematic Literature Review. Adv Ther 37, 4233–4248 (2020). https://doi.org/10.1007/s12325-020-01447-2

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