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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

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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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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Corresponding author

Correspondence to Yanhong Deng.

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Cite this article

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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Keywords

  • BRAF
  • Colorectal cancer
  • KRAS
  • Progression-free survival
  • Regorafenib
  • Tumor response