Background
Worldwide, colorectal cancer (CRC) is the third most frequently diagnosed cancer and the third leading cause of cancer death [1]. Treatment strategies that include surgery, radiation therapy, and chemotherapy remain the main treatments for patients with early-stage CRC. Systematic chemotherapy has an established role in palliative treatment, which is focused on the extension of life and improvement in the quality of life [2]. Systemic use of antitumor agents, including fluorouracil (5FU), oxaliplatin, irinotecan, bevacizumab, and cetuximab, have emerged as the primary treatment choices. However, there have been few recent developments in the treatment of patients with advanced and metastatic colorectal carcinoma (mCRC), particularly for patients with mCRC who are resistant to current treatments [3].
Regorafenib, an oral multi-kinase inhibitor, and TAS-102, a novel combined oral formulation of trifluridine (TFT) and the thymidine phosphorylase inhibitor (TPI) tipiracil, have been supported by the findings from randomized controlled trials for the treatment of patients with mCRC who have progressed following at least two previous rounds of standard chemotherapy [4,5]. Both regorafenib and TAS-102 have now been included in clinical guidelines, including the National Comprehensive Cancer Network (NCCN) guidelines, for the management of mCRC [4,5]. Regorafenib is a multi-kinase inhibitor of fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), vascular endothelial growth factor receptor (VEGFR), KIT, RET, and BRAF [4]. Regorafenib was approved for clinical use following the positive endpoint results from CORRECT, an international, multicenter, randomized, phase III trial, which showed improved overall survival (OS) compared with placebo in the treatment-refractory population with mCRC, hazard ratio (HR) of 0.77 (95% CI, 0.64–0.94; P=0.0052) [4]. Positive results were also reported for TAS-102 from the RECOURSE trial, which showed that the when compared with placebo, the median OS improved from 5.3 months to 7.1 months, and the HR for patient mortality was 0.68 (95% CI, 0.58–0.81; P<0.001) [5]. A more recently published prospective study was undertaken in an Asian population, which also showed that TAS-102 treatment resulted in a significant survival benefit compared with placebo in patients with mCRC that was refractory to standard chemotherapy, with an HR for mortality of 0.79 (95% CI, 0.62–0.99; P=0.035), regardless of previous treatment with a biologic [6].
Fruquintinib is a VEGFR inhibitor that inhibits new blood vessel growth associated with tumor proliferation. A phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted in a Chinese population with refractory mCRC, which showed that treatment with oral fruquintinib resulted in a significant increase in OS compared with placebo, with an HR for mortality of 0.65 (95% CI, 0.51–0.83; P<0.001) [7]. However, because of the lack of head-to-head comparative studies of these three compounds, regorafenib, TAS-102, and fruquintinib, no superiority data has been obtained to compare their efficacy and safety in patients with refractory mCRC.
However, two network meta-analysis studies have been recently published that compared the efficacy and safety of regorafenib and TAS-102 [8], and regorafenib and fruquintinib [9] in pretreated patients with refractory mCRC. The lack of comparison data between the three drugs remains a challenge for clinicians who are responsible for treating patients with mCRC. Also, because current RCTs have shown differences in response to treatment in different racial groups, these differences may be a potential source of study bias. For example, the recently published meta-analysis by Jing et al. [9] that compared regorafenib and fruquintinib included three RCTs, including FRESCO (for fruquintinib), CONCUR (for regorafenib), and CORRECT (for regorafenib) [9]. However, only the trial CORRECT was designed as an international RCT that included Caucasian, black, and Asian patients, and the FRESCO and CONCUR RCTs were undertaken only in Asian patients.
Therefore, this study aimed to conduct a systematic review of the literature to identify key RCTs, followed by network meta-analysis, to compare the efficacy and safety profiles of regorafenib, fruquintinib, and TAS-102 in previously treated patients with mCRC.