The efficacy and adverse events of regorafenib in advanced gastrointestinal stromal tumors after imatinib and sunitinib failure: a systemic review and meta-analysis
Authors: zhang xue , Zhang Ai-Li , Zhang Jiao , Xia Hong-Ying , Gu Xi , Ding Li-Juan , Zhang Xiaoxiao , Yin Wenjie 
Published: January 2023

Background
Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of advanced gastrointestinal stromal tumors (GISTs) previously treated with imatinib and sunitinib.
Objective
The systematic review and meta-analysis aim to quantify the efficacy and adverse events of regorafenib for patients with advanced GISTs.
Methods
Based on predetermined selection criteria, we looked through the PubMed, Embase, and Cochrane databases from establishment until September 2022 to identify pertinent papers. Combined percentages were presented as risk ratios (95% confidence intervals) using Stata 17.0 and the Review Manager 5.3.
Results
Following the screening and quality evaluation, eleven studies were included, two randomized controlled trials and nine non-randomized prospective or retrospective review articles of intervention, involving 768 patients, 400 of whom were male. This meta-analysis showed that the pooled mPFS was 7.18 (95%CI, 5.87–8.50; Z = 10.68, p < 0.001) and the pooled mOS was 19.67 months (95%CI, 11.32–28.03; Z = 4.61, p < 0.001) in patients after receiving regorafenib treatment, which was administered following failure with imatinib and sunitinib therapies. The combined analysis of the studies revealed that the incidence of any grade toxicities associated with regorafenib treatment of GISTs was 97% (95%CI, 0.96–0.98; Z = 144.09, p < 0.001). Regarding specific AEs, the most common AE was hand-foot syndrome (77%, 95%CI, 0.66–0.88; Z = 14.00, p < 0.001), followed by fatigue (55%, 95%CI, 0.41–0.69; Z = 7.83, p < 0.001), hypertension (53%, 95%CI, 0.34–0.72; Z = 5.56, p < 0.001), anemia (53%, 95%CI, 0.03–1.03; Z = 2.06, p = 0.04), thrombocytopenia (53%, 95%CI, 0.02–1.04; Z = 2.02, p = 0.04), liver damage (52%, 95%CI, 0.30–0.74; Z = 4.64, p < 0.001), diarrhea (43%, 95%CI, 0.33–0.53; Z = 8.40, p < 0.001) and hypophosphatemia (42%, 95%CI, 0.30–0.54; Z = 6.98, p < 0.001), hoarseness (34%, 95%CI, 0.18–0.51; Z = 4.06, p < 0.001), oral mucositis (31%, 95%CI, 0.21–0.41; Z = 5.96, p < 0.001), hypothyroidism (30%, 95%CI, 0.12–0.48; Z = 3.22, p < 0.001), eta. In addition, the pooled analysis of the studies revealed that grade3-4 toxicities rate was 59% (95%CI, 0.52–0.66; Z = 16.38, p < 0.001), among which the incidence of hand-foot syndrome, hypertension and hypophosphatemia was 20% (95%CI, 0.16–0.24; Z = 13.22, p = 0.15), 16% (95%CI, 0.10–0.22; Z = 30.62, p < 0.001) and 13% (95%CI, 0.05–0.22; Z = 0.13, p = 0.72).
Conclusion
The efficacy and adverse events of regorafenib in advanced GISTs after imatinib and sunitinib failure in the present study was similar with demonstrated in other tumors in real-world practice settings. The incidence of several common AEs for regorafenib was lower in our analysis than previously reported, probably due to the fact that adverse events in the included studies involved a lower than the recommended daily dose of 160 mg.