Meta-analysis of phase II/III randomized controlled trials (RCTs) to evaluate the incidence of hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia (PPE) syndrome in patients with gastrointestinal (GI) cancers treated with fruquintinib

117 Background: Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 blocks the angiogenesis associated with tumor proliferation. Recently, the US FDA approved fruquintinib as a third-line treatment for metastatic colorectal cancer (mCRC). As with any other novel cancer therapies, adverse events are always a concern and all patients should be monitored in order to early detect and appropriately treat any adverse events. This meta-analysis aims to assess the risk of HFSR or PPE syndrome in patients with GI cancers treated with fruquintinib. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024. Phase II/III RCTs utilizing fruquintinib in GI cancers mentioning HFSR or PPE as an adverse effect were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied. Results: A total of 1872 patients, of whom 1131 (60%) received fruquintinib, from 3 phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and 1 phase II RCT were eligible for evaluation of HFSR or PPE incidence. FRESCO, FRESCO-2, and phase II trials involved patients with mCRC, they compared fruquintinib vs placebo. FRUTIGA trial involved patients with gastric or gastroesophageal junction adenocarcinoma, it compared fruquintinib + paclitaxel vs placebo + paclitaxel. The incidence of any-grade and high-grade HFSR or PPE was higher in the fruquintinib group compared to the placebo group, 27.93% vs 3.64% (RR, 7.64; 95% CI: 4.08-14.33; P<0.00001), and 8.5% vs 0% (RR, 26.0; 95% CI: 6.42-105.29; P<0.00001), respectively. In the mCRC subgroup analysis, the higher incidence of any-grade and high-grade HFSR or PPE in the fruquintinib arm was also statistically significant, 29.70% vs 2.55% (RR, 10.27; 95% CI: 5.59-18.88; P<0.00001), and 8.45% vs 0% (RR, 19.34; 95% CI: 3.84-97.36; P=0.0003), respectively. Conclusions: This meta-analysis revealed increased incidence of any-grade and high-grade HFSR or PPE in patients with GI cancers including mCRC treated with fruquintinib. In the FRESCO trial, this association was also shown to confer survival benefit in Chinese patients with mCRC. Prompt identification and providing proper supportive care is crucial in managing this adverse event and ultimately, preserving the patients’ quality of life.