Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial.

The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 .

Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS: This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS: Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS: gov NCT04169672.

Surufatinib plus toripalimab in patients with advanced neuroendocrine tumours and neuroendocrine carcinomas: An open-label, single-arm, multi-cohort phase II trial.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib revealed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumours in a phase I study. PATIENTS AND METHODS: This was an open-label, single-arm, multi-cohort phase II study in China. Patients with advanced neuroendocrine tumours (NETs) or neuroendocrine carcinomas (NECs) or mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) who had failed or were intolerable of standard treatment were given surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every 3 weeks). Primary end-point was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end-points included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled into two cohorts by tumour types (NET, n = 19; NEC-MiNEN, n = 21). ORRs (95% CIs) were 21.1% (6.1-45.6) and 23.8% (8.2-47.2) in the NET and NEC-MiNEN cohorts, respectively. Median DoR was 7.1 months (6.9-not evaluable [NE]) and 4.1 months (3.0-NE), respectively. Median PFS was 9.6 months (4.1-NE) and 4.1 months (1.5-5.5); median OS was 27.3 (15.3-NE) and 10.9 months (9.1-14.6), respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 18 (45.0%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed antitumour activity and a tolerable safety profile in patients with previously treated NETs/NECs/MiNENs. Further study of this combination regimen is ongoing for advanced NECs, for which current therapeutic options remain limited. CLINICALTRIALS: gov: NCT04169672.

Phase 1b/2 trial of fruquintinib plus sintilimab in treating advanced solid tumours: The dose-escalation and metastatic colorectal cancer cohort in the dose-expansion phases.

BACKGROUND: Fruquintinib (anti-vascular endothelial growth factor 1/2/3) plus sintilimab (anti-programmed death-1) demonstrated enhanced anti-tumour effects versus monotherapy in a preclinical study. We investigated the combination in patients with advanced solid tumours, including metastatic colorectal cancer (mCRC). METHODS: In this phase 1b/2, open-label, multi-centre, multi-cohort dose-escalation and dose-expansion study, patients with advanced solid tumours (dose-escalation) or mCRC (one cohort in dose-expansion) received different doses of fruquintinib plus a fixed dose of sintilimab once every 4 weeks (Q4W) or 3 weeks (Q3W). Primary objectives were safety, tolerability, and the preliminary efficacy. This study is registered at ClinicalTrials.gov, NCT03903705. FINDINGS: By the data cut-off date (30th December 2021), 23 patients were enrolled in the dose-escalation and 37 patients in the mCRC cohort of the dose-expansion; 44 patients with mCRC who received sintilimab Q3W were pooled for analysis. One dose-limiting toxicity event (grade 3 troponin T increased) occurred during the dose escalation. Grade ≥3 treatment-related adverse events occurred in 43.5% and 47.7% of patients in the dose-escalation phase and pooled mCRC analysis, respectively. Among patients treated with the recommended phase 2 dose (fruquintinib 5 mg once daily, 2 weeks on/1 week off, plus sintilimab 200 mg Q3W) in pooled mCRC analysis, the objective response rate was 23.8% (95% CI 8.2-47.2), median progression-free survival was 6.9 months (95% CI 5.4-8.3), and overall survival was 14.8 months (95% CI 8.8-not reached); in patients with mismatch repair-proficient mCRC, these were 20.0% (95% CI 4.3-48.1), 6.9 months (95% CI 4.8-10.1), and 20.0 months (95% CI 8.1-not reached), respectively. INTERPRETATION: Fruquintinib plus sintilimab was well tolerated in patients with advanced solid tumours and showed promising efficacy in mCRC.

Effectiveness and complication rates of tension-free vaginal tape, transobturator tape, and tension-free vaginal tape-obturator in the treatment of female stress urinary incontinence in a medium- to long-term follow up. Meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the effectiveness and complications of tension-free vaginal tape (TVT), transobturator tape (TOT), and tension-free vaginal tape-obturator (TVT-O) in a medium- to long-term follow up. METHODS: We searched PubMed, EMBASE, Cochrane database, ClinicalTrials.gov, Google Scholar, and the International Continence Society (ICS) website from August to December 2012 in Guangzhou First People's Hospital, Guangzhou, China. Randomized controlled trials (RCTs) comparing the effectiveness and complications of TVT, TOT, and TVT-O were selected. RESULTS: Forty RCTs were included. The TVT and TOT had similar subjective (risk ratio [RR]: 0.99; 95% confidence interval [CI]: 0.93-1.04), and objective cure rates (RR: 0.96; 95% CI: 0.70-1.32). However, TVT had a reduced risk of groin/thigh pain (RR: 0.33; 95% CI: 0.18-0.59). The subjective (RR: 1.02; 95% CI: 0.97-1.06) and objective cure rates (RR: 1.02; 95% CI: 0.99-1.06) of TVT-O were similar to TVT, but TVT had a higher risk of bladder perforations (RR: 2.29; 95% CI: 1.18-4.45). The TVT-O and TOT had similar subjective (RR: 0.99; 95% CI: 0.93-1.06), and objective cure rates (RR: 1.01; 95% CI: 0.95-1.07). However, TVT-O had a lower risk of vaginal erosion rates (RR: 0.16; 95% CI: 0.03-0.89). CONCLUSION: The subjective and objective cure rates of stress urinary incontinence were similar among TVT, TOT, and TVT-O in a medium- to long-term follow up. The TVT had a higher risk of bladder perforation than TVT-O, and a lower risk of groin/thigh pain than TOT, and TVT-O had a lower risk of vaginal erosion rates than TOT.