Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .

Introduction/Background Maintenance therapy, particularly with Poly-ADP-ribose polymerase (PARP) inhibitors, is recommended to extend platinum-related benefits in ovarian cancer (OC). Senaparib, a potent and selective PARP inhibitor, was investigated in the FLAMES phase 3 trial to confirm its efficacy and safety as first-line (1L) maintenance therapy for Chinese patients with newly diagnosed advanced OC. Methodology In this double-blind, placebo-controlled trial, 404 eligible patients with newly diagnosed FIGO stage III-IV, high-grade serous, or endometrioid OC, who completed 1L platinum-based chemotherapy with complete (CR) or partial response (PR), were randomized (2:1) to receive senaparib or placebo at 100 mg/day orally. Stratification considered CR/PR and BRCA (breast cancer susceptibility gene) mutation status. The primary endpoint was progression-free survival (PFS), assessed by blinded independent central review (BICR) using RECIST v1.1. Results As of March 16, 2023, 270 patients received senaparib, and 133 received placebo, with a median follow-up duration of 22.3 months. Senaparib significantly improved PFS over placebo (HR 0.43, 95% CI 0.32–0.58, P < 0.0001), regardless of BRCA status (HR 0.43, P < 0.01). Secondary endpoints, supported by subgroup and investigator assessment, consistently reinforced the primary analyses. The most common adverse events (AEs) were anaemia (81%), neutropenia 76%), leukopenia (75%), and thrombocytopenia (70%) in the senaparib arm; and neutropenia (32%), leukopenia (29%), hypertriglyceridaemia (26%), and transaminase increased (26%) in the placebo arm. AEs led to dose reduction and discontinuation were 63.3% vs. 6.0% and 4.4% vs. 0% in senaparib arm and placebo arm, respectively. No MDS and fatal events reported. Conclusion First-line maintenance Senaparib significantly reduced the risk of progression or death in advanced OC patients, irrespective of BRCA mutation status. Senaparib demonstrated favorable safety profiles, no additional safety signals were identified. Disclosures All authors declared no conflicts of interest.

BACKGROUND:Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS:This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS:Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION:Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING:Akeso Biopharma. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

Introduction FLAMES is a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate efficacy and safety of senaparib as first line (1L) maintenance therapy in patients with newly diagnosed advanced ovarian cancer (OC). Methods Chinese patients with newly diagnosed, FIGO stage III-IV, high-grade serous or endometrioid OC who had achieved complete response (CR) or partial response (PR) to 1L platinum-based chemotherapy were randomized (2:1) to receive senaparib or placebo. Primary endpoint was progression-free survival (PFS ) evaluated by BICR according to RECIST v1.1. A prespecified subgroup analysis was performed based on FIGO stage (III vs IV), BRCA mutation (positive vs negative), 1L treatment response (CR vs PR), neoadjuvant chemotherapy (yes vs no) and presence of residual disease after debulking surgery (yes vs no). Results 404 patients were randomized to receive senaparib vs placebo with a median follow up of 22.4 and 22.2 months, respectively. PFS was significantly increased in senaparib arm (HR 0.43, 95% CI 0.32–0.58, P < 0.0001) over placebo. All subgroup analysis demonstrated consistent treatment benefit ( HR <0.50, P<0.0001, figure 1). Incidence rates of grade ≥3 adverse events (AEs) were 66.3% vs 20.3%, respectively. The most common grade ≥3 AEs were anemia (29.3%) , thrombocytopenia (26.7%), and neutropenia (24.8%) after received senaparib. No new safety signals were identified among all subgroups. Conclusion/Implications Maintenance senaparib significantly improved PFS regardless of FIGO stage, 1L treatment response, surgical timing and residual disease status versus placebo in patients with newly diagnosed advanced OC.

Ovarian cancer (OC) is one of the most lethal gynecologic cancers. Approximately 85% of newly diagnosed advanced OC may experience a relapse after the first line (1L) platinum-based chemotherapy. PARP inhibitors are recommended as maintenance therapy to prolong the benefit of platinum. Senaparib (IMP4297) is a novel, highly potency PARP inhibitor. The phase 3 study FLAMES is to investigate the efficacy and safety of Senaparib in Chinese patients (pts) with newly diagnosed advanced OC as 1L maintenance therapy. Eligible pts had newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid OC, who have completed 1L platinum-based chemotherapy with complete response (CR) or partial response (PR). Pts were randomized (2:1) to receive senaparib (Sena) or placebo (PBO) 100 mg/day orally, stratified by CR/PR and BRCA mutation positive/negative. Primary endpoint was progression-free survival (PFS ) evaluated by blinded independent central review (BICR) according to RECIST v1.1. 404 pts were randomized. As of 16 Mar. 2023, 270 and 133 pts received Sena and PBO with a median follow-up of 22.4 and 22.2 months, respectively. Primary analysis showed Sena significantly improved PFS over placebo (HR 0.43, 95% CI 0.32-0.58, P < 0.0001), irrespective of BRCA mutation status ( HR 0.43, P < 0.01). Secondary endpoints support the primary analysis (Table). Incidence rates of grade ≥3 adverse events (AEs) were 66.3 % vs 20.3%, AEs leading to dose reduction 63.3 % vs 6.0% and discontinuation 4.4 % vs 0% in Sena and PBO arm. No AE leading to death.Table: LBA36Senaparib (n=271), mPlacebo (n=133), mHR (95%CI), P valuePFS (BICR)NR13.60.43 (0.32-0.58) P < 0.0001PFS (BICR) BRCA +NR15.60.43 (0.24-0.76) P = 0.0026PFS (BICR) BRCA-NR12.90.43 (0.30-0.61) P < 0.0001PFS (INVR)NR11.10.43 (0.32-0.57) P < 0.0001PFS (INVR) BRCA +NR11.10.33 (0.20-0.56) P < 0.0001PFS (INVR) BRCA-NR11.10.48 (0.34-0.67) P < 0.0001TFSTNR14.40.44 (0.33-0.59) P < 0.0001BICR, blinded independent central review; INVR, investigator review; HR, hazard ratio; NR, not reached; PFS, progression-free survival; BRCA +, breast cancer susceptibility gene (BRCA) mutation positive; BRCA -, BRCA mutation negative; TFST, time to first subsequent therapy or death; m, month Open table in a new tab BICR, blinded independent central review; INVR, investigator review; HR, hazard ratio; NR, not reached; PFS, progression-free survival; BRCA +, breast cancer susceptibility gene (BRCA) mutation positive; BRCA -, BRCA mutation negative; TFST, time to first subsequent therapy or death; m, month 1L maintenance Senaparib led to an unprecedented reduction in the risk of progression or death versus placebo in OC, regardless of biomarker status. Senaparib was well tolerated, no new safety signals were identified.

随着经济的发展和社会的不断进步,配电网在城镇建设中的作用越来越广泛。同时,人们对配电网的供电性能也提出了更高的要求,所以要不断提高配电网的供电可靠性来满足用户的用电需求。本文从配电网的可靠性进行分析,指出主要影响供电可靠性的三个因素,并针对管理和技术两个方面提出提高配电网可靠性的举措。

随着经济的发展和社会的进步,人们对于电能的需求越来越高,我国城市配电网改造与建设工作的进一步发展,配电网自动化问题已越来越引起重视。本文首先阐述了配电网的自动化建设,继而提出配电网运行管理中存在的问题和解决对策,希望对于配电网建设和运行管理起到一定的帮助作用。