No abstract

ObjectiveTo evaluate sintilimab versus placebo in combination with chemotherapy (cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil) as first line treatment of unresectable locally advanced, recurrent, or metastatic oesophageal squamous cell carcinoma.DesignMulticentre, randomised, double blind, phase 3 trial.Setting66 sites in China and 13 sites outside of China between 14 December 2018 and 9 April 2021.Participants659 adults (aged ≥18 years) with advanced or metastatic oesophageal squamous cell carcinoma who had not received systemic treatment.InterventionParticipants were randomised 1:1 to receive sintilimab or placebo (3 mg/kg in patients weighing <60 kg or 200 mg in patients weighing ≥60 kg) in combination with cisplatin 75 mg/m2 plus paclitaxel 175 mg/m2 every three weeks. The trial was amended to allow investigators to choose the chemotherapy regimen: cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil (800 mg/m2 continuous infusion on days 1-5).Main outcome measuresOverall survival in all patients and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1.Results659 patients were randomly assigned to sintilimab (n=327) or placebo (n=332) with chemotherapy. 616 of 659 patients (93%) received sintilimab or placebo in combination with cisplatin plus paclitaxel and 43 of 659 patients (7%) received sintilimab or placebo in combination with cisplatin plus 5-fluorouracil. At the interim analysis, sintilimab with chemotherapy showed better overall survival compared with placebo and chemotherapy in all patients (median 16.7 v 12.5 months, hazard ratio 0.63, 95% confidence interval 0.51 to 0.78, P<0.001) and in patients with combined positive scores of ≥10 (17.2 v 13.6 months, 0.64, 0.48 to 0.85, P=0.002). Sintilimab and chemotherapy significantly improved progression free survival compared with placebo and chemotherapy in all patients (7.2 v 5.7 months, 0.56, 0.46 to 0.68, P<0.001) and in patients with combined positive scores of ≥10 (8.3 v 6.4 months, 0.58, 0.45 to 0.75, P<0.001). Adverse events related to treatment occurred in 321 of 327 patients (98%) in the sintilimab-chemotherapy group versus 326 of 332 (98%) patients in the placebo-chemotherapy group. Rates of adverse events related to treatment, grade ≥3, were 60% (196/327) and 55% (181/332) in the sintilimab-chemotherapy and placebo-chemotherapy groups, respectively.ConclusionsCompared with placebo, sintilimab in combination with cisplatin plus paclitaxel showed significant benefits in overall survival and progression free survival as first line treatment in patients with advanced or metastatic oesophageal squamous cell carcinoma. Similar benefits of sintilimab with cisplatin plus 5-fluorouracil seem promising.Trial registrationClinicalTrials.gov NCT03748134.

An ingenious interface re-engineering strategy was applied to in situ prepare a manipulated LiHPO protective layer on the surface of Li anode for circumventing the intrinsic chemical stability issues of LiGePS (LGPS) to Li metal, specifically the migration of mixed ionic-electronic reactants to the inner of LGPS, and the kinetically sluggish reactions in the interface. As consequence, the stability of LGPS with Li metal increased substantially and the cycling of symmetric Li/Li cell showed that the polarization voltage could keep relative stable for over 950 h at 0.1 mA cm within ±0.05 V. The optimized ASSLiB of LiCoO (LCO)/LGPS/Li with interface-engineered structure was able to deliver long cycle life and high capacity, i.e., a reversible discharge capacity of 131.1 mAh g at the initial cycle and 113.7 mAh g at the 500th cycle under 0.1 C with a retention of 86.7%. In addition, the factors effected on the interphases formation of the LGPS/Li interface were analyzed, and the mechanism of the stability between LGPS and Li anode with protective layer was further investigated. Moreover, the probable causes of battery degradation were also explored. Above all, this work would give an alternative strategy for the modification of Li anode in high energy density solid-state lithium metal batteries.