First-line camrelizumab(a PD-1 inhibitor)plus apatinib(an VEGFR-2 inhibitor)and chemotherapy for advanced gastric cancer(SPACE):a phase 1 study

Patients with advanced gastric cancer typically face a grim prognosis.This phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapyfor advanced gastric or gastroesophageal junction adenocarcinoma.The primary endpoints included maximum tolerated dose(MTD)in phase 1a and objective response rate(ORR)across phase 1a and 1b.Phase 1a tested three dose regimens of camrelizumab,apatinib,oxaliplatin,and S-1.Dose regimen 1:camrelizumab 200 mg on day 1,apatinib 250 mg every other day,oxaliplatin 100 mg/m^(2) on day 1,and S-140 mg twice a day on days 1-14.Dose regimen 2:same as dose regimen 1,but oxaliplatin 130mg/m.Dose regimen3:same as dose regimen 2,but apatinib 250 mg daily.Thirty-four patients were included(9 in phase 1a,25 in phase 1b).No dose-limiting toxicities occurred so no MTD was identified.Dose 3 was set for the recommended phase 2 doses and administered in phase 1b.The confrmed ORR was 76.5%(95%CI 58.8-89.3).The median progression-free survival was 8.4 months(95%CI 5.9-not evaluable[NE]),and the median overall survival(OS)was not mature(11.6-NE).Ten patients underwent surgery after treatment and the multidisciplinary team evaluation.Among 24 patients without surgery,the median OS was 19.6 months(7.8-NE).Eighteen patients(52.9%)developed grade≥3 treatment-emergent adverse events.Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer(ChiCTR2000034109).

Quality control of cell-based high-throughput drug screening

The pharmaceutical industry is presently suffering difficult times due to low productivity of new molecular entities.As a major source of drug leads,high-throughput screening(HTS)has been often criticized for its‘dead end’lead compounds.However,the fruitful achievements resulting from HTS technology indicate that it remains a feasible way for drug innovation.Because of increasing considerations of earlier stage ADMET(absorption,distribution,metabolism,excretion and toxicity)in drug development,cell-based HTS is highly recommended in modern drug discovery for its ability to detect more biologically relevant characteristics of compounds in living systems.This review provides a systematic and practical description of vital points for conducting high quality cell-based HTS,from assay development to optimization,compound management,data analyses,hit validation as well as lead identification.Potential problems and solutions are also covered.