Pembrolizumab plus chemotherapy +/- Bev has been approved as the 1L treatment for r/mCC patients (pts) with PD-L1 CPS ≥1. QL1706, a bifunctional Mabpair product of anti-PD-1 and anti-CTLA-4 antibodies, has shown good safety and promising efficacy in previously treated r/mCC pts in a phase Ib study. Here we report the latest efficacy and safety results from a Ph 2 study of QL1706 plus paclitaxel and cisplatin/carboplatin +/- Bev as 1L treatment of r/mCC. In this open-label, single arm, non-randomized, phase II study, eligible pts were pathologically confirmed r/mCC and had no prior systemic treatment. Pts were treated with QL1706 (5 mg/kg, IV, D1) plus paclitaxel (175 mg/m2 or 135 mg/m2, D1) and cisplatin (50 mg/m2, D1/D2)/carboplatin (AUC = 5, D1) (cohort 1) or with Bev (15 mg/kg, D1/D2) (cohort 2) once every 3 weeks for 6 cycles. Thereafter, treatment maintained with QL1706 +/- Bev, until disease progression, intolerable toxicity, or other discontinuation events. The primary and secondary endpoints were safety and efficacy, respectively. A total of 60 pts were enrolled. As of data cutoff (Apr 24, 2023), the median follow-up time was 14.0 months. Overall 58 pts had ≥1 post baseline tumor assessment and analyzed for efficacy. The ORR was 81% (95% CI, 68.6–90.1) (8 CRs and 39 PRs). The DCR was 98.3% (95% CI, 90.8–100.0). The mPFS was 14.3 months (95% CI, 9.2-NE). The mPFS was numerically longer in cohort 2 vs cohort 1 (16.4 vs 12.5 months). The mOS was not reached. TRAEs occurred in 60 (100%) pts. The most common TRAEs (≥30% in total population) were WBC count decreased (73.3%), neutrophil count decreased (58.3%), anemia (43.3%), platelet count decreased (38.3%), and alopecia (33.3%), Grade ≥3 TRAEs occurred in 43 (71.7%) pts. Treatment-related SAEs occurred in 20 (33.3%) pts. TRAEs leading to treatment discontinuation occurred in 16 (26.7%) pts. irAEs occurred in 36 (60%) pts (Grade ≥3, 13.3%). QL1706 plus platinum-based chemotherapy +/- Bev was well tolerated and showed promising antitumor activity as 1L treatment of r/mCC. Ph 3 study of QL1706 plus platinum-based chemotherapy +/- Bev as 1L treatment of r/mCC is ongoing.

Objective To investigate the inhibitory effect of constitutive photomorphogenic homolog subunit 3of COP9(COPS3)gene interferred by RNA on the proliferation of lung cancer A549cells,and to clarify its mechanism.Methods The tumor experimental models of nude mice were established in lung cancer cell line A549. 40nude mice were divided into experiment group(n=20,implanted with A549cells infected by si-COPS3)and control group(n=20,implanted with A549cells infected by si-CTRL.The tumor size,weight,and tumor formation rate of the nude mice were detected.The expression levels of the cell cycle related proteins,such as P21, CDK2,CDK4,cyclinB1,and cyclinD1 were detected by Western blotting method after down-regulation of expresion of COPS3gene in A549cells.Results The tumor volume and weight(P0.05),and the tumor formation rate of nude mice in experiment group were significantly lower than those in control group.Comparedwith control group,the expression level of P21protein was up-regulated(P0.05),and the expression levels of CDK4and cyclinB1protein were down-regulated(P0.05),while the expression levels of CDK2and cyclinD1 protein had no significant changes(P=0.384,P=0.605).Conclusion The proliferation of lung cancer cells can be suppressed significantly by inhibiting the expression of COPS3gene.This effect may be mediated by upregulating the expression of P21and down-regulating the expressions of cyclinB1and CDK4.