Efficacy And Treatment-related Toxicities Associated With PD-1/PD-L1 Inhibitors In Previously-treated Advanced Non-small Cell Lung Cancer(NSCLC):Systematic Review And Meta-analysis

Objective:We used this meta analysis to assess the efficacy and treatmet-related toxicities of PD-1/PD-L1 inhibitors in previously-treated advanced non-small cell lung cancer(NSCLC).Explore the relationship between PD-L1 threshold and efficacy.Indirectly compared the differences of efficacy and toxicity among nivolumab,pembrolizumab and atezolizumab,in order to provide better reference for clinical practice.Materials and methods: We collected data from the PubMed,Cocherance Library database and Wed of Science up to Sep 2017.Eligible articles included RCTs of previously-treated advanced NSCLC patients treated with PD-1/PD-L1 inhibitors were analysised.We first extracted data of the PD-1/PD-L1 inhibitor and compared the differences in efficacy and toxicity with the chemotherapy,and then indirectly compared the difference among nivolumab,atezolizumab,and pembrolizumab in PFS,OS,Grade3-5AEs,treatment discontinuation,treatment-related death and irAEs.The nominal level of signficance was set at 5%,95% confidence interval.Result:We included five RCTs,with a total of 3361 patients.As to the efficacy,PD-1/PD-L inhibitors were superior to the chemotherapy in PFS(HR: 0.85,95% CI,0.74-0.97,P<0.05),OS(HR: 0.69,95% CI,0.63-0.76,P<0.05)and ORR(RR: 1.45,95% CI,1.06-1.99,P<0.05).Further more,the patients with PD-L1 positive in PD-1/PD-L1 inhibitors group had greater advantages than the chemotherapy group in PFS(HR: 0.82,95%CI,0.75-0.90,P <0.05)and OS(HR: 0.66,95% CI,0.59-0.74,P <0.05).By indirect comparison,there were no significant difference between these three PD-1/PD-L1 inhibitors in PFS and OS,even in the patients with PD-L1 high expression status.As to the treatment-related toxicites,we concluded that the total adverse events(RR: 0.76,95% CI,0.73-0.79,P<0.05),grade 3-5 serious adverse events(RR: 0.27,95% CI,0.19-0.38,P<0.05)and treatment discontinuation(RR: 0.31,95% CI,0.18-0.54,P<0.05)were lower in PD-1/PD-L1 inhibitors groups than in the chemotherapy,but there was no significant difference in treatment-related death(RR:0.42,95%CI,0.17-0.99,P=0.05).By indirect comparison,there was no significant difference among these three drugs in treatment-related decreased appetite、fatigue、nausea、diarrhea、pneumonitis and death,there was no signficant difference between nivolumab and pembrolizumab in treatment-related ALT increased、rash、pruritus and hypothyroidism.Nivolumab had lower grade 3-5 AEs than pembrolizumab(RR:0.41,95%CI,0.28-0.61,P<0.05)and atezolizumab(RR:0.50,95%CI,0.34-0.71,P<0.05).Conclusion:The efficacy and toxicity of these three PD-1/PD-L1 inhibitors in the second-line treatment of advanced NSCLC were better than those in the chemotherapy.The overall treatment-related mortality was less than 1%,which revealed that PD-1/PD-L1 inhibitors were well tolerated.The study further confirmed the positive correlation between efficacy of PD-1/PD-L1 inhibitors and PD-L1 threshold.Besides,there was no significant difference in PFS and OS among these three drugs,even in the patients with PD-L1 high expression status.There was no significant difference among these three drugs in treatment-related decreased appetite、fatigue、nausea、diarrhea、pneumonitis and death,there was no signficant difference between nivolumab and pembrolizumab in treatment-related ALT increased、rash、pruritus and hypothyroidism.Nivolumab had lower grade 3-5 AEs than pembrolizumab and atezolizumab.