Efficacy of PD-(L)1 blockade monotherapy compared to PD-(L)1 blockade plus chemotherapy in first-line PD-L1-positive advanced lung adenocarcinomas: A cohort study

Background Single-agent PD-(L)1 blockade (IO) alone or in combination with chemotherapy (Chemotherapy-IO) are approved first-line therapies in patients with advanced lung adenocarcinomas (LUADs) with PD-L1 expression ≥1%. These regimens have not been compared prospectively. The primary objective was to compare first-line efficacies of single-agent IO to Chemotherapy-IO in patients with advanced LUADs. Secondary objectives were to explore if clinical, pathologic, and genomic features were associated with differential response to Chemotherapy-IO vs IO. Methods This was a multicenter retrospective cohort study. Inclusion criteria were patients with advanced LUADs with tumor PD-L1 ≥1% treated with first-line Chemotherapy-IO or IO. To compare the first-line efficacies of single-agent IO to Chemotherapy-IO, we conducted inverse probability weighted (IPW) Cox proportional hazards models using estimated propensity scores. Results The cohort analyzed included 874 patients. Relative to IO, Chemotherapy-IO was associated with improved ORR (44% vs 35%, p=0.005) and PFS in patients with tumor PD-L1≥1% (HR 0.75, 95% CI 0.0.61-0.92, p=0.005) or PD-L1≥50% (ORR 55% vs38%, p<0.001; PFS HR 0.74 95%CI 0.56-0.97, p=0.032). Using propensity-adjusted analyses, only never smokers in the PD-L1 ≥50% subgroup derived a differential survival benefit from Chemotherapy-IO vs IO (p=0.03). Among patients with very high tumor PD-L1 expression (≥90%) there were no differences in outcome between treatment groups. No genomic factors conferred differential survival benefit to Chemotherapy-IO vs IO. Conclusions While the addition of chemotherapy to PD-(L)1 blockade increases the probability of initial response, never-smokers with tumor PD-L1 ≥50% comprise the only population identified that derived an apparent survival benefit with treatment intensification. ### Competing Interest Statement Please see manuscript for details. ### Funding Statement Please see details in the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute IRB. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Please see details in the manuscript. * NSCLC : Non-small cell lung cancer LUAD : Lung adenocarcinoma IO : Anti-PD-(L)-1 monotherapy Chemotherapy-IO : Combination anti-PD-(L)-1 with platinum-doublet chemotherapy ORR : Overall response rate PFS : Progression-free survival OS : Overall survival HR : Hazard ratio 95%CI : 95% confidence interval NGS : Next-generation sequencing PD-L1 TPS : PD-L1 tumor proportion score