Efficacy of PD-(L)1 Blockade Monotherapy Compared to PD-(L)1 Blockade Plus Chemotherapy in First-Line PD-L1-Positive Advanced Lung Adenocarcinomas

Importance: 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. Objectives: 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. Setting: Multicenter retrospective cohort study. Participants: Patients with advanced LUADs with tumor PD-L1 >1% treated with first-line Chemotherapy-IO or IO. Exposures: Chemotherapy-IO vs IO therapy. Main outcomes: Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: The cohort analyzed included 874 patients who received first-line treatment for PD-L1-positive advanced LUAD without sensitizing EGFR or ALK alterations. 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% vs 38%, 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 and Relevance: 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.