Can PD-L1 tumor proportion score be used as the key to unlocking the KEYNOTE studies of pembrolizumab in advanced lung cancer?

Despite substantial advancements in the management of advanced non-small cell lung cancer (NSCLC) made possible with application of molecularly targeted and immune-based strategies over the last two decades, significant challenges remain (1). On the basis of these advancements, the evidence-based initial management of advanced/metastatic NSCLC is now necessarily defined by tumor molecular and immune biomarkers so as to permit optimal pairing of patients with the most efficacious and least toxic therapies—and with previously unseen extension of survival in multiple large studies in these selected populations (2-5). Reflecting this evolving reality, evidence-based international guidelines currently recommend tumor testing for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), and B-raf proto-oncogene (BRAF) mutations/gene rearrangements as well as programmed death ligand 1 (PD-L1) tumor proportion score (TPS) as part of the mandatory upfront molecular profiling paradigm for all treatment-eligible patients presenting with advanced/metastatic non-squamous NSCLC—regardless of clinical or demographic factors (i.e., tobacco history) (6,7). In squamous tumors, where the advances of targeted molecular therapies have remained disappointing to date, minimum requirements for testing include tumor PD-L1 TPS, with consideration of additional genomic testing based on clinical factors. However, the vast majority of patients with advanced NSCLC will not have an actionable driver oncogene alteration amenable to use of a precision tyrosine kinase inhibitor (TKI), and it is in this substantial cohort of patients where advances in immune-based therapies have radically transformed the therapeutic landscape (1,8). Currently, three different immune checkpoint inhibitors (ICIs)—nivolumab (anti-PD1), pembrolizumab (anti-PD1), and atezolizumab (anti-PD-L1) have secured approval from the United States Food and Drug Administration (FDA) for use in patients with advanced stage NSCLC. These ICIs alone and in combination with platinum doublet chemotherapy have demonstrated superior and durable overall survival (OS) with favorable toxicity profiles and quality of life measures when compared with chemotherapy—in both upfront and subsequent lines of treatment (9-13). These advancements have led to an implosion of the long-held hegemony of platinum doublet chemotherapy for the initial management of advanced NSCLC without actionable genomic alterations (i.e., in EGFR, ALK, and others), where the evidence-based standard of care is now necessarily ICI ± chemotherapy. On the basis of progress made in several landmark studies to date, pembrolizumab is currently FDA approved in the following settings for advanced NSCLC: (I) first-line monotherapy in tumors without EGFR/ALK alterations and PD-L1 TPS ≥1%; (II) first-line combination therapy with platinum doublet chemotherapy in tumors without EGFR/ALK alterations, irrespective of tumor PD-L1 TPS; and (III) following failure of platinum doublet or targeted therapies in ICI-naive patients with tumor PD-L1 TPS ≥1%.