FLAURA strikes again: efficacy of osimertinib is independent of PD-L1 expression

Transl Lung Cancer Res 2020 | http://dx.doi. org/10.21037/tlcr-20-628 Osimertinib, a third generation tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), achieved impressive results in first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations (1). Numerically, with a median progression-free survival (PFS) and overall survival (OS) of 18.9 and 38.6 months respectively, osimertinib surpasses outcomes of all available treatments in metastatic NSCLC including those of immune checkpoint inhibitors (ICIs) (2,3). However, unlike with ICIs, responses are not durable and disease eventually progresses. Outrunning osimertinib in first-line treatment of metastatic EGFR mutation (EGFRm)-positive NSCLC would require novel strategies such as exploring and exploiting the immune environment of EGFR driven disease. Of 231 tissue blocks available from the screened population in the FLAURA trial, 197 with sufficient tissue were stained for programmed death ligand 1 (PD-L1) expression, using the SP263 Ventana immunohistochemical assay based on tumor cell staining (TC). Immune cell (IC) scoring incorporated into the VENTANA PD-L1 (SP142) assay, was also performed as part of an exploratory analysis. In a recent paper published in the Journal of Thoracic Oncology, Brown and colleagues demonstrated that the efficacy of osimertinib in first-line treatment of EGFRmpositive metastatic NSCLC was unaffected by PD-L1 expression regardless of the selected staining threshold (1%, 25% or 50%) and the type of immunohistochemical staining assay (TC or TC and IC). Moreover, EGFR mutations and PD-L1 expression were not mutually exclusive; yet, the prevalence of PD-L1 expression was lower in EGFRmpositive tumors and the difference was more accentuated at higher PD-L1 TC thresholds (51% vs. 68% at a TC ≥1%, 8% vs. 35% at TC ≥25% and 5% vs. 28% at TC ≥50%). In EGFRm-positive patients who received osimertinib (N=54), median PFS and response rates (RR) matched those obtained in the overall FLAURA population (median PFS 18.9 months, response rate 80%) and were unaffected by PD-L1 expression (TC/IC ≥1% versus TC/IC <1% for PFS and TC ≥1% versus TC <1% for RR) (4). The key message in Brown et al.’s analysis of the FLAURA population is that the efficacy of osimertinib remains independent of PD-L1 expression which is concordant with Tang et al. and Cho et al.’s findings (4-6). A few studies reported improved survival endpoints (again endpoints were heterogeneous across studies) in EGFRmpositive patients who were also PD-L1 expressers (7,8). Other studies found adverse outcomes in PD-L1 expressers (9,10). All the studies that tried to answer this pending question were retrospective. PD-L1 status was mainly assessed by immunohistochemistry (IHC); yet thresholds varied significantly across studies. Most of these studies were monocentric and used either erlotinib or gefitinib. Data is scarce regarding the interplay between osimertinib, a more potent EGFR TKI, and PD-L1 expression. EGFR T790 mutant NCI-H1975 cell lines treated with Editorial Commentary