EGFR mutations and ALK rearrangements are well-established therapeutic targets in NSCLC, and first-line therapy with EGFR or ALK tyrosine kinase inhibitors (TKIs) is now the standard of care for these patients. Given the recent clinical interest in combining PD-1/PD-L1 inhibitors with EGFR and ALK TKIs, Gainor and colleaguesa evaluated PD-L1 expression patterns and clinical outcomes in EGFR-mutant and ALK-positive patients. PD-L1 and CD8 immunohistochemistry were performed on biopsy and resection specimens from patients with metastatic NSCLC. Membranous expression of PD-L1 in > 5% tumor cells was defined as PD-L1(+). CD8+ tumor infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0-3). The authors evaluated PD-L1 expression and CD8+ TILs in patients with metastatic, EGFR-mutant (N = 68) and ALK-positive (N = 28) NSCLC . Median progression-free survival (mPFS) on EGFR TKIs was similar between PD-L1(+) and PD-L1(-) patients at baseline (6.7 vs. 13.2 months; P = 0.08), as was median overall survival (mOS; 31.8 vs. 35.63 months; P = 0.307). mPFS on ALK TKIs was similar in PD-L1(+) and PD-L1(-) patients at baseline (5.6 vs. 11.1 months; P = 0.28), but mOS was shorter among PD-L1(+) patients (26.5 vs. 51.6 months; P = 0.045). To evaluate whether targeted therapy affects PD-L1 expression, the authors also compared pre- and post-TKI biopsies in each cohort. Among individual EGFR-mutant patients with paired, pre- and post-TKI biopsies (N = 68), PD-L1 expression levels varied between biopsies in 13 (22%) patients. Among individual ALK-positive patients with pre- and post-TKI biopsies (N = 8), PD-L1 expression levels varied between biopsies in 2 (25%) patients. The authors concluded that EGFR-mutant and ALK-positive lung cancers may express PD-L1 and demonstrate CD8+ TILs. This may underlie the low response rates seen with PD-1 pathway inhibition in never/light smokers. PD-L1 expression is dynamic in a subset of patients with changes in PD-L1 expression and immune infiltrates observed over time and/or following treatment.
