Change in PD-L1 Expression After Acquiring Resistance to Gefitinib in EGFR-Mutant Non-Small-Cell Lung Cancer

Selecting patients for anti-programmed cell death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) immunotherapy by PD-L1 expression is an important issue in lung cancer. By comparing paired biopsies from patients with EGFR-mutant nonesmall-cell lung cancer (NSCLC), we found that PD-L1 expression in tumor cells markedly increased in a subset of patients after resistance to gefitinib had developed. In addition, in vitro study results suggest that some resistant mechanisms are involved in PD-L1 overexpression in gefitinibresistant NSCLC cells. Our findings suggest that repeat biopsy should be considered when using PD-L1 expression as a biomarker after EGFR inhibitor therapy. Introduction: Therapies targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) have been successful in a subset of patients with nonesmall-cell lung cancer (NSCLC). PD-L1 expression in tumor tissues has been suggested as a predictive and prognostic marker. We examined the change in PD-L1 expression after gefitinib in patients with EGFR-mutant NSCLC. Materials and Methods: Paired tumor tissues were collected before and after gefitinib from 18 patients. PD-L1 expression on the tumor and immune cells was defined by the H-score of immunohistochemical staining (range, 0-300). The correlations between the change in PD-L1 expression and clinicopathologic characteristics were analyzed. Results: PD-L1 expression on tumor cells showed an increase in the median H-score from 25 to 40 (P = .067). Of the 18 patients, 7 (38.9%) had a marked increase in the median H-score (range, 80-180; group A) and 11 (61.1%) had no change in themedian H-score (0 for both scores; group B). In groups A and B, themedian progression-free survival for gefitinib was 13 and 12 months (P = .594), and the median overall survival was "not reached" and 38 months (P = .073), respectively. MET positivity by immunohistochemistry in biopsies after gefitinib therapy was significantly associated with group A (P = .028). The PD-L1 H-score by immunohistochemistry, but not by tumor cells, showed correlations with other immune cells; FOXP3(+) expression in biopsies before gefitinib use, and PD-1(+) and CD3(+) in biopsies after gefitinib therapy, respectively. Conclusion: PD-L1 expression in tumor cells markedly increased in a subset of patients after gefitinib treatment. Thus, rebiopsy should be considered when using PD-L1 expression as a biomarker.