Heterogeneity of EGFR-mutant and PD-L1 high-expressing clones affects treatment efficacy of EGFR-TKI and PD-1 inhibitor

Abstract

Background: Current clinical trials have suggested poor efficacies of PD-1 inhibitors for NSCLC harboring EGFR mutations. However, in EGFR-mutant NSCLC, PD-1 blockade is not always ineffective and there is controversy about predictivity of PD-L1 expression on the effect of PD-1 inhibitors. Here we showed a patient with PD-L1 highly-expressing EGFR-mutant NSCLC who responded dramatically to pembrolizumab but not to erlotinib. Case Presentation: A 62-year-old woman presented to our hospital complaining of gait disturbance due to right hip pain. A computed tomography (CT) scan revealed a 65mmmass in the right ilium and a nodule in the right lung. CT-guided biopsy showed the right iliac mass was metastasis from lung adenocarcinoma. EGFR exon 19 deletion was detected and PD-L1 TPS was 90%. Radiotherapy of 30Gy to the right ilium and 150mg erlotinib were started. Follow-up CT performed 2 months later detected multiple new metastases and CT-guided biopsy of the right chest wall metastasis was performed. Biomarker screening detected no EGFR mutations and 95% PD-L1 TPS. Pembrolizumab was administered as the second line therapy. CT after 3 cycles of pembrolizumab showed complete disappearance of primary lesion and multiple metastases. Immunofluorescent analysis of both right ilium and chest wall lesions with an anti- EGFR antibody specific to exon 19 deletion and an anti-PD-L1 antibody revealed the presence of distinct heterogeneity of EGFR-mutant and PD-L1 highly-expressing clones. Conclusion(s): Immunofluorescent analysis could successfully distinguish EGFR-mutant clones and PD-L1 highly-expressing clones in this case. Although PD-1 blockade therapy is suggested to have generally low efficacy to EGFR-mutant NSCLC, the analysis of clonal heterogeneity is critical for therapeutic decision making. Detailed pathological analysis may enable it possible to deliver efficacious PD-1 blockade therapy regardless of EGFR mutation profile.