Unraveling the nexus: Tumor mutational burden, PD-L1 expression, and oncogenic alterations in non-small cell lung cancer cytology specimens.

[BACKGROUND] PD-L1 expression and tumor mutational burden (TMB) are biomarkers for immune checkpoint inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC); however, patients harboring oncogenic alterations have limited benefit from ICIs. The impact of oncogenic alterations on TMB and PD-L1 tumor proportion score in lung cytology specimens is poorly understood. Herein, the association between oncogenic alterations, TMB, and PD-L1 in NSCLC cytology specimens is explored.

[METHODS] Next-generation sequencing results from 312 NSCLC cytology specimens were retrospectively reviewed that interrogate 610 genes and select immuno-oncology signatures. TMB and PD-L1 immunohistochemical expression across oncogenic alterations were analyzed to explore associations.

[RESULTS] Of the 312 cases evaluated, 192 harbored NSCLC-specific oncogenic alterations. Relative to EGFR-mutated tumors, TMB was significantly higher in KRAS (p = 2.7 × 10), ERBB2 (p = .023), and BRAF (p = .023) -mutated tumors but lower in ALK-rearranged tumors (p = .005). Significantly higher PD-L1 expression was seen in tumors with KRAS (p = .002) and MET exon 14 (p = 1.06 × 10) when compared to EGFR-mutated tumors. Strong positive correlations between TMB and PD-L1 were observed in ERBB2-, KRAS-, and BRAF-mutated tumors when evaluated as continuous variables. TP53 mutations further enhanced immunogenicity when co-occurring with KRAS, ERBB2, or BRAF mutations but this effect was not observed in EGFR-mutated tumors.

[CONCLUSIONS] These findings demonstrate distinct TMB and PD-L1 profiles that may identify patients who will benefit from ICI therapy. Cytology specimens provide adequate material for biomarker testing, which underscores their value in guiding immunotherapy decisions.