Characterization of histology-dependent immunobiological differences in metastatic NSCLC: Implications for treatment with PD-1 and LAG-3 inhibitors.

Abstract

8526 Background: The treatment paradigm for metastatic non-small cell lung cancer (mNSCLC) without actionable genomic alterations does not differentiate between histologic subtypes for the use of checkpoint inhibitors. However, there is growing recognition of differences between squamous (SQ) and non-squamous (NSQ) lung cancer that may impact response to treatment. For example, in the RELATIVITY-104 study, addition of the LAG-3 inhibitor relatlimab to anti-PD-1 + platinum-doublet chemotherapy (PDCT) showed improved clinical benefit among patients with PD-L1 ≥1%, which was further enriched with NSQ histology. There is an unmet need to understand differences in tumor biology between NSQ and SQ histologies in patients with mNSCLC to inform on mechanisms underlying differences in clinical activity of anti-PD-1 + PDCT, alone or in combination with a LAG-3 inhibitor. Methods: Data were obtained from molecular profiling of baseline tumor samples of treatment-naive patients enrolled in the phase 3 CheckMate 227 (NCT02477826) study. PD-L1 (N=1739) and LAG-3 expression (N=540) were evaluated using immunohistochemistry. Somatic mutations and copy number alterations were assessed using the FoundationOne panel (N=1368). Gene expression, analyzed through RNA sequencing (N=465), was used to characterize differences in tumor immunobiology, including differential gene expression, pathway enrichment, and calculation of cell type-specific scores representing different immune and stromal cell types. Results: Transcriptional and mutational analyses revealed clear differences between NSQ and SQ tumors. NSQ tumors showed enrichment of immune pathways (e.g., antigen presentation and T cells), while SQ tumors exhibited enrichment of pathways consistent with rapid cell growth and numerous oncogenic alterations (e.g., p53 and PIK3CA). Differences in the relationship between tumor PD-L1 expression and the tumor microenvironment by histology were observed; PD-L1 expression was positively correlated with immune infiltration scores in NSQ but not SQ tumors, suggesting that drivers of PD-L1 expression may differ by histology. Consistent with previously published reports for mNSCLC, PD-L1 expression enriched for 1L anti-PD-1 + PDCT benefit in NSQ but not SQ tumors (CheckMate 227 Part 2). Differences in LAG-3 ligand expression by histology and PD-L1 expression were noted. Both canonical LAG-3 ligands, MHC-II and FGL-1, were expressed at higher levels in NSQ tumors. Within NSQ tumors, relative expression of each ligand varied by PD-L1 expression, with high MHC-II expression specifically in NSQ, PD-L1 ≥1% tumors. Conclusions: These data provide a supporting mechanistic rationale for the use of tumor histology in addition to PD-L1 expression to identify patients who would benefit from the addition of a LAG-3 inhibitor to PD-1 inhibitor + PDCT. Clinical trial information: NCT02477826 .