Data from Combining Genomic Biomarkers to Guide Immunotherapy in Non–Small Cell Lung Cancer

• DOI: 10.1158/1078-0432.c.7158235
• Publication Date: 2024-04-01T07:24:00Z
• Authors: Joris van de Haar; Joanne M. Mankor; Karlijn Hummelink; Kim Monkhorst; Egbert F. Smit; Lodewyk F.A. Wessels; Edwin Cuppen; Joachim G.J.V. Aerts; Emile E. Voest

<div>AbstractPurpose:<p>The clinical value of <i>STK11</i>, <i>KEAP1</i>, and <i>EGFR</i> alterations for guiding immune checkpoint blockade (ICB) therapy in non–small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease.</p>Experimental Design:<p>To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing. The specificity of <i>STK11</i>/<i>KEAP1</i>/<i>EGFR</i> alterations for ICB unresponsiveness was assessed in the contexts of a low (<10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB).</p>Results:<p>In low TMB cases, <i>STK11</i>/<i>KEAP1</i>/<i>EGFR</i> alterations were highly specific biomarkers for ICB resistance, with 0/15 (0.0%) and 1/34 (2.9%) biomarker-positive patients showing treatment benefit in the discovery and validation cohorts, respectively. This contrasted with high TMB cases, where 11/13 (85%) and 15/34 (44%) patients with at least one <i>STK11</i>/<i>KEAP1</i>/<i>EGFR</i> alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free survival and overall survival.</p>Conclusions:<p>The unexpected ICB responses in patients carrying resistance biomarkers in <i>STK11</i>, <i>KEAP1</i>, and <i>EGFR</i> were almost exclusively observed in patients with a high TMB. Considering these alterations in context of the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.</p></div>