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

Abstract

Purpose: The clinical value of STK11, KEAP1 and EGFR 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. Experimental design: To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 NSCLC patients treated with PD-(L)1 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 STK11/KEAP1,EGFR alterations for ICB unresponsiveness was assessed in the contexts of a low (<10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB). Results: In low TMB cases, STK11,KEAP1,EGFR 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 STK11,KEAP1,EGFR alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free and overall survival. Conclusions: The unexpected ICB responses in patients carrying resistance biomarkers in STK11, KEAP1 and EGFR were almost exclusively observed in patients with a high TMB. Considering these alterations in the context the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.

The Causal Effect of Gut Microbiota and Plasma Metabolome on Lung Cancer and the Heterogeneity across Subtypes: A Mendelian Randomization Study

“…SCC, on the other hand, often arises from chronic inflammation and tobacco exposure, leading to frequent TP53 mutations and chromosomal instability. While SCC treatment typically involves surgery, radiation, and chemotherapy, targeted therapies have been less successful compared to LUAD [6,7]. An increasing number of studies have unveiled subtype-specific biomarkers and therapeutic targets, emphasizing the importance of personalized treatments tailored to each patient's tumor characteristics [8].…”