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

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

van de Haar, Joris (Netherlands Cancer Institute)
Mankor, Joanne M. (Erasmus MC)
Hummelink, Karlijn (Netherlands Cancer Institute)
Monkhorst, Kim (Netherlands Cancer Institute)
Smit, Egbert F. (Leiden University Medical Center)
Wessels, L.F.A. (TU Delft Pattern Recognition and Bioinformatics; Netherlands Cancer Institute)
Cuppen, Edwin (Netherlands Cancer Institute; University Medical Center Utrecht; Hartwig Medical Foundation)
Aerts, Joachim G.J.V. (Erasmus MC)
Voest, Emile E. (Netherlands Cancer Institute; Center for Personalized Cancer Treatment)

2024

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 patients with NSCLC treated with ligand 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 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 survival 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 context, the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.

http://resolver.tudelft.nl/uuid:495d699a-0297-40d1-9527-fb7954a9f69d

https://doi.org/10.1158/1078-0432.CCR-23-4027

1078-0432

Clinical Cancer Research, 30 (7), 1307-1318

Institutional Repository

journal article

© 2024 Joris van de Haar, Joanne M. Mankor, Karlijn Hummelink, Kim Monkhorst, Egbert F. Smit, L.F.A. Wessels, Edwin Cuppen, Joachim G.J.V. Aerts, Emile E. Voest