American Association for Cancer Research
Browse
ccr-23-4027_supplementary_table_s5_suppts5.pdf (78.48 kB)

Supplementary Table S5 from Combining Genomic Biomarkers to Guide Immunotherapy in Non–Small Cell Lung Cancer

Download (78.48 kB)
journal contribution
posted on 2024-04-01, 07:22 authored by 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

Baseline characteristics of patients in the validation cohort, stratified by the TMB and STK11/KEAP1/EGFR alteration status.

Funding

ZonMw (Netherlands Organisation for Health Research and Development)

Oncode Institute

Josephine Nefkens Foundation

History

ARTICLE ABSTRACT

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. 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). 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. 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.

Usage metrics

    Clinical Cancer Research

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC