WCLC 2025 - Posters & ePosters-P1.11.63 Shifts of Mutational Signatures Reveal Response Variability to Pembrolizumab-Based Immunotherapy in NSCLC Patients

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This study investigated the dynamic changes in mutational signatures and gene mutations in non-small cell lung cancer (NSCLC) patients undergoing first-line pembrolizumab-based immunotherapy, aiming to identify molecular factors linked to variable treatment responses. Seventy-eight NSCLC patients (median age 67–68 years) received pembrolizumab alone or combined with chemotherapy. Tumor tissues and serial liquid biopsies were collected pre-treatment and during therapy. Targeted next-generation sequencing analyzed mutational profiles over time.<br /><br />Patients were classified as long-responders (progression-free survival [PFS] ≥12 months; n=23) or short-responders (PFS <12 months; n=55). The study revealed distinct patterns of mutational signature shifts between these groups. Notably, the APOBEC-related signature (COS2), linked to activation of AID/APOBEC family enzymes, was predominantly present pre-treatment in long-responders, suggesting an association with durable responses. Conversely, the homologous recombination DNA repair failure signature (COS3) was more common in short-responders and persisted during treatment, potentially contributing to resistance. Additionally, early elimination of TP53 mutations was observed in long-responders, indicating a possible role in sustaining favorable mutational landscapes under pembrolizumab pressure.<br /><br />These findings highlight that tumor evolution under immunotherapy pressure involves dynamic shifts in mutational signatures and key driver mutations, which correlate with clinical outcomes. The study underscores the relevance of specific mutational processes—such as APOBEC activity and DNA repair deficiencies—in shaping response variability. Understanding these adaptive genomic changes may improve prediction of immunotherapy efficacy and guide personalized treatment strategies in NSCLC. The researchers advocate for further exploration of mutational signature dynamics during immune checkpoint inhibitor therapy to better tailor interventions and overcome resistance mechanisms. This work was ethically approved and funded by the Polish National Centre for Research and Development.

Asset Subtitle

Natalia Galant

Meta Tag

Speaker Natalia Galant

Topic Metastatic Non-small Cell Lung Cancer – Immunotherapy

Keywords

non-small cell lung cancer

NSCLC

pembrolizumab

immunotherapy

mutational signatures

APOBEC

homologous recombination DNA repair

TP53 mutations

treatment response

liquid biopsy