Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing
Pedro Rocha1,2, Rafael Bach1, Laura Masfarré1
1Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
Introduction:
Immunotherapy is firmly established as a treatment regimen in various solid tumors, driven by its exceptional benefits in a selected group of patients. Despite widespread adoption of immune checkpoint blockade (ICB) across diverse solid tumors, the quest for a clinically informative biomarker for long-term benefit remains unmet.
Methods:
A total of 49 patients with metastatic NSCLC treated with ICB were included. Long-term (LTR) and short-term responders (STR) were defined as those with a response to ICB lasting more than 24 months or less than 6 months, respectively. Longitudinal blood specimens were collected before ICB treatment initiation and early-on treatment. Plasma ctDNA next-generation sequencing panel (NGS) and serum proteomics were performed. GeoMx DSP on baseline tumor tissue was performed in a subset of patients.
Results:
Our analysis revealed specific characteristics of LTR compared with STR, namely higher PD-L1 in tumor cells (p = 0.005) and higher incidence of irAEs (p = 0.001). Genomic features associated with lack of benefit from ICB included co-occurring mutations in KRAS/STK11 and TP53/KMT2D (p < 0.05). At a baseline, LTR patients exhibited higher serum levels of proteins related with apoptosis (CASP8, PRKRA), chemotaxis, immune proteasome, processing of MHC class I (S100A4, PSMD9, RNF41) and immune homeostasis (HAVCR1, ARG1) (p < 0.05). Protein spatial profiling of tumor samples showed higher levels of proteins linked with the presence of immune cells (CD45), T cells (CD8), antigen presentation (HLA-DR) and immune regulation proteins (PD-L1, IDO1) within the tumor and tumor stroma component (p < 0.05) in LTR patients. Serum longitudinal analysis identified a set of proteins that presented distinct dynamics in LTR compared to STR, making them interesting candidates to evaluate as early predictors of treatment efficacy.
Conclusions:
Our multimodal analysis of patients with metastatic NSCLC treated with ICB identified clinicopathological and immunological features associated with long-term benefits. The presence of preexisting antitumor immunity emerged as a strong predictor of long-term benefits, providing insights for potential biomarkers and therapeutic strategies for enhancing ICB outcomes in metastatic NSCLC.
Insights
Identifying biomarkers for long-term benefit in immune checkpoint blockade (ICB) for metastatic non-small cell lung cancer (NSCLC) is crucial. Preexisting antitumor immunity, indicated by specific proteins and immune cell markers, predicts long-term response to ICB in NSCLC patients.
Area of Science:
- Oncology
- Immunology
- Genomics
- Proteomics
Background:
- Immune checkpoint blockade (ICB) offers significant benefits in various solid tumors, including metastatic non-small cell lung cancer (NSCLC).
- However, a reliable biomarker to predict long-term response to ICB remains elusive, hindering optimal treatment selection.
Purpose of the Study:
- To identify clinicopathological, genomic, and proteomic features associated with long-term response (LTR) versus short-term response (STR) to ICB in metastatic NSCLC.
- To explore potential biomarkers for predicting long-term benefit from ICB therapy.
Main Methods:
- Analysis of 49 metastatic NSCLC patients treated with ICB, categorizing responders into LTR (>24 months) and STR (<6 months).
- Plasma ctDNA next-generation sequencing (NGS), serum proteomics, and GeoMx digital spatial profiling (DSP) on tumor tissue were performed.
- Longitudinal blood specimens were collected pre-treatment and early during treatment.
Main Results:
- LTR patients showed higher PD-L1 expression and incidence of immune-related adverse events (irAEs).
- Genomic analysis revealed that co-occurring KRAS/STK11 and TP53/KMT2D mutations were associated with lack of ICB benefit.
- Baseline serum proteomics and spatial profiling identified elevated levels of immune-related proteins (e.g., apoptosis, chemotaxis, MHC class I processing, immune homeostasis markers) and immune cell infiltration (CD45, CD8, HLA-DR) in LTR patients.
Conclusions:
- Multimodal analysis identified clinicopathological and immunological features predicting long-term ICB benefit in metastatic NSCLC.
- The presence of pre-existing antitumor immunity is a strong predictor of long-term response.
- These findings offer insights into potential biomarkers and strategies to enhance ICB efficacy in NSCLC.
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