Exploring Genomic Biomarkers for Pembrolizumab Response: A Real-World Approach and Patient Similarity Network
Marco Filetti1,2, Mario Occhipinti2,3, Alessio Cirillo2,4
1Phase 1 Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy.
Abstract:
Purpose: Single-agent immune checkpoint inhibitor (IO) therapy is the standard for non-oncogene-addicted advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score ≥ 50%. Smoking-induced harm generates high tumor mutation burden (H-TMB) in smoking patients (S-pts), while never-smoking patients (NS-pts) typically have low TMB (L-TMB) and are unresponsive to IO. However, the molecular characterization of NS-pts with H-TMB remains unclear. Experimental design: Clinical data of 142 aNSCLC patients with PD-L1 ≥ 50% treated with first line pembrolizumab were retrospectively collected. Next-generation sequencing was performed using the FoundationOne®CDx assay to correlate genomic alterations with clinical characteristics and response outcomes. Detected mutations were classified into eleven main pathways and enrichment analysis identified patient subgroups based on mutated pathways. Additionally, a patient similarity network was constructed to analyze molecular characterization. Results were validated using data from 853 aNSCLC patients in POPLAR and OAK trials. Results: Among the patients, S-pts had higher TMB than NS-pts. Interestingly, 11 (8%) NS-pts exhibited H-TMB and were enriched in β-catenin/Wnt and DDR pathway mutations. DDR pathway mutations were confirmed to be enriched in NS-pts with H-TMB using data from POPLAR and OAK trials. In the real-world cohort, the NS/H-TMB subgroup with DDR pathway mutations demonstrated improved IO outcome. Patient similarity network analysis confirmed the clustering of NS/H-TMB patients with DDR mutations and their association with improved overall survival in both the real-world cohort and the trials. Conclusions: The DDR signature has a potential role as an additional generator of H-TMB in NS-pts. This subgroup of IO-responsive NS-pts may have better prognosis. Our findings suggest that DDR-based mutational profiling may help identify NS-pts who could benefit from IO therapy.
Insights
Never-smoking patients with advanced non-small cell lung cancer and high tumor mutation burden (H-TMB) may benefit from immune checkpoint inhibitor (IO) therapy if they have DNA Damage Response (DDR) pathway mutations. This finding could guide personalized treatment strategies.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Immune checkpoint inhibitor (IO) therapy is standard for advanced non-small cell lung cancer (aNSCLC) with PD-L1 ≥ 50%.
- Smoking is linked to high tumor mutation burden (H-TMB) and response to IO, while never-smoking patients (NS-pts) often have low TMB (L-TMB) and poor response.
- The molecular basis for H-TMB in NS-pts and their response to IO remains unclear.
Purpose of the Study:
- To investigate the molecular characteristics of never-smoking patients (NS-pts) with advanced non-small cell lung cancer (aNSCLC) who exhibit high tumor mutation burden (H-TMB).
- To identify potential genomic biomarkers predictive of response to immune checkpoint inhibitor (IO) therapy in this specific patient subgroup.
- To explore the role of DNA Damage Response (DDR) pathway mutations in generating H-TMB and influencing IO outcomes in NS-pts.
Main Methods:
- Retrospective analysis of 142 aNSCLC patients treated with first-line pembrolizumab, with PD-L1 ≥ 50%.
- Next-generation sequencing (FoundationOne®CDx) to assess genomic alterations and correlate with clinical data and treatment outcomes.
- Pathway enrichment analysis and patient similarity network construction, validated with data from POPLAR and OAK trials (853 patients).
Main Results:
- Never-smoking patients (NS-pts) with high tumor mutation burden (H-TMB) were identified (8% of NS-pts).
- H-TMB in NS-pts was enriched in DNA Damage Response (DDR) and β-catenin/Wnt pathway mutations.
- The NS-pts subgroup with H-TMB and DDR mutations showed improved outcomes with IO therapy in both real-world and trial data.
Conclusions:
- DNA Damage Response (DDR) pathway mutations may contribute to H-TMB in never-smoking patients (NS-pts).
- A subset of NS-pts with H-TMB and DDR mutations demonstrates responsiveness to immune checkpoint inhibitor (IO) therapy.
- DDR-based mutational profiling could identify NS-pts who may benefit from IO therapy, potentially improving prognosis.
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