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WCLC 2025 | Elucidating the predictive roles of PD-L1 TPS in NSCLC histologies
Valentina Santo, MD, Dana-Farber Cancer Institute, Boston, MA, discusses the predictive value of PD-L1 tumor proportion score (TPS) in advanced non-small cell lung cancer, (NSCLC) with a focus on squamous versus non-squamous subtypes. Data from over 5,000 patients treated with immune checkpoint inhibitors with or without chemotherapy indicate that increasing PD-L1 levels are associated with stepwise improvements in survival for non-squamous disease, while in squamous histology, TPS functions mainly as a dichotomous marker. Distinct immune and genomic profiles further support the need for histology-specific biomarker strategies. This interview took place at 2025 World Conference on Lung Cancer (WCLC) in Barcelona, Spain.
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Transcript
Yes, of course. So based on previous evidence showing a weaker predictive performance of PD-L1 tumor proportional score in squamous histology compared to non-squamous from both randomized clinical trial and real-world data, we performed histology-stratified analysis on a large multicenter cohort of patients with advanced non-small cell lung cancer treated with ICI-based therapy...
Yes, of course. So based on previous evidence showing a weaker predictive performance of PD-L1 tumor proportional score in squamous histology compared to non-squamous from both randomized clinical trial and real-world data, we performed histology-stratified analysis on a large multicenter cohort of patients with advanced non-small cell lung cancer treated with ICI-based therapy. First of all, our results show a clear stepwise association between increasing PD-L1 TPS categories and improved survival outcome in non-squamous histology. In contrast, in squamous non-small cell lung cancer, the predictive value of PD-L1 tumor proportional score was limited to a dichotomous cutoff, with survival benefit observed only when comparing PD-L1 negative and PD-L1 positive tumors, but not across a higher level of PD-L1 expression. Then we focus on the tumor microenvironment and we observe that squamous tumors in our cohort displayed a lower density of a key immune cell subset, suggesting a more immunosuppressive tumor microenvironment in squamous tumors compared to non-squamous. Moreover, there was no correlation between PD-L1 expression and immune cell density in squamous histology in contrast to non-squamous. Finally, we performed a genomic analysis in our squamous cohort that highlighted Notch1 mutation as a potential predictor of immunotherapy efficacy in this histology. In fact, in our cohort, a patient with Notch1 mutation was associated with improved, significantly improved progression-free survival and overall survival, even after adjustment for potential confounders. In conclusion, our findings highlight that PD-L1 tumor proportional score was limited to guide clinical decision in squamous histology and also highlight the need for histology-specific biomarker strategies that can integrate genomic, clinical, and immune features in order to optimize patient selection for immunotherapy in this challenging disease and guide the design of future clinical trials.
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