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WCLC 2025 | Biomarkers of ICI response in oncogene-negative never-smoker NSCLC
Biagio Ricciuti, MD, Dana-Farber Cancer Institute, Boston, MA, comments on findings from a multicenter analysis of patients with metastatic, oncogene driver-negative non-small cell lung cancer (NSCLC) without prior tobacco use who received immune checkpoint inhibitors. Outcomes were associated with PD-L1 expression, tumor mutational burden, and tumor-infiltrating lymphocyte density. Patients with both high PD-L1 and elevated tumor mutational burden achieved the most favorable responses, particularly when treated with dual checkpoint blockade. These results support biomarker-driven personalization of immunotherapy in this distinct patient subgroup. This interview took place at 2025 World Conference on Lung Cancer (WCLC) in Barcelona, Spain.
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Transcript
This is a work presented by a very talented research fellow working in our group called Eleonora Gariazzo. She focuses on this question because today for patients who have never smoked in their life, oftentimes the standard of care is a targeted therapy because these patients are enriched for targetable genomic drivers. But there is a large fraction of patients who have never smoked who do not have any actionable drivers and so that’s a challenging population...
This is a work presented by a very talented research fellow working in our group called Eleonora Gariazzo. She focuses on this question because today for patients who have never smoked in their life, oftentimes the standard of care is a targeted therapy because these patients are enriched for targetable genomic drivers. But there is a large fraction of patients who have never smoked who do not have any actionable drivers and so that’s a challenging population. For these patients, ultimately, the standard of care remains immunotherapy with or without chemotherapy. And we were interested in learning who are the patients that do eventually respond to these therapies despite being never smokers. We do know that patients who have never smoked tend to have a low response rate to immunotherapy, but some of them do respond and it’s critical for us to understand who those patients are. And in this study, what we identified is that PD-1 expression again or mutational burden, which usually do not work as well as we would hope in patients with oncogene drivers, for example, are still predictive of benefit, but we really need very high levels of PD-L1, 90% or greater, or mutational burden, higher than the 90th percentile, for example, of mutational burden. These tumor markers can help us identify patients who respond. Interestingly, we also did note in the study specifically that using dual immunotherapy with PD-L1 blockade in combination with chemotherapy and CTLA-4 blockade was the treatment that resulted in the longest progression-free survival in this population, suggesting that in the subset of patients we might need to consider this approach. Again, this is a study that is retrospective in nature, but it highlights how these patients could potentially benefit from immunotherapy, but we really need to understand better biomarkers of response in this population. Something that is very exploratory is the immunophenotype. We have learned through this study, for example, that the density of CD8-positive T cells, for example, correlates with better outcomes. And so those are additional findings that support the idea that a fraction of these patients might have variable biomarkers that can ultimately produce also long-term survival benefits.
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