Abstract A124: Beyond PD-L1: Unraveling the enigma of immunotherapy response in PD-L1 negative (&lt;1%) NSCLC patients through quantification of PD-1/PD-L1 engagement in the tumor microenvironment
Authors: Gumuzio Juan , Calleja Veronique , Miles James , Sancehz-Magraner Lissete , Aguirre Fernando 
Published: December 2023

Profound advances in cancer patient treatments have come with the advent of immunotherapies directed at blocking immune-suppressive ligand-receptor interactions. However, while there has been success in the use of these immune checkpoint interventions, there has been limited success in stratifying patients for these interventions with response rates at approximately 14%.To address this issue of patient stratification, we have determined the extent of the molecular target, intercellular PD-1/PD-L1 interaction, in formalin-fixed paraffin embedded tumor samples from non–small cell lung carcinoma patients, using a high-throughput automated quantitative imaging platform (QF-Pro®). The multi-site blinded analysis across a cohort of 188 IO-treated patients (treated with nivolumab, pembrolizumab, atezolizumab or durvalumab) demonstrated the intra- and inter-tumoral heterogeneity of the PD-1/PD-L1 immune checkpoint engagement and notably showed no correlation between the extent of PD-1/PD-L1 interaction and PD-L1 expression (rs=0.05, P=0.55). Importantly, PD-L1 expression scores used clinically to stratify the patients, correlated poorly with overall survival. By contrast, patients showing a high PD-1/PD-L1 interaction had significantly better responses to anti-PD-1/PD-L1 treatments, as evidenced by increased OS (median 31 months vs 10 months). This relationship was particularly strong in the setting of first line treatments. Even more critically, in a subset of patients determined as being PD-L1 negative (PD-L1 TPS &lt;1%), response to treatment was still observed in those patients with PD-1/PD-L1 interactions (median &gt;60 months vs 14 months). This therefore may yield a mechanism to successfully treat those patients who, under current guidelines, are not be considered for these therapies, despite the therapeutic target existing within their tumor microenvironment. In conclusion using the functional read out of this immune checkpoint engagement (PD-1/PD-L1 interaction) as a predictive biomarker for the stratification of NSCLC patients instead of PD-L1 expression should significantly improve the response rates to immunotherapy. This would both capture patients excluded from checkpoint immunotherapy (high PD-1/PD-L1 interaction but low PD-L1 expression, 24% of patients), and additionally avoid the treatment of patients resistant to this type of treatment (low PD-1/PDL1 interaction but high PD-L1 expression) who may benefit- from alternative cancer therapeutics, such as other immunotherapies. Even at this early stage, QF-Pro® has set an unbiased quantitative cut-off to be considered for anti-PD-1/PD-L1 therapies which can be deployed directly into clinical practice.

Citation Format: Juan Gumuzio, Veronique Calleja, James Miles, Lissete Sancehz-Magraner, Fernando Aguirre. Beyond PD-L1: Unraveling the enigma of immunotherapy response in PD-L1 negative (&lt;1%) NSCLC patients through quantification of PD-1/PD-L1 engagement in the tumor microenvironment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A124.