A multiparametric approach to improve the prediction of response to immunotherapy in patients with metastatic NSCLC

Abstract

Background It is still unclear how to combine biomarkers to identify patients who will truly benefit from anti-PD-1 agents in NSCLC. This study investigates exosomal mRNA expression of PD-L1 and IFN-γ, PD-L1 polymorphisms, tumor mutational load (TML) in circulating cell-free DNA (cfDNA) and radiomic features as possible predictive markers of response to nivolumab and pembrolizumab in metastatic NSCLC patients. Methods Patients were enrolled and blood (12 ml) was collected at baseline before receiving anti-PD-1 therapy. Exosome-derived mRNA and cfDNA were extracted to analyse PD-L1 and IFN-γ expression and tumor mutational load (TML) by digital droplet PCR (ddPCR) and next-generation sequencing (NGS), respectively. The PD-L1 single nucleotide polymorphisms (SNPs) c.-14-368 T > C and c.*395G > C, were analysed on genomic DNA by Real-Time PCR. A radiomic analysis was performed on the QUIBIM Precision® V3.0 platform. Results Thirty-eight patients were enrolled. High baseline IFN-γ was independently associated with shorter median PFS (5.6 months vs. not reached p = 0.0057), and levels of PD-L1 showed an increase at 3 months vs. baseline in patients who progressed (p = 0.01). PD-L1 baseline levels showed significant direct and inverse relationships with radiomic features. Radiomic features also inversely correlated with PD-L1 expression in tumor tissue. In subjects receiving nivolumab, median PFS was shorter in carriers of c.*395GG vs. c.*395GC/CC genotype (2.3 months vs. not reached, p = 0.041). Lastly, responders had higher non-synonymous mutations and more links between co-occurring genetic somatic mutations and ARID1A alterations as well. Conclusions A combined multiparametric approach may provide a better understanding of the molecular determinants of response to immunotherapy.

23 Validation of PD-L1 dynamic expression on extracellular vesicles as a predictor of response to immune-checkpoint inhibitors and survival in non-small cell lung cancer patients

“…4 5 Extracellular vesicles (EVs) are cell-derived structures involved in cell communication and represent a potential minimally invasive alternative to predicting ICI response. [6][7][8][9] Based on this and our preliminary results presented at SITC 2020, 10 we hypothesize that EV PD-L1 predicts response to ICIs in NSCLC. Methods This study evaluates an exploratory cohort of advanced/metastatic NSCLC patients receiving ICIs (cohort A) and a validation cohort receiving Pembrolizumab+docetaxel or docetaxel alone (PROLUNG Phase 2 randomized trial) (cohort B).…”

A deep look into radiomics

“…Ultrasound techniques have also been exploited for radiomics analysis in predicting breast cancer [77]. Radiomics is also expected to increasingly affect the clinical practice of treatment of lung tumors [78,79]. A myriad of new radiomicsbased evidence for lung cancer has been published [80,81].…”

Current Landscape and Future Directions of Biomarkers for Immunotherapy in Hepatocellular Carcinoma

“…Recently, in a study with metastatic non-small cell lung cancer patients, the multiparametric analysis gave a better diagnostic performance than single parameters like radiomic signature, PD-L1, or IFN-γ expression regarding clinical response, sensitivity, and specificity. 61 In another interesting study, an astronomical algorithm was applied to multiplex immunofluorescence labeling of pathology specimens to establish spatial relationships between tumor cells and multiple immune elements and immunoarchitectural characterization of the tumor. 62 With only six markers, they identified key features in pretreatment melanoma specimens that predicted response to immunotherapy, suggesting that this approach might give more accuracy regarding treatment response prediction than individual IHC markers like PD-L1 expression.…”