3MO - Comprehensive biomarkers (BMs) analysis to predict efficacy of PD1/L1 immune checkpoint inhibitors (ICIs) in combination with chemotherapy: a subgroup analysis of the Precision Immuno-Oncology for advanced Non-Small CEll Lung CancER (PIONeeR) trial

Background

Prediction of ICIs efficacy in combination with chemotherapy remains an unmet need in patients (pts) with advanced NSCLC. The PIONeeR trial aims to predict response/resistance to PD1/L1 ICIs through a comprehensive multiparametric BMs analysis.

Methods

We focused on the first 155 ECOG PS0-1 pts treated with pembrolizumab in combination with platinum-based chemotherapy as 1^st line therapy. Tumor tissue was collected at baseline and pts were re-biopsied at 6 weeks, and blood-sampled every cycle throughout 24 weeks. Immune contexture was characterized in tumor & blood through FACS for circulating immune cell subtypes quantification and endothelial activation, blood soluble factors dosage, dual- & multiplex IHC / digital pathology to quantify immune cells infiltrating the tumor, WES for TMB & ICI plasma pharmacokinetics, leading to 298 assessed BMs. Multimodal data integration through supervised machine learning (SML) was performed with bootstrap LASSO on a train (N=116) and a test dataset (N=39) to establish a BMs signature able to predict progression-free-survival (PFS) at 1 year.

Results

Pts were mainly male (65%), smokers (96%) and <70yrs (82%). Tumors were mainly nonsquamous (87%) with PD-L1 TPS>1% in 38.4% of cases. With a median follow of 11.4 months, median PFS was 9.8 months and median overall survival was not reached. Using baseline data, SML identified a 15 BMs signature including classical (age, ECOG PS, PD-L1 TPS…) but also experimental parameters (CD45+ CD16+ cells density in tumor, CD45- CD73+ cells density in stroma, tissue factor and CD31+ CD41+ AnC+ microparticles blood concentrations…) with high predictive performance for PFS. On the train dataset, C-index was 0.79±0.13 and AUC was 0.81±0.28. These scores were confirmed on the test dataset, with C-index of 0.80 and AUC of 0.84.

Conclusions

The PIONeeR trial provides a novel comprehensive BMs analysis to establish predictive models of response/resistance to ICI in advanced NSCLC pts. Combination of BMs can individually predict outcomes of chemo-immunotherapy.

Clinical trial identification

NCT03493581.

Legal entity responsible for the study

Assistance Publique des Hôpitaux de Marseille.

Funding

French National Research Agency.

Disclosure

F. Monville, L. Ghezali, J. Fieschi-Meric: Financial Interests, Personal, Full or part-time Employment: Veracyte. All other authors have declared no conflicts of interest.