A multiparametric approach to improve the prediction of response to immunotherapy in patients with metastatic NSCLC
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ORIGINAL ARTICLE
A multiparametric approach to improve the prediction of response to immunotherapy in patients with metastatic NSCLC Marzia Del Re1 · Federico Cucchiara1 · Eleonora Rofi1 · Lorenzo Fontanelli1 · Iacopo Petrini2 · Nicole Gri3 · Giulia Pasquini2 · Mimma Rizzo3 · Michela Gabelloni4 · Lorenzo Belluomini5 · Stefania Crucitta1 · Raffaele Ciampi6 · Antonio Frassoldati5 · Emanuele Neri4 · Camillo Porta3,7,8 · Romano Danesi1 Received: 2 July 2020 / Accepted: 23 November 2020 © The Author(s) 2020
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. Exosomederived 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. Keywords NSCLC · Liquid biopsy · Biomarkers · Radiomics · Immunotherapy Abbreviations ACTB Human β-actin ARID1A AT-Rich Interaction Domain 1A bp Base pair
Romano Danesi and Camillo Porta co-last authorship of this manuscript. Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s0026 2-020-02810-6. * Romano Danesi [email protected] Extended author information available on the last page of the article
c.*395G > C 395 Nucleotides downstream of the stop codon guanine to cytosine substitution c.-14-368 T > G Intron nucleotides upstream of the start codon thymine to guanine substitution CBR Clinical benefit rate cfDNA Circulating cell-free DNA CR Complet
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