Integrating Clinical and Biological Prognostic Biomarkers in Patients With Advanced NSCLC Treated With Immunotherapy

The DEMo Score System

Arsela Prelaj; Claudia Proto; Giuseppe Lo Russo; Diego Signorelli; Roberto Ferrara; Mavis Mensah; Giulia Galli; Alessandro De Toma; Giuseppe Viscardi; Marta Brambilla; Riccardo Lobefaro; Benedetta Trevisan; Francesco Trovò; Valter Torri; Gabriella Sozzi; Marina Chiara Garassino; Mattia Boeri


Transl Lung Cancer Res. 2020;9(3):617-628. 

In This Article

Abstract and Introduction


Background: Several biomarkers have been separately described to select patients for immunotherapy (IO), but few studies integrate these markers. Di Maio, EPSILoN and the plasma microRNA signature classifier (MSC), are three different clinico, biochemical and molecular markers able to independently predict prognosis in non-small cell lung cancer (NSCLC).

Methods: Complete data such as sex, histology, ECOG-PS, stage, smoking status, presence of liver metastasis, LDH and neutrophils-to-lymphocyte ratio were collected to generate Di Maio and EPSILoN. The MSC risk level was prospectively assessed in plasma samples collected at baseline IO. The 3 markers were integrated into the DEMo score system prospectively tested in a cohort of 200 advanced NSCLC patients treated with IO. Endpoints were overall survival (OS), progression-free survival (PFS) and overall response rate (ORR).

Results: DEMo separated patients in 7-risk groups whose median OS had a trend ranging from 29.7 to 1.5 months (P<0.0001). When comparing patients with the lowest (n=29) and the highest (n=35) DEMo scores ORR was 45% and 3%, respectively (P<0.0001). Considering the 53 PD-L1 ≥50% patients, DEMo identified a group of 13 (25%) patients who benefit less from IO in terms of both OS (HR: 8.81; 95% CI: 2.87–20.01) and PFS (HR: 6.82; 95% CI: 2.57–18.10). Twelve out of 111 (11%) patients who most benefit from IO according to OS (HR: 0.21; 95% CI: 0.07–0.62) and PFS (HR: 0.28; 95% CI: 0.12–0.65) were identified by DEMo in the PD-L1 <50% group.

Conclusions: The DEMo prognostic score system stratified NSCLC patients treated with IO better than each single marker. The proper use of DEMo according to PD-L1 could improve selection in IO regimens.


Despite the improvement in overall survival (OS) of unselected advanced non-small cell lung cancer (NSCLC) patients treated with the immunotherapy (IO), biomarkers able to identify ideal candidate patients with adequate accuracy remain an unmet need. Continuous changes of the IO suggestion scenery, moving from second or further to first-line therapy or from single agent to the combination therapy with other companions [IO + chemotherapy (CHT), IO + CHT + bevacizumab or IO + IO], are among the main delay causes on finding the optimal biomarkers.[1–8]

Up to today, the expression of the programmed-death ligand one (PD-L1) on tumor cells by immunohistochemistry (IHC) is the only approved biomarker. Indeed, despite patients expressing high levels of PD-L1 (≥50%) respond better to IO, some of them do not benefit from single agent IO. Conversely, a subgroup of patients with low PD-L1 (1–49%) still may benefit from IO alone, thus avoiding the toxicity added by other possibly companions such as chemotherapy. Another aspect includes the possibility to identify subjects with a non-negligible risk of early clinical failure (ICF) or hyper-progressive disease independently of PD-L1 expression.[4–8]

According to literature, many attempts to discover predictive biomarkers outside PD-L1 have been made so far. The tumour mutation burden, CD8-positive tumour-infiltrating lymphocytes and immune gene signatures showed promising results as tissue biomarkers.[9] However, tumor heterogeneity and the difficulties to obtain adequate tissue samples from aNSCLC patients, prompt for the use of scores systems based on clinical information or circulating biochemical and molecular factors. In this respect, markers such as the Lung Immune Prognostic Index (LIPI), based on the lactate dehydrogenase (LDH) levels and neutrophil-to-lymphocyte ratio (NLR), were created and associated with clinical outcome in IO settings.[10,11] By adding information about the Eastern Cooperative Oncology Group Performance Status (ECOG-PS), sex, smoking habits and metastases sites, more complexes prognostic score systems such as Di Maio and EPSILoN were further generated.[12–14] Among molecular biomarkers, the plasma microRNA signature classifier (MSC), developed for early lung cancer detection and reflecting an immunesuppressive host status,[15,16] has recently shown its prognostic value also in aNSCLC patients treated with single agent IO.[17]

The 3 markers were here compared and integrated in a unique score system called DEMo (Di Maio, EPSILoN, MSC). The aim of this prospective study was to assess if DEMo score is able to better categorize outcome of aNSCLC patients treated with IO and if the combination of these three biomarkers could improve the performance prediction compared to each single biomarker alone potentially helping clinical decision making.