PEOPLE (NTC03447678), a phase II trial to test pembrolizumab as first-line treatment in patients with advanced NSCLC with PD-L1 <50%: a multiomics analysis

Abstract

BackgroundChemoimmunotherapy represents the standard of care for patients with advanced non-small cell lung cancer (NSCLC) and programmed death-ligand 1 (PD-L1) &lt;50%. Although single-agent pembrolizumab has also demonstrated some activity in this setting, no reliable biomarkers yet exist for selecting patients likely to respond to single-agent immunotherapy. The main purpose of the study was to identify potential new biomarkers associated with progression-free-survival (PFS) within a multiomics analysis.MethodsPEOPLE (NTC03447678) was a prospective phase II trial evaluating first-line pembrolizumab in patients with advanced EGFR and ALK wild type treatment-naïve NSCLC with PD-L1 &lt;50%. Circulating immune profiling was performed by determination of absolute cell counts with multiparametric flow cytometry on freshly isolated whole blood samples at baseline and at first radiological evaluation. Gene expression profiling was performed using nCounter PanCancer IO 360 Panel (NanoString) on baseline tissue. Gut bacterial taxonomic abundance was obtained by shotgun metagenomic sequencing of stool samples at baseline. Omics data were analyzed with sequential univariate Cox proportional hazards regression predicting PFS, with Benjamini-Hochberg multiple comparisons correction. Biological features significant with univariate analysis were analyzed with multivariate least absolute shrinkage and selection operator (LASSO).ResultsFrom May 2018 to October 2020, 65 patients were enrolled. Median follow-up and PFS were 26.4 and 2.9 months, respectively. LASSO integration analysis, with an optimal lambda of 0.28, showed that peripheral blood natural killer cells/CD56dimCD16+ (HR 0.56, 0.41–0.76, p=0.006) abundance at baseline and non-classical CD14dimCD16+monocytes (HR 0.52, 0.36–0.75, p=0.004), eosinophils (CD15+CD16−) (HR 0.62, 0.44–0.89, p=0.03) and lymphocytes (HR 0.32, 0.19–0.56, p=0.001) after first radiologic evaluation correlated with favorable PFS as well as high baseline expression levels of CD244 (HR 0.74, 0.62–0.87, p=0.05) protein tyrosine phosphatase receptor type C (HR 0.55, 0.38–0.81, p=0.098) and killer cell lectin like receptor B1 (HR 0.76, 0.66–0.89, p=0.05). Interferon-responsive factor 9 and cartilage oligomeric matrix protein genes correlated with unfavorable PFS (HR 3.03, 1.52–6.02, p 0.08 and HR 1.22, 1.08–1.37, p=0.06, corrected). No microbiome features were selected.ConclusionsThis multiomics approach was able to identify immune cell subsets and expression levels of genes associated to PFS in patients with PD-L1 &lt;50% NSCLC treated with first-line pembrolizumab. These preliminary data will be confirmed in the larger multicentric international I3LUNG trial (NCT05537922).Trial registration number2017-002841-31.

Blood-based biomarkers in patients with non-small cell lung cancer treated with immune checkpoint blockade

“…Although predictive markers to identify clinical responders following ICI have largely focused on the T cell compartment, several recent studies have interrogated other lymphocyte populations in peripheral blood for association with clinical outcome following immunotherapy (Supplemental Table 3 ). Lo Russo et al evaluated the circulating immune profile of 65 patients with advanced NSCLC enrolled in a prospective phase II study of first line pembrolizumab prior to therapy and at the time of first radiological evaluation and found that abundance of the ratio of total natural killer cells/CD56 dim CD16 + NK cells ( p < 0.006) at baseline, and numbers of non-classical CD14 dim CD16 + monocytes ( p = 0.0039), and eosinophils (CD15 + CD16 − , p = 0.0301) after therapy correlated with favorable PFS [ 76 ]. Another study, by Xia et al, evaluated the association between patient response and baseline levels of circulating B cells in patients with NSCLC who were treated with anti-PD-1 ( n = 120) or anti-PD-L1 ( n = 30) [ 77 ].…”

Identification and Application of Emerging Biomarkers in Treatment of Non-Small-Cell Lung Cancer: Systematic Review

“…These include monotherapy with immune checkpoint inhibitors (ICIs) such as pembrolizumab, as well as targeted therapy combinations with chemotherapy. The treatment regimens have spanned from specific targeted therapies, like ALK and EGFR inhibitors, to immunotherapies and their integration with chemotherapy [49,59,70].…”

“…Regarding the blinding of participants and personnel (performance bias), many studies were evaluated as having a high risk due to the open nature of many clinical trials, which exposes them to possible performance bias. This includes the studies by Garon et [45,[47][48][49]51,52,54,62,64,66,69,70,[73][74][75][76][77][78][79]. The concern around unblinding in open clinical trials underscores a significant issue, as both the researchers and participants are aware of the assigned treatments, potentially influencing the outcomes and adherence to treatment.…”

“…Conversely, studies with an unclear risk lacked detailed reporting, while a high risk indicated insufficient transparency, potentially undermining the study's validity. [45,[47][48][49]51,52,54,62,64,66,69,70,[73][74][75][76][77][78][79]. Allocation concealment (selection bias) was primarily rated as low risk, indicating that the allocation process was sufficiently concealed to reduce selection bias in most studies.…”

“…al., 2021; Yang et al, 2023; G. Lo Russo et al, 2022; Garon et al, 2023; Si et al, 2021; Jiang et al, 2021; Zhang et al, 2024; Kim et al, 2022; Peters et al, 2022; Shi et al, 2022; Papadimitrakopoulou et al, 2020; Park et al, 2021; Gu et al, 2023; Zhong et al, 2023; Nomura et al, 2020; West et al, 2022; Lo Russo et al, 2023; Zhou et al, 2023; Sakai et al, 2020a; Redman et al, 2020; Hirsch et al, 2022; Schuler et al, 2020; Gadgeel et al, 2022; Ramalingam et al, 2022; Song et al, 2022; Anagnostou et al, 2023; and Park et al, 2020, were evaluated as having a low risk for random sequence generation (selection bias), suggesting thorough and well-documented randomization procedures[45,[47][48][49]51,52,54,62,64,66,69,70,[73][74][75][76][77][78][79].…”