Patient-derived cell-based pharmacogenomic assessment to unveil underlying resistance mechanisms and novel therapeutics for advanced lung cancer.

BACKGROUND: A pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for patients with advanced or refractory lung cancer. METHODS: Drug sensitivity screening and multi-omics datasets were acquired from lung cancer PDCs (n = 102). Integrative analysis was performed to explore drug candidates according to genetic variants, gene expression, and clinical profiles. RESULTS: PDCs had genomic characteristics resembled with those of solid lung cancer tissues. PDC molecular subtyping classified patients into four groups: (1) inflammatory, (2) epithelial-to-mesenchymal transition (EMT)-like, (3) stemness, and (4) epithelial growth factor receptor (EGFR)-dominant. EGFR mutations of the EMT-like subtype were associated with a reduced response to EGFR-tyrosine kinase inhibitor therapy. Moreover, although RB1/TP53 mutations were significantly enriched in small-cell lung cancer (SCLC) PDCs, they were also present in non-SCLC PDCs. In contrast to its effect in the cell lines, alpelisib (a PI3K-AKT inhibitor) significantly inhibited both RB1/TP53 expression and SCLC cell growth in our PDC model. Furthermore, cell cycle inhibitors could effectively target SCLC cells. Finally, the upregulation of transforming growth factor-ß expression and the YAP/TAZ pathway was observed in osimertinib-resistant PDCs, predisposing them to the EMT-like subtype. Our platform selected XAV939 (a WNT-TNKS-ß-catenin inhibitor) for the treatment of osimertinib-resistant PDCs. Using an in vitro model, we further demonstrated that acquisition of osimertinib resistance enhances invasive characteristics and EMT, upregulates the YAP/TAZ-AXL axis, and increases the sensitivity of cancer cells to XAV939. CONCLUSIONS: Our PDC models recapitulated the molecular characteristics of lung cancer, and pharmacogenomics analysis provided plausible therapeutic candidates.

Cardiac Safety Assessment of Lazertinib: Findings From Patients With EGFR Mutation-Positive Advanced NSCLC and Preclinical Studies.

INTRODUCTION: Lazertinib is a potent, irreversible, brain-penetrant, mutant-selective, and wild-type-sparing third-generation EGFR tyrosine kinase inhibitor (TKI), creating a wide therapeutic index. Cardiovascular adverse events (AEs), including QT prolongation, decreased left ventricular ejection fraction (LVEF), and heart failure, have emerged as potential AEs with certain EGFR TKI therapies. METHODS: Cardiac safety of lazertinib was evaluated in TKI-tolerant adults with EGFR mutation-positive locally advanced or metastatic NSCLC receiving lazertinib (20-320 mg/d). QT intervals corrected with Fridericia's formula (QTcF) prolongation, time-matched concentration-QTcF relationship, change of LVEF, and cardiac failure-associated AEs were evaluated. The clinical findings were supplemented by the following three preclinical studies: an in vitro hERG inhibition assay, an ex vivo isolated perfused rabbit heart study, and an in vivo telemetry-instrumented beagle dog study. RESULTS: Preclinical evaluation revealed little to no physiological effect on the basis of electrocardiogram, electrophysiological, proarrhythmic, and hemodynamic parameters. Clinical evaluation of 181 patients revealed no clinically relevant QTcF prolongation by centralized electrocardiogram in any patient and at any dose level. The predicted magnitude of QTcF value increase at maximum steady-state plasma concentration for the therapeutic dose of lazertinib (240 mg/d) was 2.2 msec (upper bound of the two-sided 90% confidence interval: 3.6 msec). No patient had clinically relevant LVEF decrease (i.e., minimum postbaseline LVEF value of <50% and a maximum decrease in LVEF value from baseline of ≥10 percentage points). Cardiac failure-associated AE occurred in one patient (grade 2 decreased LVEF) and resolved without any dose modifications. CONCLUSIONS: Our first-in-human study, together with preclinical data, indicates that lazertinib is not associated with increased cardiac risk.

Response evaluation after immunotherapy in NSCLC: Early response assessment using FDG PET/CT.

ABSTRACT: The present study aimed to evaluate the role of early F-18 2-deoxy-2-[fluorine-18] fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT) in non-small cell lung cancer patients undergoing immune checkpoint inhibitor (ICI) treatment.Twenty-four non-small cell lung cancer patients who received nivolumab or pembrolizumab and underwent FDG PET/CT as an interim analysis after 2 or 3 cycles of ICI treatment were retrospectively enrolled. Tumor response was assessed using the PET Response Criteria in Solid Tumors 1.0 (PERCIST) and the European Organization for Research and Treatment of Cancer (EORTC) criteria after 2 or 3 cycles of ICI treatment (SCAN-1) and after an additional 2 cycles of ICI treatment (SCAN-2). The best overall response was determined by FDG PET/CT or chest CT at ≥ 3 months after therapy initiation, and the clinical benefit was investigated. progression-free survival was investigated, and its correlation with clinicopathologic and metabolic parameters was examined using a Cox multivariate proportional hazards model.In the interim analysis, 4 patients achieved a complete metabolic response (CMR), 1 patient exhibited a partial metabolic response (PMR), and 14 patients had Progressive metabolic disease (PMD) according to the PERCIST and EORTC criteria. Four patients showed stable metabolic disease (SMD) according to the PERCIST criteria, and 2 patients showed different responses (i.e., PMR) according to the EORTC criteria. Patients with a CMR or PMR at SCAN-1 had a clinical benefit. Among the 4 patients with SMD at SCAN-1, only 1 experienced a clinical benefit regardless of the percent change in the peak standardized uptake value. Two patients with discordant response assessments between the PERCIST and EORTC criteria showed conflicting clinical benefits. Among the 14 patients with PMD, none experienced any clinical benefit. Only metabolic parameters were significant factors for predicting progression in the multivariate analysis (peak standardized uptake value and metabolic tumor volume, HRs of 1.18 and 1.00, respectively).Based on early F-18 FDG PET/CT after ICI treatment, metabolic parameters could predict post-treatment progression. Responses after ICI treatment were correctly assessed in patients with a CMR, a PMR, and PMD, but patients with SMD required a meticulous follow-up because of varying clinical benefits.