Identification of alternative strategies in advanced non-small cell lung cancer (NSCLC) patients resistant to immune checkpoint inhibitors (ICIs) or with rare histologies

Immune checkpoint inhibitors (ICIs), such as antibodies directed against PD-1/PD-L1, have led to a paradigm shift in the management of non-small cell lung cancer (NSCLC). However, the effectiveness of these drugs appears to be limited only to a minority of NSCLC patients, particularly to those cancers with a strong PD-L1 expression. Many of the knowledge on the molecular mechanisms of primary and acquired resistance, which may be related to the tumor or to the tumor or circulating microenvironment, during ICIs therapy come from studies conducted on other tumors; by contrast, few data are available in NSCLC. The PhD research project is part of a project that has received funding from the Ministry of Health’s Finalized Research 2018 (GR-2018-12368031, P.I: dr. Francesco Gelsomino) and entitled “Understanding molecular mechanisms of resistance to immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC)”. The activity of the PhD project focused on two strands of research: a. the role of PD-L1 and interferon-gamma (IFN-γ) as regulators of tumor plasticity and ICIs resistance in cell models derived from patients with NSCLC and hyperprogressive disease (HPD) during ICIs; b. EGFR tyrosine kinase inhibitor (EGFR-TKI) activity in cell models derived from patients with advanced NSCLC and Class 3 BRAF mutation progressed on ICIS treatment. In addition, during the PhD program I have been engaged in two further lines of research regarding the ICIs use in the clinic in two specific settings: c. patients with advanced NSCLC and PD-L1 ≥50% with early progression disease on ICIs as first line therapy: the role of salvage chemo-immunotherapy; d. patients with advanced NSCLC and rare histology: atezolizumab activity.