A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives

Uncommon Epidermal Growth Factor Receptor (EGFR) mutations represent a distinct and highly heterogeneous subgroup of Non-Small Cell Lung Cancers (NSCLCs), that accounts for approximately 10% of all EGFR-mutated patients. The incidence of uncommon EGFR mutations is growing, due to the wider adoption of next-generation sequencing (NGS) for diagnostic purposes, which enables the identification of rare variants, usually missed with available commercial kits that only detect a limited number of EGFR mutations. However, the sensitivity of uncommon mutations to first- and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs) is widely heterogeneous and less well known, compared with classic mutations (i.e., exon 19 deletions and exon 21 L858R point mutation), since most of the pivotal studies with EGFR TKIs in the first line, with few exceptions, excluded patients with rare and/or complex variants. Recently, the third generation EGFR TKI osimertinib further revolutionized the therapeutic algorithm of EGFR-mutated NSCLC, but its role in patients harboring EGFR mutations besides exon 19 deletions and/or L858R is largely unknown. Therefore, a better knowledge of the sensitivity of uncommon mutations to currently available EGFR TKIs is critical to guiding treatment decisions in clinical practice. The aim of this paper is to provide a comprehensive overview of the treatment of NSCLC patients harboring uncommon EGFR mutations with currently approved therapies and to discuss the emerging therapeutic opportunities in this peculiar subgroup of patients, including chemo-immunotherapy combinations, next-generation EGFR TKIs, and novel targeted agents.

Nivolumab is a novel therapeutic option in NSCLC, associated with a significant survival gain compared with Docetaxel. However, predictive biomarkers are lacking. The presence of systemic inflammation has been correlated with poor outcome in many cancer types. We aimed to evaluate whether there is a correlation between some indicators of inflammation and response to Nivolumab or Docetaxel in pre‐treated NSCLCs. Data of 62 patients receiving Nivolumab or Docetaxel were analyzed. Baseline neutrophilia and thrombocytosis were not associated with response. High dNLR was associated with no response to Nivolumab, but not with Docetaxel, whereas high PLR correlated with low treatment response in both groups. Among refractory patients, a higher incidence of thrombocytosis, neutrophilia, high PLR, and high dNLR levels were observed compared with the overall population. This is one of the first reports in this field and suggests that indicators of inflammation might be included together with other predictive biomarkers in the baseline evaluation of patients candidate for immunotherapy.