Cytology versus histology for programmed death-ligand 1 expression evaluation in the landscape of non-small cell lung cancer patients selection for immunotherapy

Programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) represent key targets for specific monoclonal antibody inhibitors, such as pembrolizumab, nivolumab and atezolizumab, currently used in clinical practice for the management of metastatic non-small cell lung cancer (NSCLC) patients (1). PD-L1 expression evaluation was not required to administrate nivolumab, an anti-PD-1 inhibitor, and atezolizumab, an anti-PD-L1 inhibitor, in NSCLC second-line treatment. Conversely, pembrolizumab, an anti-PD-1 inhibitor, can be administered as single-agent, only in NSCLC patients whose sample tumours show ≥50% of PD-L1 expression, in first-line (2), or ≥1%, in second-line setting (3). More recently, the KEYNOTE-189 clinical trial demonstrated that when combined with first-line chemotherapy, pembrolizumab can be administered regardless of PD-L1 expression status (4). Thus, in non-oncogene-addicted advanced NSCLC patients, especially in first-line setting, the determination of PD-L1 expression is needed despite the possibility to use the combination of chemotherapy plus pembrolizumab. The evaluation of PD-L1 expression, in absence of head-to-head trials comparing pembrolizumab versus chemotherapy plus pembrolizumab in strong-positive PD-L1 NSCLC and in order to avoid chemotherapy administration, is still of paramount importance (2). An important consideration is that the histological sample is available only in a limited number of advanced stage NSCLC patients, in relation to sample collection difficulties (2,5). This has led to the improvement of minimal invasive procedures in collecting, directly from NSCLC central or distant lesions, cytological samples both for morphological evaluation and molecular characterization. The possibility to prepare a cytology sample as a cell block to be used in the analytical procedure validated on histological samples represent an important point to properly manage NSCLC patients. To date, the evaluation of PD-L1 expression is validated using immunohistochemistry (IHC) and in all the phase III clinical trials this analysis was performed on formalin-fixed, paraffin-embedded (FFPE) tissue specimens. Based on these considerations, the reproducibility of the survival results, showed by these trials, in the clinical practice depends also on tissue samples availability