Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out

Immunotherapy has dramatically changed the therapeutic scenario in treatment naïve advanced non-small celllung cancer (NSCLC). While single agent pembrolizumab has become the standard therapy in patients with PD-L1 expression on tumor cells ≥ 50%, the combination of pembrolizumab or atezolizumab and platinum-basedchemotherapy has emerged as an effective first line treatment regardless of PD-L1 expression both in squamousand non-squamous NSCLC without oncogenic drivers. Furthermore, double immune checkpoint inhibition hasshown promising results in treatment naïve patients with high tumor mutational burden (TMB). Of note, thepresence of both negative PD-L1 expression and low TMB may identify a subgroup of patients who has littlebenefit from immunotherapy combinations and for whom the best treatment option may still be platinum-basedchemotherapy. To date, first-line single agent immune checkpoint blockade has demonstrated limited activity inEGFR mutated NSCLC and the combination of immunotherapy and targeted agents has raised safety concerns inboth EGFR and ALK positive NSCLC patients. Finally, in EGFR mutated or ALK rearranged NSCLC, atezolizumabin combination with platinum-based chemotherapy and bevacizumab is emerging as a potential treatment optionupon progression to first line tyrosine kinase inhibitors.