Role of immunotherapy in stage IIIA non-small cell lung cancer: a narrative review

Abstract

: Non-small cell lung cancer (NSCLC) is one of the main leading causes of death by cancer worldwide. Approximately one third of cases are diagnosed at stage III, whose therapeutic strategy based on multimodal treatment has reached a plateau of effectiveness. Treatment with anti-PD-1/PD-L1 [anti-PD-(L)1] antibodies have been stablished in advanced stages due to their improved clinical benefit and acceptable profile of related adverse events. Lately, numerous clinical trials have been designed with diverse approaches to introduce immunotherapy into stages IIIA. The objective of this review is to discuss the different strategies that are being taken in the ongoing clinical trials, taking into account the peculiarities of stage IIIA and the tumor microenvironment. PubMed, major international conferences and clinicaltrials.gov databases were searched from January 1, 1990, to May 11, 2020 using the terms NSCLC, stage III, resectable, unresectable, immunotherapy, checkpoint inhibition, neoadjuvant and adjuvant. In this review we describe, in the context of stage IIIA disease, the impact of anti-PD-(L)1 and conventional therapies on the tumor microenvironment. Moreover, we describe the role of immunotherapy, through the heterogeneous landscape of stage IIIA NSCLC, summarizing ongoing clinical trials in incidental, potentially resectable, and unresectable tumors. We finally discuss the potential of PD-L1, tumor mutation burden (TMB), and T-cell receptor (TCR) repertoire analysis as predictive biomarkers in stage IIIA NSCLC. Initial results seem to favor neoadjuvant over adjuvant treatment, with chemoimmunotherapy combination standing out. Ongoing trials will answer whether immunotherapy can transform stage IIIA from lethal to a curable disease. Additionally, higher pathological response rates observed, open the possibility to establishing it as survival surrogate, speeding up the potential immunotherapy implementation in stage IIIA NSCLC.