Neoadjuvant chemo-immunotherapy in non-small cell lung cancer: clinical rationale and methods of pathological assessment

Non-small cell lung cancer (NSCLC) remains a common cancer with poor outcomes, with even early stage, resectable tumours having a high recurrence rate. Over the past decade immunotherapy has been paradigm-changing in advanced, metastatic NSCLC while more recent evidence has demonstrated its important role as a neoadjuvant agent in surgically resectable disease. This has led to a significant shift in clinical practice and, in doing so, has altered requirements in the pathological assessment of surgical resection specimens. In this paper, we summarize the clinical, biological and pathological rationale behind neoadjuvant immunotherapy, describe the evidence base for this change in clinical practice and detail the central role of histopathology. Clinical trials have demonstrated marked event-free and overall survival advantages for combined immunotherapy and chemotherapy with pathological response an important surrogate marker of long-term outcome. We describe the key histopathological and molecular characteristics that render a patient eligible for neoadjuvant treatment as well as the requirements for assessment of surgical specimens to enable the accurate quantification of pathological response. In addition, the potential future roles for alternative measures of disease response are discussed, including circulating tumour DNA, immune cell phenotyping and artificial intelligence-based analyses.