Facts and hopes in neoadjuvant immunotherapy combinations in resectable non-small-cell lung cancer

Abstract Antibodies targeting immune checkpoints, such as PD-1, PD-L1, or CTLA-4, have transformed the treatment of patients with lung cancers. Unprecedented rates of durable responses are achieved in an imperfectly characterized population of patients with metastatic disease. More recently, immune checkpoint inhibitors have been explored in patients with resectable non-small-cell lung cancers. Following a traditional paradigm, antibody therapies were first studied in the adjuvant setting, after surgery and chemotherapy. Pivotal trials supported global approvals of the PD-L1/-1 antibodies atezolizumab and pembrolizumab in this setting. Exciting observations were made when checkpoint inhibitors were moved to the preoperative window: Several signal-finding studies explored a limited number of cycles prior to surgery, and reproducibly reported complete or major histopathological responses. So far, six published phase III trials have demonstrated the superiority of combining the PD-1/-L1 antibodies nivolumab, pembrolizumab, durvalumab, tislelizumab or toripalimab with 3 to 4 courses of preoperative platinum-based chemotherapy over preoperative chemotherapy alone in terms of response rates and survival endpoints. Those patients achieving complete or major histopathological responses experienced particularly favorable long-term outcomes. It is yet unclear, whether there is true synergism between immunotherapy and chemotherapy, and whether outcomes are further improved by adding postoperative checkpoint inhibition. While these pivotal trials qualify neoadjuvant chemo-immunotherapy as another option in curative lung cancer treatment, there is hope that the chemotherapy backbone will be ultimately replaced by rationally selected and targeted combination partners. Here, the current status and future avenues of neoadjuvant combination immunotherapies in patients with non-small-cell lung cancer are reviewed.