Evolution of systemic therapy for stages I–III non-metastatic non-small-cell lung cancer

Abstract

The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the modality of definitive local treatment (surgery or radiotherapy) and the associated systemic therapies to further improve the likelihood of cure. Trial evidence supports cisplatin-based adjuvant therapy either after surgical resection or concurrently with radiotherapy. Consensus guidelines support neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based regimens for patients who are ineligible for cisplatin. The incorporation of newer agents, now standard for patients with stage IV lung cancer, into the curative therapy paradigm has lagged owing to inefficient trial designs, the lengthy follow-up needed to assess survival end points and a developmental focus on the advanced-stage disease setting. Surrogate end points, such as pathological response, are being studied and might shorten trial durations. In 2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage III lung cancer after concurrent chemoradiotherapy. Since then, the study of targeted therapies and immunotherapies in patients with early-stage lung cancer has rapidly expanded. In this Review, we present the current considerations in the treatment of patients with early-stage lung cancer and explore the current and future state of clinical research to develop systemic therapies for non-metastatic lung cancer. The authors of this Review present the current considerations in the treatment of patients with early-stage lung cancer, discussing the critical determination of resectability by thoracic surgical oncologists and the management of both resectable and unresectable disease with a focus on systemic therapy selection. They also address innovations in drug development, trial design and efforts to identify early-stage cancers. Cisplatin-based adjuvant chemotherapy remains the standard of care for patients with resected high-risk non-metastatic non-small-cell lung cancer (NSCLC). Anti-PD-L1 therapy with durvalumab after concurrent chemotherapy and radiotherapy for unresectable or inoperable non-metastatic NSCLC improves overall survival. Osimertinib for 3 years after standard adjuvant therapy improves disease-free survival in patients with NSCLC harbouring EGFR mutations. Immunotherapy is being extensively studied in the preoperative and postoperative settings. Novel clinical trial designs are needed to accelerate advances in the treatment of patients with curable NSCLC. Cisplatin-based adjuvant chemotherapy remains the standard of care for patients with resected high-risk non-metastatic non-small-cell lung cancer (NSCLC). Anti-PD-L1 therapy with durvalumab after concurrent chemotherapy and radiotherapy for unresectable or inoperable non-metastatic NSCLC improves overall survival. Osimertinib for 3 years after standard adjuvant therapy improves disease-free survival in patients with NSCLC harbouring EGFR mutations. Immunotherapy is being extensively studied in the preoperative and postoperative settings. Novel clinical trial designs are needed to accelerate advances in the treatment of patients with curable NSCLC.