4.5 Review

First-Line Treatment of Advanced Non-Small-Cell Lung Cancer with Immune-Checkpoint Inhibitors: New Combinations and Long-Term Data

Journal

BIODRUGS
Volume 36, Issue 2, Pages 137-151

Publisher

ADIS INT LTD
DOI: 10.1007/s40259-022-00515-z

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The treatment of metastatic non-small-cell lung cancers (NSCLCs) has traditionally relied on cytotoxic chemotherapy, but the introduction of immune checkpoint inhibitors has revolutionized therapeutic standards. These inhibitors are now the first-line therapy and have shown efficacy in patients with specific expression profiles. Combination therapies of immune checkpoint inhibitors with chemotherapy have demonstrated significant improvements in overall survival, but the use of combination immunotherapies requires further investigation.
Treatment of metastatic non-small-cell lung cancers (NSCLCs) has long been based on cytotoxic chemotherapy. Immune checkpoint inhibitors (ICIs), notably monoclonal antibodies directed against programmed cell death protein-1 (PD-1) or its ligand (PD-L1), have transformed therapeutic standards in thoracic oncology. These ICIs are now the reference first-line therapy, and numerous phase III trials have established their efficacy in treatment-naive patients. First-line pembrolizumab monotherapy was validated for patients with >= 50% of tumor cells expressing PD-L1 and, in the USA, for patients with >= 1% PD-L1 positivity. More recently, cemiplimab as monotherapy was also validated for patients whose tumors expressed >= 50% PD-L1. Several ICIs (pembrolizumab, atezolizumab, nivolumab, and recently durvalumab) in combination with chemotherapy achieved overall survival gains among all comers, compared with chemotherapy alone. The results were more contrasting for paired immunotherapies combining anti-PD-L1 and anti-cytotoxic T-lymphocyte antigen-4 agents, with the benefit/risk balance not yet fully established. Recently, nivolumab-ipilimumab and two chemotherapy cycles limited patient exposure to chemotherapy and obtained positive results compared with the latter alone. However, those phase III trials included selected patients in good general condition and without active brain metastases. Little is known about immunotherapy and combination immunotherapy-chemotherapy efficacies in never-smokers or patients with tumors harboring an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation. In this review, we report our analysis of the main results available on first-line ICI use, as monotherapy or combined or in combination with chemotherapy, to treat metastatic NSCLCs in general and also for specific populations: the elderly, never-smokers, patients with brain metastases, and those with an EGFR mutation or ALK translocation.

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