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We also address pertinent clinical decision-making queries encountered in everyday practice, such as the optimal treatment strategy for PD-L1\u2013high patients, predictive factors for response to immune checkpoint inhibitors (ICI) both in terms of patient and cancer characteristics, the potential benefits of dual checkpoint blockade, and the unresolved issue of safe discontinuation strategies for long-term responders. Around one in five patients falls into this latter category while the majority develop either primary or acquired resistance to ICI-based first-line therapy, necessitating effective subsequent lines of treatment. Docetaxel, with or without combination of antiangiogenic agents, serves as the backbone of treatment, although evidence in the post-ICI setting is limited. Given that an inflamed tumor microenvironment (TME) is crucial for ICI responses, targeting the TME in cases of acquired resistance alongside continued ICI administration appears rational, although clinical trials so far have failed to confirm this hypothesis. Antibody-drug conjugates have emerged as a promising treatment modality, offering the potential for reduced toxicity and improved efficacy by targeting specific cancer antigens. Moreover, several chemotherapy-free approaches are currently under investigation for treatment-na\u00efve patients, including alternative ICI and drugs targeting epitopes on both cancer and immune cells. <\/jats:p>","DOI":"10.1200\/edbk_432524","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T20:01:18Z","timestamp":1714161678000},"source":"Crossref","is-referenced-by-count":24,"title":["Non\u2013Small Cell Lung Cancer Metastatic Without Oncogenic Alterations"],"prefix":"10.1200","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7452-7129","authenticated-orcid":true,"given":"Nikolaj","family":"Frost","sequence":"first","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Berlin, 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