At the crossroads of immunotherapy for oncogene-addicted subsets of NSCLC

• Published in: Nature reviews. Clinical oncology 2023-03, Vol.20 (3), p.143-159
• Main Authors: Otano, Itziar, Ucero, Alvaro C., Zugazagoitia, Jon, Paz-Ares, Luis
• Format: Article
• Language: English
• Subjects: 631/67/1059/2325; 631/67/1612/1350; 631/67/69; Antineoplastic Agents - therapeutic use; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung - genetics; Chemotherapy; Clinical trials; Humans; Immune checkpoint inhibitors; Immunotherapy; Lung cancer; Lung Neoplasms - drug therapy; Medicine; Medicine & Public Health; Microenvironments; Mutation; Non-small cell lung carcinoma; Oncogene Addiction; Oncogenes; Oncology; Patients; PD-1 protein; PD-L1 protein; Precision medicine; Review Article; Small cell lung carcinoma; Tumor microenvironment; Tumors
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/s41571-022-00718-x

Non-small-cell lung cancer (NSCLC) has become a paradigm of precision medicine, with the discovery of numerous disease subtypes defined by specific oncogenic driver mutations leading to the development of a range of molecularly targeted therapies. Over the past decade, rapid progress has also been made in the development of immune-checkpoint inhibitors (ICIs), especially antagonistic antibodies targeting the PD-L1–PD-1 axis, for the treatment of NSCLC. Although many of the major oncogenic drivers of NSCLC are associated with intrinsic resistance to ICIs, patients with certain oncogene-driven subtypes of the disease that are highly responsive to specific targeted therapies might also derive benefit from immunotherapy. However, the development of effective immunotherapy approaches for oncogene-addicted NSCLC has been challenged by a lack of predictive biomarkers for patient selection and limited knowledge of how ICIs and oncogene-directed targeted therapies should be combined. Therefore, whether ICIs alone or with chemotherapy or even in combination with molecularly targeted agents would offer comparable benefit in the context of selected oncogenic driver alterations to that observed in the general unselected NSCLC population remains an open question. In this Review, we discuss the effects of oncogenic driver mutations on the efficacy of ICIs and the immune tumour microenvironment as well as the potential vulnerabilities that could be exploited to overcome the challenges of immunotherapy for oncogene-addicted NSCLC. Immune-checkpoint inhibitors (ICI) constitute a paradigm shift in the treatment of non-small-cell lung cancer (NSCLC); however, identifying the minority of patients who derive long-term benefit remains problematic, particularly among those with targetable oncogenic drivers who have typically been under-represented in or excluded from clinical trials of ICIs. This Review summarizes the associations of common oncogenic drivers of NSCLC with sensitivity or resistance to ICIs as well as the underlying effects on the immune tumour microenvironment. Potential vulnerabilities that could potentially be exploited to overcome primary resistance to ICIs conferred by certain oncogenic drivers are also highlighted. Key points In the era of immuno-oncology, emerging evidence indicates that driver oncogenes have different effects on the immune tumour microenvironment that influence the potential for clinical benefit from treatment with immune-checkpoint inhibit