At the crossroads of immunotherapy for oncogene-addicted subsets of NSCLC
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Itziar Otano1,2, Alvaro C Ucero3,4,5, Jon Zugazagoitia3,4,6
1H12O-CNIO Lung Cancer Clinical Research Unit, Health Research Institute Hospital 12 de Octubre (i+12)/Spanish National Cancer Research Center (CNIO), Madrid, Spain. iotanoan@alumni.unav.es.
Abstract:
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.
Insights
Precision medicine in non-small-cell lung cancer (NSCLC) advances with targeted therapies and immune-checkpoint inhibitors (ICIs). This review explores overcoming resistance to immunotherapy in oncogene-driven NSCLC.
Area of Science:
- Oncology
- Immunotherapy
- Precision Medicine
Background:
- Non-small-cell lung cancer (NSCLC) treatment has evolved with targeted therapies for specific oncogenic driver mutations.
- Immune-checkpoint inhibitors (ICIs), targeting the PD-L1-PD-1 axis, show promise but face intrinsic resistance in some NSCLC subtypes.
- Oncogene-addicted NSCLC presents challenges for immunotherapy due to a lack of predictive biomarkers and combination strategies.
Purpose of the Study:
- To review the impact of oncogenic driver mutations on ICI efficacy in NSCLC.
- To discuss the immune tumor microenvironment in oncogene-driven NSCLC.
- To identify vulnerabilities for improving immunotherapy in oncogene-addicted NSCLC.
Main Methods:
- Literature review of studies on NSCLC, targeted therapies, and ICIs.
- Analysis of the effects of oncogenic drivers on immune response.
- Exploration of potential combination strategies for immunotherapy.
Main Results:
- Major oncogenic drivers in NSCLC can be associated with intrinsic resistance to ICIs.
- Certain oncogene-driven NSCLC subtypes may benefit from immunotherapy, but predictive biomarkers are lacking.
- Optimal combination strategies involving ICIs, chemotherapy, and targeted agents remain under investigation.
Conclusions:
- Understanding the interplay between oncogenic drivers and the immune microenvironment is crucial for effective NSCLC immunotherapy.
- Further research is needed to develop predictive biomarkers and effective combination therapies for oncogene-addicted NSCLC.
- Exploiting specific vulnerabilities may enhance immunotherapy outcomes in challenging NSCLC cases.
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