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Checkpoint Blockade in Lung Cancer With Driver Mutation: Choose the Road Wisely
Antonio Calles1, Jonathan W Riess2, Julie R Brahmer3
1Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Abstract:
Immune checkpoint blockade with PD-(L)1 antibodies has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Similarly, the identification and targeting of oncogene drivers in metastatic NSCLC has dramatically improved patient outcomes with an expanding list of potentially actionable alterations and targeted therapies. Many of these molecular aberrations are more common in patients with little or no smoking history and adenocarcinoma histology. Certain molecular subsets of NSCLC, though gaining greatly from targeted therapy approaches, may derive less benefit from immune checkpoint blockade. The optimal identification, targeting, and sequencing of targeted therapies, immunotherapy, and chemotherapy are essential to continue to improve patient outcomes in advanced NSCLC. Herein, we review the role of immunotherapy in locally advanced and metastatic disease for patients with actionable driver alterations. Never-smoking patients have a high probability of having lung cancer that harbors one of these molecular aberrations that can be matched to a tyrosine kinase inhibitor with greatly improved clinical outcomes. Some of these patients with driver mutations may derive less benefit from immune checkpoint inhibitor approaches (either alone or combined with chemotherapy), especially compared with smoking-associated NSCLC. Given that PD-1 blockade alone or with platinum-based chemotherapy is the de facto first-line therapy (depending on level of PD-L1 expression) for nontargetable metastatic NSCLC, we also review treatment in never-smoking patients for whom molecular testing results are pending and the likelihood of identifying a driver mutation is high.
Insights
Targeted therapies improve outcomes in advanced non-small cell lung cancer (NSCLC) with driver alterations, particularly in never-smokers. Immunotherapy may be less effective in these patients, necessitating optimal treatment sequencing.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune checkpoint inhibitors (PD-(L)1 antibodies) and targeted therapies have transformed advanced non-small cell lung cancer (NSCLC) treatment.
- Molecular aberrations, often found in never-smokers with adenocarcinoma, are increasingly targeted with tyrosine kinase inhibitors, improving outcomes.
- Some molecular subsets may respond less favorably to immune checkpoint blockade compared to chemotherapy or targeted agents.
Purpose of the Study:
- To review the role of immunotherapy in advanced NSCLC patients with actionable driver alterations.
- To discuss treatment strategies for never-smoking NSCLC patients, considering molecular testing results and potential driver mutations.
- To highlight the importance of optimal sequencing of targeted therapies, immunotherapy, and chemotherapy for improved patient outcomes.
Main Methods:
- Literature review of immunotherapy and targeted therapy in advanced non-small cell lung cancer.
- Analysis of treatment outcomes based on smoking history and molecular aberration status.
- Discussion of clinical guidelines and emerging treatment paradigms for NSCLC management.
Main Results:
- Targeted therapies offer significant clinical benefits for NSCLC patients with specific driver mutations, especially never-smokers.
- Certain molecular alterations in NSCLC may be associated with reduced efficacy of immune checkpoint inhibitors.
- Optimal sequencing of treatments is crucial for maximizing patient benefit in advanced NSCLC.
Conclusions:
- Personalized treatment approaches integrating targeted therapy, immunotherapy, and chemotherapy are essential for advanced NSCLC.
- Never-smokers with NSCLC often harbor targetable driver mutations, benefiting from tyrosine kinase inhibitors.
- Further research is needed to define the optimal role and sequencing of immunotherapy in specific molecular subsets of NSCLC.
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