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Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung CancerA Review

Educational Objective
To review the treatment of patients with non–small lung cancer.
1 Credit CME

Importance  Non–small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non–small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker–targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease.

Observations  Systemic therapy for metastatic non–small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non–small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non–small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non–small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor–containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of ≥50%) and 40% among patients with ALK-positive tumors.

Conclusions and Relevance  Improved understanding of the biology and molecular subtypes of non–small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non–small cell lung cancer.

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Article Information

Corresponding Author: Gregory J. Riely, MD, PhD, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (

Accepted for Publication: July 29, 2019.

Author Contributions: Both authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Both authors.

Acquisition, analysis, or interpretation of data: Riely.

Drafting of the manuscript: Both authors.

Critical revision of the manuscript for important intellectual content: Both authors.

Administrative, technical, or material support: Riely.

Supervision: Riely.

Conflict of Interest Disclosures: Dr Arbour reported serving as a consultant to AstraZeneca; and receiving nonfinancial research support from Novartis and Takeda. Dr Riely reported receiving grants and nonfinancial support from Pfizer, Roche/Genentech/Chugai, Novartis, Merck, and Takeda; having US patent 20170273982A1 pending for an alternate dosing of erlotinib for which he has no right to royalties; and being paid by the National Comprehensive Cancer Network to participate in a committee that oversaw solicitation and selection of grants to be awarded by AstraZeneca.

Funding/Support: This work was partially supported by grant P30 CA008748 from the National Cancer Institute awarded to Memorial Sloan Kettering Cancer Center.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Clare Wilhelm, MD, PhD (Memorial Sloan Kettering Cancer Center), for providing editorial support. Dr Wilhelm was not paid for his contribution.

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