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

Abstract

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 Ն50%) 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.

Liquid Biopsy in Non-Small Cell Lung Cancer: Highlights and Challenges

“…In the last decade, tailored treatments for solid tumors, including non-small cell lung cancer (NSCLC), have emerged as novel therapeutic approaches, resulting in a clinically meaningful improvement in terms of survival. More specifically, oncogenic drivers such as activating mutations of the epidermal growth factor receptor (EGFR), as well as rearrangements of the anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) are crucial targets for biological therapies in selected subgroups of NSCLC patients [1]. More recently, treatment with immune checkpoint inhibitors targeting the axis involving the programmed death protein 1 (PD-1) and its ligand (PD-L1) have revolutionized the management of a large proportion of NSCLC patients; with regards to immune checkpoint blockade, data on reliable predictive biomarkers are limited in comparison with targeted agents, although the expression of PD-L1 in tumor specimens is currently employed for the selection of patients considered eligible for first-line treatment with single-agent immune checkpoint inhibitors [2].…”

Isoliquiritigenin Suppressed Esophageal Squamous Carcinoma Growth by Blocking EGFR Activation and Inducing Cell Cycle Arrest

“…Owing to its importance, in some tumor types such as lung adenocarcinoma, the somatic mutations of EGFR can act as a driver to accelerate tumor growth. And the tumors with EGFR mutations have shown great response to EGFR inhibitors [6]. Although the sensitive mutations were rare in ESCC, EGFR overexpression was frequently observed and found to be closely related to clinical stages, tumor invasion, and patient survival [7].…”

Initial Experience after Transition to Immune Checkpoint Inhibitors in Patients with Non-small Cell Lung Cancer Treated in a Rural Healthcare Region

“…Since real-world data from rural patient cohorts might differ from those obtained in clinical trials, it is necessary to conduct additional and larger studies about ICI-associated patterns of terminal care. 1 2 2 2 2…”

“…The systemic treatment of advanced non-small cell lung cancer (NSCLC) has recently undergone significant transformations [1,2]. Platinum-based first-line chemotherapy and previous second-line regimens have been replaced by treatment with immune checkpoint inhibitors (ICI) such as pembrolizumab, atezolizumab, and nivolumab, both as monotherapy in first-or second-line treatments or in combination with chemotherapy in first-line treatment [3][4][5][6][7].…”