Non-Small Cell Lung Cancer


Smoking Status and Actionable Alterations in Younger Patients

patient care perspectives by Bruce E. Johnson, MD

Comprehensive genomic testing has an important role in the evaluation of non–small cell lung cancer (NSCLC). This is especially true for younger patients, many of whom have actionable oncogenic drivers. There are now 11 genomic alterations for which there are US Food and Drug Administration (FDA)–approved therapeutics, and more are on the way.

Expert Commentary
“Younger patients will often have an oncogenic driver, meaning a genomic alteration, and between 40% and 80% will respond to a targeted agent.”
— Bruce E. Johnson, MD

The epidemiology of cigarette smoking has changed over the past 80 years, but one thing that has held true is that the majority of people start smoking between the ages of 12 and 18 years. Additionally, the smoking prevalence peaks between 20 and 30 years of age, and then it begins to fall off at approximately 1% to 2% per year. At the time that most people are diagnosed with lung cancer—the median age in the United States is 70 years—most of these individuals have already quit smoking, so the smoking patterns vary quite a bit.


These smoking patterns have implications for young individuals with NSCLC (often defined as those <50 years of age), noting that lung cancer is relatively rare in those younger than 40 years of age. First, there is a bit of a higher smoking prevalence than you might anticipate because of that pattern in which there is a peak at approximately age 25 years and then it begins to fall off. Among those who develop lung cancer at age 20 to 49 years, approximately half are smoking, while approximately 28% have either quit or have never smoked.


The other important thing to remember is that smoking exposure in this younger age group is substantially less than that of a person with NSCLC who was diagnosed at a typical age (ie, the median age of 70 years), and this impacts the types of genomic changes that are seen. At this young age, those with a history of smoking have less smoking exposure, and a greater proportion of them are going to have targetable mutations. Younger patients will often have an oncogenic driver, meaning a genomic alteration, and between 40% and 80% will respond to a targeted agent.


We have been identifying EGFR alterations for almost 20 years now, and today we test not only for EGFR but also for 10 other genomic changes or markers for which FDA-approved agents are available. More are in development, so it is critically important to identify all of the genomic changes with broad testing. You do not want to have to repeat the testing each time a new treatment for another oncogenic driver is approved by the FDA, so you want to make sure that patients are comprehensively tested from the start.


We find EGFR alterations in approximately 30% of patients with lung cancer who have never smoked. Those with EGFR mutations who are treated with the third-generation EGFR inhibitor osimertinib have a progression-free survival (PFS) of approximately 1.5 years and an overall survival (OS) of approximately 3 years. ALK alterations can be effectively targeted with alectinib, which has a median PFS of approximately 3 years and an OS of more than 5 years.


ROS1 alterations are less common (ie, they are found in approximately 3% of lung cancers in never smokers) and can be treated with entrectinib or crizotinib. In clinical trials, the median treatment duration was approximately 1 year with entrectinib and 2 years with crizotinib, and both resulted in a several-year OS benefit. RET alterations are found in 1% of this patient population, and most people respond to treatment with pralsetinib or selpercatinib, with PFS measured in years for selpercatinib.


When we treated people with chemotherapy, the median survival was only approximately 1 year. So, we are quite happy that we are now able to identify genomic changes in our patients and treat them with effective targeted agents. Still, people under 50 years of age are supposed to live for another 30 to 50 years, so there is certainly more work to be done.


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Bruce E. Johnson, MD

Institute Physician
Dana-Farber Cancer Institute
Professor of Medicine
Harvard Medical School
Boston, MA