Expert Discusses Translating EGFR Mutation Status Into Action in NSCLC

Jane de Lartigue, PhD
Published: Wednesday, Feb 24, 2016
Mark A. Socinski, MD

Mark A. Socinski, MD

Three generations of drugs are now available to treat patients with EGFR-mutant non–small cell lung cancer (NSCLC), and mutation testing for patients diagnosed with advanced or metastatic disease has been incorporated into clinical practice guidelines.

Yet many questions about translating these new tools into clinical practice linger. In this interview with OncologyLive, Mark A. Socinski, MD, tackles some of these issues. Socinski is a professor of Medicine and Cardiothoracic Surgery at the University of Pittsburgh Medical Center (UPMC) and co-director of the UPMC Lung Cancer Center of Excellence. He also is clinical associate director of the center’s Lung SPORE research program.

OncologyLive: How important are EGFR mutations in the genomic landscape of NSCLC?

Socinski: Incredibly important. For a subset of largely adenocarcinoma of the lung, the standard of care has changed over the past 5 or 6 years as EGFR TKIs have been shown in multiple phase III trials to be superior to the former standard, which was combination chemotherapy. The population with this subtype, depending upon the patient mix in a practice, is probably between 5%-20%. By that I mean how many women, how many never-smokers, how many adenocarcinomas, how many Asians you may have.

For that 5%-20%, lung cancer is a different disease now. It’s associated with a much better prognosis, and the median survival in many studies is in excess of 2 years, even up to 3 years. The treatment is taking a pill once a day versus the standard old-fashioned chemotherapy. So the detection and diagnosis of EGFR mutations is critically important in day-to-day practice today.

Please briefly discuss the current testing methods and ongoing research in this area.

There are multiple different testing methodologies, and they range from old-fashioned Sanger sequencing to next-generation sequencing and PCR-based technologies, all of which have increasing levels of sensitivity. We are also in a time where blood-based testing is a reality. There are a number of tests that look at circulating tumor DNA or circulating tumor cells to make the diagnosis of these mutations. We certainly will see more blood-based testing in the future.

I think it’s important that physicians realize that there may be different levels of sensitivity with different techniques. If, for instance, you have a clinical situation where you have a high suspicion of NSCLC—a never-smoking female with adenocarcinoma who happens to be Asian— this is a population that might have a 50%-60% chance of having an EGFR mutation. But if you get a negative result back on Sanger sequencing, I might in that setting do next-generation sequencing on that patient just to be absolutely sure. I do think that establishing a diagnosis of an EGFR mutation is a game-changer in adenocarcinoma of the lung.

What are the most significant unanswered questions and barriers to effective EGFR-targeted agents in EGFR-mutant NSCLC?

I think the biggest challenge is the development of resistance. It’s very gratifying to diagnose EGFR mutations because you have a patient you can comfort by saying you have a better prognosis, and that this is a different type of lung cancer that’s driven by an oncogene for which we have a targeted therapy that is pretty effective. Response rates are usually in the 60%-80% range.

Unfortunately, it’s not a 100% response because we do have some de novo resistance issues. Patients get on oral therapy. There are toxicities that are problematic, but I think the toxicities with all the TKIs are manageable, certainly easier than chemotherapy side effects can be.

The median progression-free survival time is always in the 9- to -13-month range. So, I always think I have about a year with EGFR TKI therapy before patients are going to start to develop resistance. Certainly, we can have the experience where patients are on TKI therapy for 2 to 3 years—which is very gratifying for both doctor and patient—but what to do at the time of resistance is a key question.

A number of studies have determined that the predominant mechanism of resistance is the development of a secondary mutation in exon 20, which is the T790M mutation, in 50%-60% of patients. That means that 40%-50% of patients have other mechanisms of resistance, whether it’s MET amplification or PI3K alterations or another growth pathway. HER2 has been implicated in certain instances, as has BRAF, and histologic transformation is another issue in this population.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 18th Annual International Lung Cancer Congress®Oct 31, 20181.5
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
Publication Bottom Border
Border Publication