Precision medicine is defined as biomarker-driven care, which includes both targeted therapies and immunotherapies, as well as treatments in which a biomarker or lack of biomarker indicates another care path, such as surgery. LUNGevity’s Take Aim Initiative focuses on ensuring that all people diagnosed with advanced-stage NSCLC have access to timely, high-quality comprehensive biomarker testing—a key component of precision medicine—at diagnosis and progression of their disease. LUNGevity believes that comprehensive biomarker testing is the first step for advanced-stage NSCLC patients to secure personalized and specific information about their cancer to guide critical decisions about the treatments that offer the highest potential for long and high-quality lives.
Nikki Martin, LUNGevity’s Director of Precision Medicine Initiatives, dives into the role of comprehensive biomarker testing with Justin Gainor, MD, Medical Oncologist, Center for Thoracic Cancers, Massachusetts General Hospital and Assistant Professor of Medicine at Harvard Medical School. Dr. Gainor is the primary oncologist for Melissa Crouse, a non-small cell lung cancer (NSCLC) patient survivor who gave us her perspective on biomarker testing and clinical trials last week.
What kind of comprehensive biomarker testing do you recommend for advanced-stage NSCLC patients?
For patients who have advanced NSCLC, the current standard of care is to have molecular testing done. At the bare minimum this includes both PD-L1 testing to guide the use of immunotherapies and testing for five genomic alterations for which we have FDA-approved therapies. Those include EGFR, ALK, ROS1, BRAF V600E, and NTRK. However, in my view, it is inadequate just to test for the markers with approved drugs because there are very, very promising targets out there with therapies in clinical development. For example, MET exon 14 skipping mutations and RET fusions are genomic alterations for which we have some very promising data using targeted therapies in clinical trials. My recommendation is for all patients with advanced NSCLC to have broader, multiplex biomarker testing, which means the tumor tissue tested for all of the markers is done at the same time via next-generation sequencing for targeted therapies and PD-L1 testing for immunotherapies.
How often should advanced-stage NSCLC patients have comprehensive biomarker testing performed?
The most crucial time to have this performed is at the time of initial diagnosis. In addition, among people who are receiving targeted therapy, if the cancer begins to grow that’s when we want to think about repeating genomic analysis. Repeat testing after progression of the cancer could be done through a blood test, a so-called liquid biopsy, or it could be with a repeat tissue biopsy. The reason to do the comprehensive biomarker testing again is to try to understand how the tumor has evolved and whether there are now new vulnerabilities—changes in the tumor DNA—that we could target therapeutically.
Are there certain types of patients, for example those with EGFR or ALK, who should be sure to have comprehensive biomarker testing re-performed at progression of their cancer?
One reason both patients and providers may want to do repeat molecular analysis is if it's going to then inform the next treatment strategy, ideally another targeted therapy. While we have next generation targeted therapies for some molecular subtypes of lung cancer, we don't have them universally for all mutations. As an example, there are multiple generations of EGFR inhibitors and multiple approved next generations of ALK inhibitors. Currently, those are the patients for whom repeat molecular genotyping may help guide use of subsequent FDA-approved targeted therapies.
On the other hand, for some mutations such as BRAF V600E, we use targeted therapies as a standard of care. But unlike EGFR and ALK, we don't have a next-generation targeted therapy currently available after using the approved BRAF and MEK inhibitor combination . For these patients, a repeat biopsy may still be considered from a research perspective to help our understanding of things, but such a biopsy is less likely to inform use of another targeted therapy specific to the BRAF mutation. I would encourage patients to ask the questions "Why should we do repeat molecular analysis? Is it to help inform my next treatment? Is it to help inform our understanding of the disease? Is it both?" Those are some of the things that should be considered.
Just as with Melissa Crouse, oncologists may find they have a patient who has a mutation but no FDA-approved therapy and no clinical trials for the marker. What is the approach you take to addressing this type of a patient?
This question is a good illustration of how sometimes the drug development process can lag behind the science a bit. Take RET fusions as an example: they were identified in lung cancer around 2012. At the time there were multiple targeted therapies, but nothing for RET. All indications were that RET fusions were biologically similar to other fusions, namely ALK and ROS1. That means, the way that RET altered the function of cells was similar to ALK and ROS1. So, people started looking at whether we could target RET-positive tumors the same way we do for ALK- and ROS1-positive tumors. At the time, our drugs were relatively limited, and we were relying on drugs that are termed "multi kinase inhibitors." These drugs didn't just block one kinase, for example, RET. They blocked many kinases. When you have a drug that blocks multiple kinases, it commonly leads to toxicity and side effects. So, as you try to push a dose higher to block your intended target kinase, you're also blocking other kinases, and that leads to side effects. And so as a field, early on trying to target RET, we were really using repurposed inhibitors that weren’t designed to target RET.
Fortunately, there was a concerted effort to catch up with the science and develop better and more selective RET inhibitors. In the last two years, we've seen the emergence of two selective RET inhibitors (LOXO-292 and BLU-667) that are available in clinical trials. These new RET inhibitors have much higher response rates and improved tolerability compared to what we saw with the multi-kinase inhibitors of five years ago. This really underscores that using science to guide the identification of new therapeutic targets, while coupling this with development of cleaner drugs can produce a transformative outcome for patients.
If you’d like to hear Melissa’s perspective, check out her blog.
If you’d like to learn more about biomarker testing, check out Biomarker Testing.
Nicole Martin is LUNGevity's Director of Precision Medicine Initatives .