Targeted Therapy in NSCLC: Improvements in Molecular Testing

David R. Gandara, MD: The old paradigm was test for EGFR because that’s what we knew and that’s what we had drugs for. But you were rattling off up to 8 oncogenes that are now either recommended or emerging in the guidelines. How do you go about doing that? How do you identify even a rare mutation in a patient who could dramatically benefit, but who is 1 out of 100?

Benjamin P. Levy, MD: If you have that 1 out of 100 and you treat that patient, you know the importance of testing when you see the outcomes that are quite different than treating patients with chemotherapy. We’ve made a lot of advances with targeted therapies, but perhaps as important and parallel has been the testing. We started out with single-gene testing, PCR [polymerase chain reaction] or Sanger sequencing, and FISH [fluorescence in situ hybridization] testing on single genes. This has dovetailed and moved quickly into comprehensive genomic profiling. We now have contemporary platforms that are next-generation sequencing approaches and can comprehensively profile a tumor molecularly so that we get all of our information up front.

Most of us, even in the community, are becoming a lot better with this. Testing is not perfect, and there are certain challenges and issues with tissue sufficiency and exhaustion of tissue. But we have begun to routinely test all of our patients with lung cancer with next-generation sequencing platforms. There are commercially available platforms and platforms that are grown in-house at academic centers. I think the important point is that they test for a wide variety of genes: not just 8, but probably 50 or 100 or 300. We’re learning more and more about other alterations that may be potentially actionable.

Tissue has been the gold standard for molecular testing, and we’re making headway. There are certain challenges with tissue, maybe to discuss at another time. But we’ve also made some inroads with liquid biopsies. This is an ability to capture circulating tumor DNA [ctDNA]: not circulating tumor cells, but circulating tumor DNA that is shed from cancer as a product of apoptosis and necrosis. We can identify this at low levels in the plasma and interrogate it. Importantly—and David, you’ve been intimately involved in a lot of the liquid biopsy studies—the concordance rate of genetic alterations found on liquid biopsies when using tissue as a reference is quite high. Unfortunately, with liquid biopsies, there is potential for results to be false negative. Not every cancer sheds ctDNA, but the use of tissue in liquid biopsy has moved the field forward, where we’re more able to capture these genetic alterations. If we can identify them up front, we can give the right drug to the right patient.

David R. Gandara, MD: That’s a great introduction to how you go about making these decisions. Last year, we published recommendations from the IASLC, our International Association for the Study of Lung Cancer, regarding liquid biopsy. Later this year, we’re going to have a workshop. I’m afraid it may turn out to be virtual instead of face-to-face depending on the situation, but I know you’ll be involved in that. We’re getting to the point where liquid biopsy can be used up front with certain caveats, as you mentioned. What’s your practice? Do you employ liquid biopsy or always start with tissue? Or is it based on the patient situation?

Benjamin P. Levy, MD: We have been more routinely, recently at least, adding a liquid test or a plasma-based test to all patients with a tissue biopsy. The data clearly are emerging that concurrent use of these in parallel may increase your chances of identifying actionable mutations. We’ve learned from some data, specifically the NILE study data. Those data do have some faults in terms of how the tissue was interrogated, but we’ve certainly learned that adding liquid biopsies to standard tissue biopsies may enhance your capture of actionable mutations.

Now, do I use it for every single patient? No. If I have tissue in which I know the result and I’m confident in the result, I don’t need a liquid biopsy. But if a small sample biopsy was done or even a core biopsy in which the results may take time, and I need to get moving on a treatment plan sooner, I will layer in the liquid biopsy and use that routinely to make decisions. The turnaround time is obviously quicker than with tissue biopsy, the caveat being that a negative result doesn’t tell you much. A positive result in plasma essentially rules it in.

Transcript edited for clarity.