Targeting NSCLC with Uncommon EGFR Mutations - Episode 1

Optimal Molecular Testing Strategies in Non–Small Cell Lung Cancer

Expert perspectives on the current landscape of molecular profiling in patients with non–small cell lung cancer.


Sandip P. Patel, MD: Non–small cell lung cancer is a broad category of disease that has multiple targeted therapy and immunotherapy options. The best road map to understanding which treatment a patient should get with metastatic non–small cell lung cancer is through next-generation sequencing in a multiplex panel. These test for genes such as EGFR. It’s important to know not only that a patient has an EGFR mutation, but whether it’s an exon 20 insertion vs an exon 19 deletion or L858R. Other mutations—ALK, ROS1, RET, MET and TRAK, HER2 [human epidermal growth factor receptor 2], KRAS, G12C, and others—will increase over time. Testing is key because half of the patients with nonsquamous non–small cell lung cancer will have access to targeted therapy. As much as these tests help you understand what you should be doing in terms of targeted therapy, they also help you understand what you should not be doing in terms of certain molecular subsets such as EGFR and ALK. Giving expensive immunotherapy would not work, but also be highly toxic, especially if you introduce targeted therapy later on. Next-generation sequencing, done on tissue or as a liquid biopsy, is key to ensuring patients get not only the right therapy but avoid the wrong therapy as well.

There are multiple tests that can be utilized for multiplex testing in non–small cell lung cancer and other types of cancer. These panels more fundamentally are the how: liquid biopsy, which is usually 2 tubes of blood and often cell-free DNA, or tissue-based biopsy. Those are the 2 tissue inputs or biologic inputs specifically. Then the question is what. What’s the actual sequencing? For a liquid biopsy or cell-free DNA, these are DNA-based tests. Over tissue-based biopsy, you could have DNA- and RNA-based sequencing. [RNA-based sequencing is] slightly better for detecting fusion events.

Finally, a third category that’s typically done in blood or saliva is germline testing, which we don’t do as often in non–small cell lung cancer, but we do in other cancer types. We try to understand if there’s a hereditary cancer disposition that can optimally be done by sequencing germline as well. In my view, the sensitivity of these tends to be quite good the closer you get to the source; however, liquid biopsies can often get you the results in the metastatic setting in a week or so. That convenience factor can often be important in making sure patients are able to get on frontline therapy in a timely fashion.

In terms of when to do molecular testing, all patients with non–small cell lung cancer with a new diagnosis of metastatic disease [should get tested], particularly if they’re nonsquamous. In my view, there are often biopsy selection issues, whereas squamous tissue can be adenosquamous. My view is that all patients with metastatic non–small lung cancer should at least be tested before they start immunotherapy. That way, if they end up having an EGFR mutation, then you can start immunotherapy.

Then the risk of pneumonitis when you start a targeted therapy would be much higher, [as would the risk of] immune hepatitis with an ALK inhibitor. It’s better to test and not guess. In the neoadjuvant settings, which are more localized and more recent scenarios, understanding patients’ EGFR, ALK, and to some degree in PD-L1 status is key. As for the value of a broader-based panel, we’ll see as we progress and have more therapies in this area.

Transcript edited for clarity.