Testing for the ALK Rearrangements


Jyoti Patel, MD, and Karen Reckamp, MD, discuss strategies for identifying ALK rearrangements in patients with advanced NSCLC and which patients should be tested for these alterations.

Karen Reckamp, MD: Dr Patel, can you talk about testing for ALK rearrangements in the clinic?

Jyoti Patel, MD: Yes, thank you, and it’s so clinically relevant. The evolution of how we test our patients has rapidly changed in recent years. Certainly, there was a time in which we felt that DNA sequencing or allele-specific sequencing, or PCR [polymerase chain reaction], was essentially enough because we had a small number of oncogenic drivers. The field has changed. We have a multitude of oncogenic drivers now; we look to immunohistochemistry [IHC] for PD-L1 for immunotherapy combinations. Similar to others, I prefer DNA and RNA testing, this is next-generation sequencing [NGS]. Advantages of this are that you can do multiple genes at once, that you can have less cellularity. That’s one of the things with allele-specific testing, you must have a high number of tumor cells to really get a good result and can have a false negative. Moreover, the next-generation sequencing with both DNA and RNA at the same time can also look for intronic gene alterations that normally you’d only get with FISH [fluorescence in situ hybridization].

Now, most of us would say if you have a patient who is newly diagnosed with metastatic or advanced non–small cell lung cancer, at our institution, we do reflex testing and PD-L1, and normally we do that in-house, I get it within 24 hours. Then I do next-generation sequencing, and usually I try to get that result within 2 weeks. There are other places that will get a quick result with PCR for EGFR, so common mutations, and then do FISH testing or IHC. Certainly FISH and IHC for ALK are very reasonable. IHC is specific and sensitive depending on cellularity. Moreover, you get the result in a single day along with PD-L1. FISH testing, at multiple institutions, and as we started this journey on targeted therapies, people often did FISH for ROS1 and ALK simultaneously. Certainly, all of those are reasonable methodologies, but we’re still looking at testing thoroughly for patients for BRAF, RET fusions, NTRK fusions, MET exon 14. You’re looking at a much larger pie.

Tissue stewardship is the biggest issue. When you do multiple cuts of IHC, you’re using a slide for each one, and then you’re doing sequential testing, or maybe you check for EGFR. If that’s negative, then you go on to FISH, and that can introduce delays for our patients. When feasible, I would recommend PD-L1 testing with IHC on all patients as well as concurrent NGS for a broad number of drivers.

The other piece that’s changed a lot is looking at blood testing. That has been from thinking maybe we’ll get a hit a decade ago to fully ingrained in most of our practices. Essentially, you’re looking for circulating tumor cells, more frequently you’re looking for cell-free DNA for most vendors. Sometimes you get an early turnaround, the turnaround time tends to be shorter. It tends to be between 7 and 10 days. Sometimes it’s easier because you do it at the point of care. You draw the blood, and it goes out, rather than tracking the tissue down and the delays that can be involved in that.

The sensitivity has gotten much better with the different platforms, and that’s something that we all need to keep in mind. There are some people who may have had experience a couple of years ago, and they may think it’s hard to get fusions or large mutations, particularly fusions like NTRK and ALK. More and more we’re understanding that the platforms have changed significantly, and often the blood-based biomarkers are great. An important caveat is although they are specific, they’re not always as sensitive. There are some patients who are shedders and have more circulating DNA. There are others who may have lower burden of disease so it’s harder to catch. Concordance is about 70% between blood and tissue.

There was an interesting study from the World Conference on Lung Cancer this year that looked at doing both simultaneously, and that again is my practice. There’s a cost savings by doing it simultaneously, adding the blood to the tissue in terms of getting people to the right targeted therapy over costly chemotherapy or immunotherapy. There’s a cost savings plus it’s better for patients, you’re more likely to get a hit. What do you do, Karen, at your institution? What’s your practice in testing?

Karen Reckamp, MD: I’ll just say that a cost savings is hard to argue with, and those are great data to start to get out there. Generally, we have a reflex test that we’re doing. By the time that I see a patient, generally it’s nearly complete for our NGS testing, and our NGS includes both DNA and RNA, so it’s more likely to see the fusions or larger alterations. Generally, we haven’t been getting blood unless the tissue is insufficient, and again, in a frontline patient with advanced disease, blood is usually a good source to find alterations.

I would ask you, for our viewers out there, when you have an IHC or a FISH test that’s positive, are you satisfied with that and would you move forward, or do you need additional testing?

Jyoti Patel, MD: If I’ve had a couple of FISH tests, I end up getting curious and looking, and usually doing NGS. What we’re learning are a couple of things. One, co-mutations probably matter. Understanding the company you keep may have impacts on progression-free survival. We’ve certainly learned that with the KRAS and EGFR stories, for example. It’s maybe not as important for ALK right now, but certainly I think an evolving field. The second piece is that if I have a positive test by FISH or IHC, I do believe it. I think the false positive rate is quite low, so you’re probably good to start finding a drug for your patient at that juncture.

Karen Reckamp, MD: That’s great to know, especially if there is insufficient tissue for doing additional tests.

Transcript edited for clarity.

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