Testing for TRK Fusions at Diagnosis and Progression in NSCLC

Ben Levy, MD: TRK [tropomyosin receptor kinase] fusions are tough to identify. As a pathologist, what’s the best way to detect these fusions, or any fusion for that matter?

Timothy Craig Allen, MD, JD: As this journey has progressed from EGFR to a plethora of new findings, rare mutations, and common features—all of which have to some extent a targetable future—with more to come, this lends us toward a next-generation sequencing platform. It’s becoming impossible, if not already impossible, to find everything that’s out there using kits or immunohistochemistry [IHC]. There’s still perhaps a role for immunohistochemistry in settings, but I don’t think that excludes a full next-generation sequencing profile on our patients. Because, as we said, we never know what we’re going to see. Even a small percentage of patients with lung cancer with a certain mutation, with all the lung cancer patients we have, are going to be a reasonably large number of folks around the country who could benefit from therapy. Next-generation sequencing is proving itself more just from this discussion as being the method of choice.

Ben Levy, MD: I agree with you, Tim. That was well said. There are a lot of questions on what the optimal next-generation sequencing is. For fusions, both DNA and RNA are probably the best way. RNA is going to get you a better capture of these fusions. We at Johns Hopkins finally switched over to both a DNA and an RNA. We only had a DNA. We’re doing FISH [fluorescence in situ hybridization] for the fusions, but we’ve moved to a fusion panel in combination with DNA sequencing.

Timothy Craig Allen, MD, JD: To that end, there also may still be a role for IHC followed by reflex FISH in certain situations. RNA is more expensive than DNA next-generation sequencing, and costs are always there for us. If one already has a FISH laboratory setup, it may be appropriate to go with immunohistochemistry and FISH. Still, at some point, DNA and RNA next-generation sequencing is going to take over. It’s going to have to.

Ben Levy, MD: Fernando, what’s your preferred approach for newly diagnosed TRK fusion non–small cell lung cancer?

Fernando C. Santini, MD: The answer is pretty straightforward. The TKI [tyrosine kinase inhibitor] therapies should be the first-line approach for all patients with NTRK fusion–positive cancer. Larotrectinib [Vitrakvi] is probably a little more active and powerful. The response rates are amazing, along with the duration of response activity in the brain. It’s a no-brainer. We should try to make [the] most of our efforts to detect them, because the earlier the better.

Ben Levy, MD: Hatim, briefly, because we need to move on for the sake of time, are you biopsying these patients who are TRK fusion-positive who are on a TRK-directed therapy? Is it important? Do you put these people on trial? How do you manage the time of progression?

Hatim Husain, MD: This is important and sets the stage for oncogene-directed paradigms here. We’re getting a repeat biopsy, perhaps both the tissue and plasma if it can be achieved, or plasma or tissue, depending on what’s feasible. But we’re sequencing these patients, trying to figure out if there’s a new second-site mutation that may be explaining resistance. Importantly, as EGFR set the stage, there can potentially be targetable second-site mutations in these spaces, such as NTRK or other fusion events. Interestingly, some multikinase inhibitors can target some of these second-site mutations. In fact, there are preclinical data for cabozantinib [Cabometyx] having efficacy against some of the resistant second-site mutations that can be seen. The same paradigms have been seen with MET and ALK with sequential therapies in that strategy.

Importantly, there can be oncogene-independent mechanisms of resistance, meaning not dependent on that specific oncogene that the patient is being treated for. While those are still being fully understood in rare populations, 1 of the common themes that we see across even some fusion events is upregulated MET. As a field, getting repeat biopsies is critical. If patients have oligometastatic disease, sometimes radiation can be used as a paradigm to treat some of those with oligometastatic progression. We’re trying to get patients on clinical trials for these next-generation TRK inhibitors.

Ben Levy, MD: You made a good point with defining progression. Is this progression that truly warrants a systemic switch? Or is it progression, like oligoprogression, where we can employ other modalities, like radiation, and keep them on the drug?

Transcript edited for clarity.