Clinicopathologic Features and Response to Therapy of NRG1 Fusion–Driven Lung Cancers - Episode 4

NRG1 Fusion-Driven Lung Cancer: Future Directions in Care


Experts Alexander Spira, MD, PhD, FACP, and D. Ross Camidge, MD, PhD, highlight the importance of global registries before sharing their closing thoughts on NRG1 fusions and the future treatment landscape of lung cancer.


Alexander Spira, MD, PhD, FACP: What do you think about these global registries and how it adds to the understanding of these rare fusions? You were a part author of this registry we should point out.

D. Ross Camidge, MD, PhD: I was, and so it’s is kind of like the band’s back together. There’s a group of centers that have been doing molecular testing. We’ve just expanded what we do in molecular testing over the years. We contribute to these things. The key thing to remember is, this is the first sighting, the first description of a new beast. Sometimes there are going to be inaccuracies in there. I remember when the first registry of ALK came out, they thought there was a male preponderance and that sort of fell away over time. Some of what we’re seeing suggests patterns may fall out as we increase the numbers, but it’s the beginning. It’s the start of saying if your molecular testing panel doesn’t include NRG1 fusions or doesn’t include the facility to detect those, you’ve got to be thinking about what the future is going to be. These drugs are going to get licensed at some time, you might as well start thinking about it now.

Alexander Spira, MD, PhD, FACP: Yes, that’s a great point, especially with these rare entities. What do you think some of the next steps are?

There are some ongoing clinical studies. We should find these patients wherever we can and put them on clinical studies, right? This is only going to get answered in a prospective manner. As an important part of those studies, we need to be looking at some of the biology. I know they’ll be looking at the response rates, and I know they’ll be looking at efficacy, because that’s the most important thing. But we need to be getting some sense of do they respond to platinum therapy? What’s the natural biology of these? They won’t be able to tease all of these out, but they’ll be able to tease some of them out.

D. Ross Camidge, MD, PhD: Yes. The drugs that are starting to be developed are directed against that HER3 vulnerability, so the NRG1 has to bind to HER3. There are some anti-HER3 monoclonal antibodies, there’s even a HER2/HER3 bispecific that is being tried. These are showing some responses in relatively small data sets. Are they going to work in everybody? Are all of these NRG1 fusions going to be equally sensitive, equally responsive? If they are, what happens if they spread to the brain? Are antibodies going to be our solution? Probably not. It’s the beginning of the journey.

Alexander Spira, MD, PhD, FACP: The only challenge of this journey is this is rare. We say ALK is rare, but that’s 4%; here, we’re less than 1%. ALK used to be able to be tested with FISH [fluorescence in situ hybridization], which is was little bit more common than NGS [next-generation sequencing]. So it’s going to be a challenge, and then I’m not even going to get to the point of CNS [central nervous system] activity and those other very important things that we should reach. But they are all great and important questions, and clearly there’s a lot of work to be done. Let’s get a drug and get these patients on the study.

D. Ross Camidge, MD, PhD: The thing that I take away from it is, we are way past the tipping point for saying, “What is that other thing we’re supposed to test for?” All you have to do is make sure you have a panel. Have one time when you look through the list of things that you’re supposed to be finding, and you check that it’s all going to be detected, and then you’re good. You don’t need to be checking individual boxes, you just need to make sure that your panel covers all of the relevant things. It’s funny, we used to complain that people wouldn’t get out of bed for a 4% positivity rate for ALK, and now we’re talking about 0.2%. We’ve embraced this in thoracic oncology. If it’s there and it exists and it’s going to be in our panel, we’re just going to find it. That is the way to go. If it was your mom or my mom, you would look for these things. You wouldn’t say, “I can’t be bothered, it’s only 1 in 50 people.” What if that 1 in 50 is your mom?

Alexander Spira, MD, PhD, FACP: Right. I think the 2 things are, one is there are so many of these 4 percenters right now. You put them all together, and I know EGFR is the majority, but you’re up to 40% to 50%, especially when most of the patients, at least that I see, and I’m sure it’s similar by you, are nonsmokers. That’sNo. 1. Then even if it’s only that small percentage, we don’t need to remind everybody the difference it makes for those individual people. Even if it’s a fraction of a percent, for that 1 patient, it’s a game changer. That’s the important thing.

Great, thanks for all this time. As always, it’s fun to talk with you Ross, and I look forward to doing this again with you.

D. Ross Camidge, MD, PhD: Yes, sounds great, it was really fun.

Alexander Spira, MD, PhD, FACP: I just want to thank you, Dr. Camidge, for joining me in this discussion regarding NRG1 fusion-driven lung cancers, and I hope you the viewer enjoyed this [CancerNetwork®] Between the Lines journal club experience. Thank you for tuning in.

Transcript edited for clarity.