Precision Medicine: Key Updates for Treatment of NSCLC - Episode 13

RET Fusions in Non–Small Cell Lung Cancer

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Benjamin Levy, MD: Let’s move on to RET fusion, which is yet another fusion that can be seen in non–small cell lung cancer. There are some very good drugs coming out that target RET fusions and alter the way we approach these patients and treat them. We’ll talk about how to test for fusions at the end in our testing section. Josh, do you want to walk us through the data we have with LOXO-292 in RET fusion lung cancer and the Blueprint Medicines drug pralsetinib?

Joshua Bauml, MD: Yes. I did a bit of foreshadowing a moment ago when I mentioned cabozantinib because previously, the only drugs that we had for treating RET fusions were from medullary thyroid cancer. We know that in RET-mutated cancers, cabozantinib and vandetanib have efficacy, but they bring substantial toxicity. When those drugs were used in RET fusion-positive lung cancers, the efficacy wasn’t there, in terms of response rate or progression-free survival. More recently, there have been 2 drugs that have come out that are highly active in RET fusion-positive cancers, both papillary thyroid cancer and non–small cell lung cancer. Those are selpercatinib, which has recently been granted FDA approval, and pralsetinib, for which I’m sure the approval is coming down the pike.

Selpercatinib and pralsetinib both had response rates, at least from the treatment-naïve standpoint—66% for pralsetinib, 85% for selpercatinib. Those are really impressive. Both have CNS [central nervous system] penetrance, and both pretty well tolerated. With the RET-fusion inhibitors, the big adverse effect that we see across both of them is high blood pressure, but that’s controllable with antihypertensives. There are some LFT [liver function test] abnormalities, but nothing to write home about. These are a game changer. When these drugs were only available on trials, if I found a RET fusion, I would tell a patient, “If you don’t have a trial available at your site, this is something to travel for. This is something to get on a plane for, pre-COVID-19 [coronavirus disease 2019].” This is a huge advance for our patients, and I’m very excited that now we have access to selpercatinib.

Benjamin Levy, MD: Yes. We’ve been involved with selpercatinib and the LIBRETTO-001 trial. This is a very clean drug, which hits its target nicely and selectively. We’ve had medullary thyroid patients and lung cancer patients who have come in. Specifically in our lung cancer patients, some of them who are symptomatic start to feel a difference in 5 to 7 days. These are some of the things we see with osimertinib. But it is well tolerated, aside from maybe some dry mouth. Becca, what are your thoughts on these drugs? Have you been part of some of these efforts, and where do you see this field heading?

Rebecca Heist, MD: Yes, we’ve had both drugs in studies at our institution. We have had patients on both, and I agree. A couple of years ago, there was this talk of RET. Is it really a driver? As it turns out, we just didn’t have the right drug. If you have a very potent and selective inhibitor, then yes, it’s a driver. We just didn’t get to the drug levels we needed with the other drugs that were being used before because of the ancillary toxicity. These are great drugs, as you’ve said, and are game changers for the RET-fusion population.

Benjamin Levy, MD: Lyuda, what are your thoughts? Are there differences between these 2 drugs—pralsetinib and selpercatinib—based on the data?

Lyudmila Bazhenova, MD: There are not clinically meaningful differences. Josh was very elegant in discussing the slight difference in toxicities, but I don’t think they’re clinically important. I don’t have experience with pralsetinib. I have experience with LOXO-292, and my experience is exactly as it’s published in terms of toxicity.

Transcript Edited for Clarity