Advances in Testing and Targeted Therapy for NSCLC: Translating Evidence to Clinical Practice - Episode 15

Non–Small Cell Lung Cancer: Targeted Agents for HER2, METExon14 and RET Alterations

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Expert oncologists consider novel targeted agents in the setting of NSCLC with mutations in HER2, MET exon14, and RET, respectively.


Benjamin Levy, MD:Let’s move to HER2 [human epidermal growth factor receptor 2]. HER2 mutations; maybe 2% to 5% of all lung cancer, lung adenocarcinoma and we have some new therapies here, Jonathan. For the sake of time trastuzumab emtansine is a drug presented by Bob Li with a response rate of roughly 40%, and a PFS [progression-free survival] around 5 to 6 months. We’ve got poziotinib, which is a pretty toxic drug but has a response rate I think of 30% to 40% but perhaps what’s leading the way is trastuzumab deruxtecan. Do you want to walk us through those data and the importance of this? To me this 1 is on the leading edge and is practice changing.

Jonathan Wesley Riess, MD: The trastuzumab deruxtecan data are very impressive: very good response rate, very good progression-free survival. There are pitfalls to cross-trial comparisons but numerically it appears to be better than many other agents that have reported out clinical trials. It’s got its own unique adverse effect profile, but it’s something I’ve used. It’s not FDA approved, but it’s something I definitely use. I have seen activity and would even consider it potentially in the first-line setting. But then you look at poziotinib. There are data regarding poziotinib that have been presented. It does have a pretty good response rate. The PFS—again, a cross-trial comparison of the pitfalls—seems a bit less than trastuzumab deruxtecan. It’s a tough drug in terms of adverse effects such as diarrhea and rash. That’s where some of these drugs have a therapeutics index issue in terms of toxicity vs maintaining a dose that would give a benefit in terms of PFS and tumor shrinkage.

Benjamin Levy, MD: I love ADCs [antibody-drug conjugates] because they’re easy. There are just 3 components. They’re single agents. It’s a little complex how these drugs work and why trastuzumab deruxtecan doesn’t work in HER2 overexpressed but works in the HER2 mutant. We’re still trying to learn, but we’ll see. There will be more data forthcoming. Alex, with MET exon 14 skipping, we’ve got 2 drugs, again with amivantamab rearing its head.

Alexander Spira, MD: Capmatinib and tepotinib are great drugs and have been around for a while, with great response rates and CNS [central nervous system] penetration; they’re great drugs. Then you have amivantamab, which is the drug that keeps on giving. We talked about it in exon 20. You talk about it in EGFRand then in MET. It’s going to be hard to explain to physicians. It was originally designed to overcome standard EGFR resistance. Lo and behold, of course it’s got these other aspects as well.

There were very good data presented yesterday at ASCO [American Society of Clinical Oncology Annual Meeting]. We participated in the study, in patients who had never received another TKI [tyrosine kinase inhibitors] but also in the refractory setting. It works really well. I don’t think it’s ever going to replace it. The CNS penetration of these antibodies has always been a question, so CNS penetration is of course important. Of course there are difficulties with IV [intravenous] infusions given weekly and infusion reactions, but you’ll have a great drug as a backup. Then the real question is, what happens when you combine it? I know what the studies show. My median duration of response on these drugs—there a small number of patients—is about a year. But if you combine these 2 and increase it even longer, you’ll have a home run.

Benjamin Levy, MD: Another story is trying to figure out the right combination strategies of 2 active drugs for a specific molecular niche and if it’s tolerable. Let’s round this out with RET fusions. Heather, where are we with RETfusions?

Heather Wakelee, MD: We’ve got 2 drugs available: selpercatinib and pralsetinib. Efficacy data are a little hard to tease out between the 2 of them. They do have different toxicity profiles, so I’ve started with each. I’ve had to switch sometimes, but I’ve also had some patients doing beautifully. We’re at a point of not being able to distinguish too well. The problem is they’re targeted therapies. They stop working between 1 and 2 years, sometimes less. What’s great is there are multiple agents being developed that are going to work as the next-generation RET inhibitors, so it will work after that.

We also have several other things on the market that you can use off label, like cabozantinib. I’ve thought about that and done that for some of the RET patients. This is another 1 where pemetrexed works phenomenally well—better than some of the targeted agents. I’m still often starting on chemotherapy with pemetrexed first line before I go to the targeted agents. I’m in the minority, but I talk with the patients about which order to go in. It’s great now that we understand it. We have options that we never had before. Some of these patients can get really sick really fast, so it’s just great to have all these different possibilities.

Benjamin Levy, MD: All these possibilities underscore again what we were talking about in the first section: testing and making sure you’re doing the right next-generation sequencing testing, probably DNA and RNA, to pick up those fusions. It’s critical. You may not find them in liquid, but if you’re going to do a tissue, make sure you’re doing DNA and RNA.

Transcript edited for clarity.