Healthcare Unfiltered Express
Healthcare Unfiltered Express curates quick-hit conversations between Dr. Chadi Nabhan and his guests on hot-button topics in the healthcare world today.
Healthcare Unfiltered Express
Episode 47: The Approval of Zongertinib
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Dr. Eric Singhi of the MD Anderson Cancer Center joins Healthcare Unfiltered EXPRESS to describe this newly approved drug, its target, the trial that led to its approval, and how it fits into the treatment armamentarium for lung cancer. Please rate, subscribe, share, and join the conversation.
Well, he's back, Dr. Eric Sinji. Thank you so much for coming. You know, Eric, um the podcast we taped me and you was actually listened and viewed by several thousand people. Oh wow. So that's why I got you back. See? Has nothing to do with lung cancer approval and any of these drugs. Welcome back to the show, Healthcare on Filtered Express. Thanks for having me. Excited to be back. So I reached out to you because over the past week or so, there's a lot of buzz about this new therapy that was approved for lung cancer. And uh on Healthcare on Filtered Express, we'd like to make sure that everybody is aware of these new developments, new research, new approvals, and so on. So tell us about this new drug. Why is it approved, and why is it so important to make sure people are aware of it?
SPEAKER_00Yeah, no, thanks for the invitation and spreading awareness. That's always really important to me. And so the drug you're referring to is Zonggirtnib. So Zonggirtnib is a oral, highly selective, irreversible tyrosine kinase inhibitor. And it's going to bind to both wild type and mutated HER2. And so this is for patients with HER2 mutated non-small cell lung cancer. What's really important about its mechanism of action is that it actually spares EGFR. And as a result, it's going to reduce some of those common EGFR-related side effects like severe diarrhea, severe rash in patients. And so we actually just got a frontline approval for this drug as of February 26th of this year. So literally last week, right? And this was a granted accelerated uh approval from the FDA. And it's for patients now in the frontline setting who again have metastatic non-spalcillin cancer. They have to have a HER2 or ERB2 activating mutation in the tyrosine kinase domain. So really excited to have this approval.
SPEAKER_01So you said wild type?
SPEAKER_00Yes. So this is actually an irreversible TKI. And what it does is it's binding to the kinase domain of both wild type and mutated HER2, but it spares the EGFR pathway. And so that's why you see less of those severe EGFR-related side effects.
SPEAKER_01Amazing. Can you tell us a bit on about the trial that led to the approval?
SPEAKER_00Yeah. So this data and the approval comes from the Benian Lung 1 study. This is a phase one, A, phase one B study, had multiple cohorts. And what they saw in the patients, importantly, and where we got this recent FDA approval, is it was about 72 patients. They were treatment naive. They had to have had HER2 or ERB2 mutations that were activating in the tyrosine kinase domain. And what we saw was for these patients an objective response rate of 76%. So to put that into context, for patients in the frontline setting, what we had before this frontline approval for precision therapy was chemotherapy-based regimens. And we saw objective response rates of 30 to 40%. So this is a very significant improvement, 76%. And notably, we saw duration of responses six, 12 months, 64%, 44%, respectively. So it's great to have this option in the frontline now.
SPEAKER_01So how often you see what's the what's the prevalence of like how many lung cancer patients could potentially benefit from this?
SPEAKER_00Yeah. So if you look at non-squamous, non-small cell lung cancer, or B2 mutations or HER2 mutations happen in about 3 to 5% of cases. More common in patients with a never smoking history, light smoking history, typically younger female of Asian heritage, but really important that we're testing all patients, because I myself even have patients outside of these demographic variables. So really biomarker testing is important to make sure we're not missing it.
SPEAKER_01Yeah, interesting. And it's first line, and you said it accelerated approval. Correct. Are they doing a confirmatory trial now for this?
SPEAKER_00Yeah, they absolutely are. So actually, August of 2025 is when we got the approval for this drug, but the key was it had to be in the second line or beyond setting. So patients had to have had a prior systemic therapy before they could get it. And what we're waiting for now is a confirmatory phase three trial. This is the Bemian Lung Two study. And this one will be comparing first lines Longertonid versus standard of care, so chemotherapy plus immunotherapy in newly diagnosed patients. Um so that's actively uh still being enrolled, and we'll wait to see what the results are from that study.
SPEAKER_01Eric, I have to tell you, sometimes, I mean, not to segue, but it makes me wonder if we need confirmatory trials.
SPEAKER_00Yeah.
SPEAKER_01Or I mean, what you what you cited is on I mean, uh it to me it sounds like an unprecedented response rate. It's a very specific patient population. Uh what's your philosophical approach? I realize a regulatory capture and what's needed, but do you think we sometimes take it too much, or do you think this is the right thing to do?
SPEAKER_00Yeah, I mean, I think this is a great question. You know, there's been a lot of what I call FOMO in this space, the feeling of missing out for patients with this particular activating mutation, because we've been able to offer targeted therapies, precision therapy for patients in the frontline setting several years earlier than for patients with HER2 disease. And so this is finally a huge advancement. And so you're right, you have to wonder, you know, how is this going to impact and affect trial enrollment? Um, there's several phase one, uh phase three studies that are confirmatory looking at other drugs, even in this space, compared to standard of care. Um, so sevabertnib is another drug that's a tyrosine kinase inhibitor being compared to standard of care. And that's in the SOHO O2 study. We're also looking at the Destiny Lung 4 study with an ADC trust who's an obterextican versus standard of care. So the whole sequencing strategy is completely changing for patients. And um, I'm actually really excited about this approval with Songurtnib in the front line because this is actually one of the more recent drugs that made its way through the new FDA National Priority Review Voucher Program. Um, and so that actually cut down that review process from one year to about 66 days. Um pretty impressive to see that. And I don't know if you've heard more about that program.
SPEAKER_01Yeah, I have. So I'm trying to just think. So so let's say a patient walks in the door today who meets the phenotype and the genotype of patient that you'll give them zungritinib. But at the same time, if you had that trial open, yeah, it seems to me it's counterintuitive because you can give them the drug, but if you have the trial open, you would say, but you could get on this trial and you may not get the drug again chemotherapy. How does that even work?
SPEAKER_00Yeah, I mean, I think this whole process of informed consent, right, is going to be really important. I mean, you have to tell patients the options and you have to say, yes, we have this accelerated approval now for the frontline setting. Um, of course, I still think you know, we don't know ADC or this drug, right? And so there's a lot of nuances here. And I think we're learning in real time. There's actually just a case report, even a month ago, two months ago in clinical lung, where we're learning more about acquired mechanisms of resistance on this drug, like zongirt nib, and can you salvage response therapies with trestuzenab Dorextocan afterwards, right? Um, so even more important to reprofile patients, understand mechanisms of acquired resistance, and sort of move forward from that standpoint.
SPEAKER_01Any side effects we should uh be aware of with this particular drug?
SPEAKER_00Yeah, so I think the main things really with this drug, you have to watch your LFTs. And so actually the label and the guidance says for the first 12 weeks, you want to be checking every other week LFTs, um, AST ALT elevations. Grade three was pretty low. I think it was about five to eight percent for AST ALT elevations, but still something to be watching. Thankfully, uh, we are not seeing really any ILD or pneumonitis of significance, which is great, which is something we do see with trestosome abdorexican. You can see some diarrhea, you can see some rash, so you have to watch for those things. And then there is a recommendation to uh periodically in a baseline monitor cardiac function, so the left ventricular ejection fraction.
SPEAKER_01That's great. And maybe my last question to you, Eric, uh, is what's what's uh aside from the confirmative trial, what else is happening for this particular drug? Any other, I guess, combinations, no combinations, anything specific that's happening in developing this particular target or the particular drug?
SPEAKER_00Yeah, I mean, I think there's this space is becoming very uh exciting and there's a lot of new developments. So I've talked about sevabertnib, which is sort of another competitor drug in the space. There's also NBL330 from New Valent, which is showing that it's highly selective, has excellent CNS penetration. I think really understanding the intracranial efficacy, the durability, intracranial progression-free survival of all these drugs is going to be huge in decision making. And so there's more data that's actively coming out, trying to help us figure out for a patient with intracranial disease or trying to offer CNS protection, which drug do we pull? How do we pull it? What is the best results from it? Um, so that's what I'm really looking forward to because unfortunately, in this specific driver population, CNS metastases are high. Over half of the patients at some point in their journey going to develop CNS metastases at de novo, it's even high as well.
SPEAKER_01Yeah. And and and pathologists right now, even at community hospitals, are reporting uh the uh expression and so on.
SPEAKER_00So it's confusing, right? So um HER2, ERB2, just the nomenclature in general is confusing. Also, there's different ways to check for oncogenic drivers. So there's actually three different types of RB2 oncogenic drivers. You can have the RB2 mutation, which we've talked about. You can have ERB2 gene amplification, and then you can also have HER2 protein overexpression. So these are different ways to check for oncogenic drivers. They're not necessarily because you have one, you'll have the other, or vice versa. And so it's it's confusing. I think there's a huge opportunity for education. This is why I'm so glad you're doing honestly your podcast and explaining it to patients and to providers.
SPEAKER_01Anything else I should have asked you that is of relevance that's important to folks who are listening and viewing this?
SPEAKER_00I am just really thrilled for patients with HERTI-positive disease. I mean, this is something we've been waiting for to move precision therapy into the frontline setting and we're seeing it play out. We have confirmatory trials that are still ongoing and hope to see those results. And just I think emphasizing the hope in this space that there is progress, even for this rare subset but still meaningful subset of patients.
SPEAKER_01Dr. Eric Sinji, thank you so much for coming on Healthcare and Frontal Express. Thanks for having me. So, anything you want to add that I may have forgotten to ask you that you think viewers and listeners would need to hear about?
SPEAKER_00Yeah, no, I'm just grateful that we have this opportunity to chat and to really highlight this rare but very meaningful subset of patients, right? We're seeing precision therapy moving into the frontline setting. We have these confirmatory trials that are ongoing. We'll continue to provide guidance, I think, for patients that we're seeing. Um really grateful to see this progress and to know that there's hope in this space.
SPEAKER_01Thank you so much for always giving us time. Uh Eric Sinji, thank you so much for coming on Healthcare Unfolded Express.
SPEAKER_00Thanks for having me. Take care.