Chapters Transcript Video HER2: TKIs Thank you and thank you for the invitation. Certainly echo those, um, comments. It's too bad because I was gonna debate PR on the ADC versus CTIIS, but I guess I'll have to strike more of a collegial note. Let me find my, um, clicker here. All right. All right, so last talk, um, you heard about HER2 ADCs, in particular, TDXD, which is now approved for both HER2 overexpressing and HER2 mutant non-small cell lung cancer. So, this talk is really going to be focused on HER2 TKIs, which are oral drugs that bind to the intracellular domain, um, the. kinase domain of of HER2 and have mostly been studied in HER2 mutant lung cancer. So, as you heard last talk, as opposed to overexpression of the protein on the cell surface, which can be picked up by IHC, we're talking about actual changes in the ERBB2 gene, um, usually found in the tyrosine kinase domain, usually picked up by NGS these days. Um, and the majority, um. Are this YVMA mutation that you can see bolded, which is an Exxon 20 insertion in, in the ERBB gene. Um, so, HER2 mutations are found in about 2 to 4% of non-small cell lung cancer, relatively small subset, and, um, are associated with, uh, non-smoking, um, uh, status, as well as a high rate, about 30% of brain metastases. So, the first attempts to target HER2 mutations in lung cancers actually used um pan HER2 non-selective TKIs. You might recognize some of these from the EGFR space. Drugs like fatinib and dacomitinib did produce some stable diseases, but response rates were, you know, generally less than 20%. Newer Pan-HERTKIs. Such as pozotinib and pyrotinib had some structural advancements that allowed them to bind a little bit better to the, um, tyrosine kinase domain. Um, so, response rates were above 20%, 20 to 30% range, but, um, still plagued by significant toxicities, in particular rash and GI toxicities that really arose from this pan-ERBB2 activity. So we are now entering um the era of selective HER2 TKIs, two of which had very exciting data just recently presented, which are going to be obviously the focus of this talk. So, we're going to start with zonertinib. So this is an irreversible selective HER2 TKI. It inhibits both wild type and mutant HER2, but very crucially spares wild type EGFR. And what, you know, EGFR inhibition, this is what has really, um, given rise to some of those dose limiting GI skin toxicities that hamper the development. Of the earlier agents that we were talking about. Um, so Zangertinib was studied in the Bon lung one study. This was presented first at AACR and then published in the New England Journal earlier this year. There are really multiple cohorts in this phase one B study, which are on the right, um, and 3 cohorts were in this initial readout, all treated with 120 mg daily dose. So, the main cohort and the largest cohort was cohort one, which is in yellow, um, highlight here, and this was patients with mutations in the HER2 tyrosine kinase domain, um, who were previously treated with chemo with or without immunotherapy, but naive to prior HER2 ADCs like TDXD. So, um, here, the response rate we saw was 71%, um, with a median PFS of 12 months. So pretty, pretty impressive results. We also saw data from the orange cohort 5, which were patients who had prior ADC exposure, where the response rate was a little lower at 48%, and also a smaller cohort of patients with non-tyrosine kinase domain mutations, where the response rate was significantly lower at 30%. Uh, safety, really important with these agents was pretty good with Sourtinib. Mostly patients experienced, uh, low grade diarrhea and rash. Importantly, you can see very few grade 3 events as was more common with the earlier Panher TKIs. Um, there were some LFT elevations, um, including some grade 3 events, um, but importantly, only 3% discontinued treatment due to toxicity. So with this impressive data, the FDA. Did, uh, provide accelerated approval August of 2025. Um, and so, um, even more recently at ESMO last month, we actually saw results for cohort two. This was the true frontline treatment naive cohort, um, and all these patients had to have tyrosine kinase domain mutation. So really expecting impressive numbers. And indeed in this cohort of 74 patients, uh, they reported a response rate of 70%. 7% with some CRs, as you can see on the right of the waterfall plot and a median timed response of 1.4 months. Keep in mind all of these were tyrosine kinase domain mutations. Um, uh, most of them had the YVMA mutation, that Exxon 20 insertion that I mentioned earlier. Those are shown in the solid purple boxes. Um, and those patients did seem to have a little bit deeper responses clustered on the right-hand side of the curve. Um, uh, PFS as well as durability with response, uh, of response with this treatment naive cohort was also, um, pretty impressive with median PFS not reached at this data cutoff. So, of course, these impressive data beg the question for patients with HER2 mutations, can an oral TKI strategy supplant chemo immunotherapy in the frontline setting similar to what we have with um the EGFR inhibitors. So, to answer this question, the BM on lung 2 study is ongoing and we'll read out in a few years. All right, so we are moving on now to agent number 2. This is Sevaburtinib, a reversible HER2 EGFRTKI. Um, this targets both HER2 as well as mutant EGFR, including some of the clinically relevant, uh, EGFR, um, resistance mutations and, uh, more uncommon mutations like Exxon 20 insertions, but is highly selective and does also spares wild type EGFR. So, again, mitigating some of those, um, toxicities that we talked about. So, sebabutinib was studied in the Soho 01 study at a twice daily dose. Of 20 mg. We again here have three cohorts to look at, but importantly, these were, these cohorts were purely defined based on prior treatment receipt, not based on type of mutation. So that's important when we interpret the results, um, which were published, um, again in New England Journal just last month, as well as presented at ESMO last month. Um, so cohort D where the patients with, um, uh, prior. Chemo plus minus immunotherapy, but again, no prior HER2 directed ADCs. And the response rate here was 64%. In the middle, you see cohort E, those are patients who had prior ADC exposure, where the response rate was 30%. And then over on the right hand side, cohort F where the actual true frontline treatment naive patients, um, where the response rate was 71%. So, you, You know, if you were keeping track and kind of comparing these results to what we saw with Zongutinib, it might seem like these numbers are a little bit lower, but important to keep in mind that this was a mix of TKD and non-TKD mutations. So you can see in the purple bars, a couple of those non-TKD lighter purple mutations, which were probably, you know, pulling these response rates down a little bit compared to the more, um, mutation selected, um, cohorts in the Zungerttinib trial. So, indeed, um, if we narrow down cohort D, so the pre-chemo treated, um, cohort to patients with TKD mutations, you see the response rate, uh, goes up to 71%, which was actually exactly the same response rate that was seen with Zongutinib. Um, and this compiled waterfall plot from the New England Journal publication really makes the point, um, strongly that the type of mutation in HER2 matters a lot, right? So, if you have a TKD mutation, your response rate is 70% versus 14%. If it's a non-TKD mutation, and then within TKD mutations, that YVMA mutation does seem to be, uh, more highly responsive than other mutations. So moving on to safety, again, most commonly we saw low grade diarrhea and rash, although I will point out that there seemed to be more grade 3, diarrhea, um, events, uh, in this drug than with, um, zongutinib and slightly higher rates of dose reduction. LFT elevations may be a little bit less prominent here, um, with. Both of these TKIs, um, importantly, in distinction to the ADCs, we did not really see ILD as a prominent side effect to worry about. Um, and uh ceritinib did receive FDA breakthrough designation last year, but based on these data that are, um, really just newly emerging, we may see an accelerated approval soon. And as with Zongutinib, there is a phase 3 frontline trial looking atsebabutinib versus standard of care, you know, keynote 189, um, and that's going to read out a little bit later, um, than the Zonerttinib trial. So, of course, one of the very exciting, um, aspects of these small molecule TKIs is intracranial penetration and efficacy, especially, as I mentioned, the pretty with a pretty high rate of CNS mets, uh, seen in this patient population. Uh, both of these studied. Had a pretty significant, um, proportion, 20 to 37% of patients with brain mets, um, and their response rates were pretty similar to the overall cohort. So, um, Zonertinib also did report an a reno BM intracranial response rate of 41%. But I will just point out that both of these studies actually have specific CNF active CNS metastasis cohorts. So untreated brain mets that There, um, have not yet read out and are going to give us a better sense of true CNS efficacy, uh, with these small molecule TKIs which we expect to, uh, to, to be pretty exciting. So, how do we sequence treatment in the year 2025? Our frontline standard of care is still chemo with or without immunotherapy. Um, in the second line, we have multiple approvals, TDXDs, ongutinib, and we'll see whether sebabutinib, you know, joins that list soon. Um, and then, of course, in a few years, um, we may see one or more of these agents entering the frontline space based on these ongoing phase 3 trials. And this together with, um, how some of these newer agents, um, pan out in terms of their development that I haven't had really time to mention is going to make treatment selection even more exciting for this rare cohort of patients. Um, so, you know, we've really seen a new bar set with these 2 HER2, uh, TKIs. I've tried to provide kind of an apples to apples comparison of the. Bottom, but in general, we're seeing response rates greater than 70% in the frontline setting, maybe 60 to 70% post chemo IO and lower if patients have been exposed to, um, HER2 ADCs, certainly lower with a non-TKD mutation. So, all of the phase 3 trials I showed you are actually limiting to TKD mutations. Uh, certainly better toxicity than what we have seen with the Pan-HER TKIs and minimal to no ILD risk, which is certainly, um, a distinction to the, the ADCs we heard about. In the last talk, um, so we look forward to seeing how, um, the CNS activity and the, the frontline trials read out. Um, that's all I have prepared, but I did want to shout out, it did not make it onto this slide, but Blaz had maybe the best tweet of ESO from this year where, um, I don't want to put words in your mouth, but it was basically Esmo gave us two twins in Zonertinib and Sevabertinib. Both act really well. One just poops a little more, so. Thank you. Created by Related Presenters Lova Sun, MD, MSCE Assistant Professor of Medicine (Hematology-Oncology), Penn Medicine's Abramson Cancer Center
