FDA Approval of Zongertinib for HER2 Mutated Non-Small Cell Lung Cancer (NSCLC) - Dr. Joshua Sabari

Introducing Zongertinib and HER2 Mutation Prevalence Hello and welcome back to another episode of the Oncology Brothers Podcast. I'm Rohit Gosain and as always with my brother and Co host Rahul Gosain. Speaker 2 Today we're touching on yet another approval in the world of lung cancer. I feel like I say this almost every single time we're talking through these FDA approvals that the field is moving so fast, but this is the fifth approval in lung cancer and we still have few more months to go in 2025. Today, we're going to focus on zongertinib, first oral TKI to be approved for her two positive lung cancer. And to touch on the study design, it's finding side effects well to look out for, especially sequencing. We're joined back by doctor Joshua Subbari from NYU Langone Cancer Center. Josh, thanks for joining us. Speaker 3 Rahul and Rohit, thanks for having me. I always love discussing new therapeutic approvals with you guys. And I agree, it's an exciting time in lung cancer. Speaker 1 Indeed, Josh, we keep bringing you back because you've been involved in all these pivotal trials. Congratulations for being part of yet another approval. Before we dive into Bimian study, Josh, can you please briefly touch on the prevalence of her two disease in non small cell lung cancer? And importantly how are we defining this positivity criteria? Is it IHC or FISH? Or rather based off of ERBB 2 mutation on NGS testing? Speaker 3 Yeah, Rhode, it's a great question. I think there's a lot of confusion and practice on what is a her to alteration. And I think it's important to sort of define three separate entities of her to the 1st and most common her to alteration is a her to mutation, the most common one being the Y VMA, you know Exxon 20 insertion. We picked this up by doing broad panel next generation sequencing. Now we can also identify her to overexpression and remember that's protein expressed on the cell surface there. If you look at high rates of expression 3 plus it's relatively rare, about 1% in non small cell lung cancer. Just to make things even more confusing, there's also her two amplification which can be identified by FISH or next generation sequencing. So it's really important to understand what mutation you're looking for, what alteration you're looking for, and to match patients the appropriate therapy. Speaker 2 Josh, thanks for laying that foundation and it's important, important for us out in the community because her two stories started off with breast cancer where that her two IHC amplification is more important and we often don't see these ERBB 2 mutation. Also, a lot of the approvals are based off that IHC and FISH amplification testing rather than ERBB 2, whereas it's a little different when it comes to lung cancer. Beamion LUNG-1 Results and Treatment Sequencing Decisions Josh, can you walk us through the study design and its findings for Beaming Lung One? Speaker 3 Yeah. So first of her two mutation and lung cancer occurs in about 2 to 4%. We talked about the why VMA being the most common. The BMA in lung O1 study was a phase one dose escalation followed by the part 1B expansion study. And this was an important study. It's the first targeted therapy to be looked at specifically a her two specific targeted therapy. So it does not inhibit EGFR and it had multiple cohorts. What we Saw, presented by John Hamack from MD Anderson at the American Association of Cancer Research meeting in 2025 and subsequently published in the New England Journal of Medicine, looked at 3 cohorts. Cohort 1, which are patients with pretreated non small cell lung cancer who had her two tyrosine kinase domain mutations. What is a tyrosine kinase domain mutation? That's the active part of the gene occurring between Exxon 18 and 24, very similar to what we think about in the EGFR gene. We also looked at cohort 3 which were pre treated patients with her two directed therapies including and her two trastuzumab duroxatecan. Cohort 5 were patients that had non TKD mutations. These are mutations that occurred outside of this active machinery of the gene. There are other ongoing cohorts including cohort 2 which are treatment naive patients as well as cohort 4 which are patients with active untreated CNS metastases and we look forward to seeing that data in the near future. This study particularly in patients who had activating mutations in the tyrosine kinase domain who were treated with prior chemotherapy or immunotherapy, we saw a 71% response rate in this patient population, complete response rate in that 5 to 6% range depending if you look on the FDA label versus the clinical trial. And we saw a partial response rate here of about 64%. So we're seeing true targeted therapy response rates with this therapy. We also saw impressive median progression free survival of 12.4 months and a median duration of response of 14.1 months. And I think Rohit and Rahul, what's most important for me with this therapy is it's truly targeted and we don't really see off target toxicity. So very low rates of GI toxicity, very low rates of cutaneous or skin toxicity, truly making this a targeted therapy in the her two space. Speaker 1 Thanks so much for covering that. You're talking about overall response rate of 70 to 75% and this isn't the population as you stated, who did not get TDXD and who did get TDXD about 45% response rate and those are very, very impressive. We'll have to see how the long term PFS and OS data plays out here. Josh, in your clinic today, especially from the practical implications when you have the options of Zoom Gertner approved along with TDXD, are you going to utilize this before TDXD or after TDXD? And also, is CNS Mets going to play any role in deciding the treatment option? Speaker 3 Yeah, great questions. I think you need to have a discussion with your patients and you know what are the current approvals and the her to mutation space what we have and her to trastuzumab duroxatican with about a 55% response rate and a median progression free survival in the 9 to 10 month range. But remember trastuzumab duroxatican has a topo 1 payload, A chemotherapy warhead and patients are experiencing chemotherapy like side effects, effects things like fatigue, potentially nausea, hair loss, hematologic toxicity. And one toxicity that really concerns me the most is the risk for pneumonitis. Although low about 15%, it is a potential real toxicity when we think about a targeted therapy or true tyrosine kinase inhibitor like Zon Gertner, we talked about the efficacy data about a 71% response rate like you mentioned. When you look at patients who had prior her to targeted therapy including at her or two, you do see that mid fourty percent response rate. So for me I'll be using zongertinib first prior to using and her two. Again remember these are all pre treated patients. Standard of care remains chemotherapy and immunotherapy or chemotherapy alone in the frontline setting. It's important to note that there are three ongoing trials potentially going to replace chemotherapy and immunotherapy. We are looking at zongertinib versus chemotherapy and immunotherapy and that's the B lung two study. We're also looking at N her two trastuzumab, doroxitican versus chemotherapy and immunotherapy. And lastly, there is another drug in development called sevabertinib which is a her two and EGFR Exxon 20 TKI. So you know like you guys said, this is a really exciting time in the her two space. But because zongertinib is more targeted, has less toxicity, does not inhibit EGFR, that would be my standard of care choice in the second line setting. Speaker 2 Two things to reiterate, whenever we have an actionable mutation in clinical practice, there's this thought of shying away of immunotherapy, but her two is 1 place where chemo immunotherapy is still the standard of care. These agents are active in first line and then second. Josh, you brought this up, the side effects when it comes to TDXD, we have to worry about alopecia, fatigue, nausea and of course ILD because mortality is associated with this. Managing Side Effects and Future HER2 Therapy Directions But when it comes to Zonkertinib, any clinical polls on how to manage some common side effects and what are we expecting here? Speaker 3 Yeah. The most common side effects with zonkertinib are diarrhea and about 50% of patients report either grade one or grade two. Grade 3 or clinically significant diarrhea occurs in 1% of patients. So in a patient who has side effects of diarrhea, using Imodium can be a very effective strategy. The rate of cutaneous toxicity is quite low, but topical emollients creams are very helpful. Rates of paronychia are extremely low and the rates of ILD or interstitial lung disease are 0. This is an important sort of advance for patients with her two mutation. And you brought up the idea earlier, Rohit, about CNS activity and I think that's an important question in our driver mutation patient population. I think we need further data to better assess this. We saw about a 41% response in CNS, but these were prior treated patients. There is this cohort 4 that is ongoing of active untreated CNS metastases. We know that and her two also has in that 30 to 40% CNS activity. So currently I would radiate CNS metastases upfront prior to starting any systemic therapy unless we have further data in the near future. Speaker 1 Again, toying in with the side effect profile, patient share decision making is always the key aspect that we have to tie in. Josh, before we close, do we have any hint of Zoon Gertner activity in patients with her two IHC 3 plus or two plus for which are FISH amplified but rather NGS negative for ERBV 2 mutation? And would you use this in your practice in your patients today? Speaker 3 Yeah, this is a great question and I get this question a lot. You know particularly from community oncologist, we don't yet have robust data to say Zon Gertenib the tyrosine kinase inhibitor is active in her to over expression. I think further data is needed. Those trials are ongoing and we're also looking at the therapy and breast cancer as well as gastric cancer. For now the approval is based on the tyrosine kinase domain or non tyrosine kinase domain mutations. For those who have over expression 3 plus, recommended still is to use and her to two plus is quite tricky because the data for two plus within her 2 does not look that great in my opinion. Speaker 2 Even when we're using TDXD with three plus, the response rate looks very different than what we're comparing with ERB B2. Something to keep in mind and setting that expectation for our patients. Speaker 3 Yeah, completely agree. I mean we're seeing 2530% response rates with the her two mutation. We're seeing 70 plus percent response rates and you mentioned durability as well. True targeted therapies. I expect to see response rates north of 50% and PFS north of nine months median. Hopefully with next generation her two inhibitors, we continue to move the needle forward for our patients. Speaker 1 And again, just to read right before we close here that what you started off with Josh and Rahul, you stated that the approval here is based on mutation. Josh, thank you so much for walking us through the treatment approval and talking about the implication in our clinical practice today. And congratulations for being part of yet another FDA approval in non small cell lung cancers. We will eagerly await and look forward to bigger studies and more mature data in this particular space. For our listeners, let us go over a quick recap from the discussion today. In today's episode we're Doctor Joshua Sabari from NYU Lingo Cancer Center. We touched on the accelerated approval of songertenib for her two mutated non squamous non small cell lung cancer space. This is the first oral TKI to be approved in this space. Speaker 2 Remember her two mutation which is ERBP 2 mutation on NGS turns up in about 1 to 4% of all non small cell lung cancers. We now have TDXD and Songertenib approved. In this space, Zongerton have showed close to 70 to 75% of overall response rate in patient population that was not exposed to her two directed AD CS versus close to 45% overall response rate if they had seen her two directed ADC previously. In Bimian Longo Wan, the study that got Zongerton approved, we're seeing median PFS of 12.4 months for previously treated patients. Speaker 1 We also touched on the side effects and clinical portals around diarrhea and rash, which are usually mild. Thanks for joining us today. Keep an eye out for other episodes on the new approvals, side effect management, and practice changing data in oncology space. We are the oncology brothers.