Joshua K. Sabari, MD, of NYU Langone Health discusses promising results for zongertinib in HER2-mutant NSCLC; the tyrosine kinase inhibitor offers high response rates and improved quality of life with minimal toxicity.
In late April, the investigational tyrosine kinase inhibitor (TKI) zongertinib (Boehringer Ingelheim) was the star of the annual meeting of the American Association for Cancer Research (AACR) in Chicago, Illinois, with results for the phase 1a/1b Beamion LUNG-1 trial (NCT04886804) showing progression-free survival (PFS) at 12.4 months and median duration of response at 14.1 months in patients with previously treated HER2-mutated non–small cell lung cancer (NSCLC).1,2 Besides a 71% overall response rate, investigators reported no cases of interstitial lung disease, which can be seen in some patients treated with the antibody-drug conjugate trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo).
A month later, results presented at the same venue for the annual meeting of the American Society of Clinical Oncology (ASCO) brought more good news: Investigators said patient-reported outcomes (PROs) for 30 patients in the study showed “rapid improvement followed by stability in physical functioning” based on the NSCLC Symptom Assessment Questionnaire total score.3 According to Boehringer Ingelheim, the FDA is expected to act on the application for zongertinib in second-line NSCLC during the third quarter of 2025.4
Joshua K. Sabari, MD | Image: NYU Langone
Joshua K. Sabari, MD, a thoracic medical oncologist and assistant professor of medicine at Perlmutter Cancer Center, New York University (NYU) Langone Health in New York, is a coauthor of Beamion LUNG-1 and presented the PRO data at ASCO. He discussed both sets of results in an interview with The American Journal of Managed Care® (AJMC®) during ASCO. During the interview, Sabari compared results for zongertinib with those for sevabertinib (Bayer), which has received Priority Review status from the FDA for the treatment of HER2-mutant NSCLC.5 He noted that Beamion LUNG-2 (NCT06151574), which is studying zongertinib in the frontline setting,6 is enrolling patients, which Sabari called “a great opportunity.”
This interview is lightly edited for clarity.
AJMC: The 2 things we are hearing about from Beamion LUNG-1 are the response rates and the lack of adverse events (AEs). Can you discuss each one, based on results from the study thus far?
Sabari: We’reseeing very high response rates—71% or best in class, in my opinion. If you compare this with other agents [with new results at ASCO], for sevabertinib, the response rate was just showing in the 60% range.7 And if you look [at trastuzumab deruxtecan], that’s in the 55% range.8
We really want responses for patients, but we also want them to have good quality of life. So when you talk about adverse event profile, medicines like [trastuzumab deruxtecan] have high rates of chemotherapy-type adverse events, such as fatigue, hair loss, diarrhea, and nausea. We also worry about interstitial lung disease. Upward of 15% of people can have inflammation in the lung tissue, and that’s a concern.
Zongertinib is a very clean medicine. It’s selective for HER2 and spares EGFR,1,2 so we don’t see significant diarrhea, we don’t see significant rash. And there was really no interstitial lung disease. It’s a very well-tolerated oral therapy.1,2 So it’s the response together with the improvement in quality of life that is important.
One question is, what is the durability? How long are people on therapy? If you look at the different agents, zongertinib, to me, is best in class—the duration of response is more than 14 months. When we look at progression-free survival, which is how long someone is on a medicine before the cancer grows, the median progression-free survival is about 13 months for zongertinib. So it’s really a differentiator. Moving forward in the HER2 exon 20 space, there are many other medicines coming in the space as well, but to me, this is probably one of the most differentiated, best-tolerated medicines available at this time.
AJMC: The data you presented at ASCO focus on patient-reported outcomes and quality of life.3 What do patients tell you about quality of life in terms of their ability to stay on medication? What are the differentiators—is it the ability to go to work, do physical activities, or other things?
Sabari: When I first meet patients, they always want to know, “What is the therapy that’s going to give me the best shot at living longer?” When it comes to living well, they hear the data, and that’s the second part of our discussion, after we talk about efficacy—things like response rate and progression-free survival.
What we want is overall survival—we want people to live longer. The second question is, “What is my quality of life?”
A lot of people are afraid of chemotherapy—and as a clinician, if I can avoid chemotherapy, that’s benefiting patients. Because chemotherapy requires patients to come into the office every 3 weeks. They’re not feeling well from day 3 to day 8 after getting the infusion; they have lower blood counts or higher risk of infection.
"Zongertinib is a very clean medicine. It’s selective for HER2 and spares EGFR, so we don’t see significant diarrhea, we don’t see significant rash. And there was really no interstitial lung disease. It’s a very well-tolerated oral therapy. So it’s the response together with the improvement in quality of life that is important."
—Joshua K. Sabari, MD,
Perlmutter Cancer Center, NYU Langone Health
Patients don’t want to change their day-to-day routine. I have a young patient, a mother of three, who’s active and working; she’s a CPA [certified public accountant]. She doesn’t want to change her routine. She told me that she’d be OK not doing car pool, but she doesn’t want to have to change her day-to-day practice. If she’s on chemotherapy, she would be having effects on her quality of life. But on an oral therapy, she’s able to come in and potentially see us only every 3 months. So that is the hope for patients in the future—good quality of life, not having to come into cancer centers for care. When it comes to HER2-directed adverse events, we worry about diarrhea and things like rash, so trying to mitigate those is critical in the HER2 space.
AJMC: Who are the patients with HER2-mutant NSCLC? Are they smokers or nonsmokers? What are their characteristics?
Sabari: It’s a great question. So HER2 exon 20 insertion is one of those complicated mutations. First, there are different types: The YVMA [insertion] is the most common one.9 We probably see that in 70% to 80% of our patients. Then you have other activating mutations, and then you have these non–tyrosine kinase domain mutations; people don’t do as well with those mutations.
You may be familiar with the non–tyrosine kinase domain. Now, in general, HER2 mutations occur in about 2% to 4% of people with lung cancer. So it’s not uncommon; it’s more common than RET and ROS1 and BRAF. And HER2 is one of those mutations that we can see in people who’ve never smoked, but we also see it in patients who have smoked or are currently smoking. Upward of 30% to 40% of people with HER2 exon 20 have a prior smoking history,10 so it’s uniquely different from some of the other mutations, such as RET and ROS1, which are more exclusively seen in people who’ve never smoked.
AJMC: The first screening guidelines for lung cancer in high-risk patients were approved by the US Preventive Services Task Force (USPSTF) more than a decade ago and updated in 2021.11 Have you seen the effects of increased screening over time? Is it making a difference?
Sabari: Lung cancer screening has been a major success story. The best way to cure lung cancer is to identify it early and to surgically resect it—and now we’re thinking about strategies to prevent recurrence in the neoadjuvant or adjuvant setting.12 Medicines such as zongertinib have a real opportunity to be utilized in that setting as well. I have a colleague, Dr Elaine Shum, at NYU13 who’s leading one of the largest national studies of screening women who have never smoked, and that’s an important population, because we’re not screening those patients based on the USPSTF guidelines. We’re screening people who have a heavy smoking history. So think about that. We’d be missing 60% of the patients who developed HER2 exon 20 insertions per her study; she’s identified many patients, upward of 1.5% to 2% of the population screened, and it is a higher-risk patient population, such as family members of people diagnosed with lung cancer.13 She’s identified a very high rate of driver mutations. Screening is critical, but further studies need to be done to understand how we screen patients effectively who have never smoked, who may have a lower pretest probability but would also benefit if identified to have a cancer.
AJMC: Women who have never smoked are a population that we don’t think of as having lung cancer that is being examined. Are there other populations that we don’t necessarily think about with lung cancer that we should be thinking about?
Sabari: Younger patients. I have a woman in her 20s who for months had a cough that went undiagnosed as reflux and other symptoms. It is critical that if you have a young patient who has never smoked that we think more broadly, especially when people are having symptoms. Some people have scans done, and despite findings on scans, are still not worked up appropriately because they don’t fit the image of the [White] 85-year-old male who smoked for 50 years.
AJMC: Are environmental and other causes driving the increase rates among young patients?
Sabari: We are seeing an increase in rates of lung cancer in younger patients, particularly women and never-smokers, and we are thankfully seeing decreases in lung cancer in smokers because we’re seeing fewer and fewer people who’ve smoked, and that’s a huge success. I think we need to have that same success story in our younger patient population who are never-smokers. And that’s where we’re starting to think about how we screen this patient population cost-effectively.
AJMC: The initial Beamion LUNG-1 data presented at AACR involved zongertinib as a monotherapy.1,2 However, there was discussion that the ultimate use of this TKI will be in combinations. Will that improve durability even further?
Sabari: So even before we get to combinations, the thing that’s exciting to me is that as drugs are shown to be more effective for patients and better tolerated, we are better able to use them. I hope that zongertinib is approved for second line by mid-August 2025—maybe sooner….4 We just saw the data for [sevabertinib]; hopefully we get an approval there down the road as well in second line.
Then the question is, how do we then move these therapies to the frontline setting for newly diagnosed people? And there are 3 ongoing phase 3 trials looking to answer that question.6,14,15 These are really important studies that allow us to take this exciting opportunity and then move it to the front line, where all patients can get it when they’re newly diagnosed. I’m a big believer in giving the best medicine first.
The question of combination strategies is a great one because resistance mechanisms are real, and that’s a common reason for disease progression. We are talking and thinking about how we combine novel therapies. How do we think about combination strategies? And is it a possibility in the future to potentially use zongertinib with trastuzumab deruxtecan? So those are the things [being discussed] in the academic communities now—and it’s exciting [that] as we have better therapies for patients, maybe we can escalate or potentially de-escalate patients based on their risk factors.
References
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