Zongertinib Shows Durable Responses in Previously Treated HER2-Mutated NSCLC: John Heymach, MD, PhD

John Heymach, MD, PhD, chair of the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center and lead investigator of the phase 1A/1B Beamion LUNG-1 trial (NCT04886804), shares data from the study, which he presented today at the American Association for Cancer Research Annual Meeting 2025 in Chicago.

The trial demonstrated that zongertinib, a HER2-targeted tyrosine kinase inhibitor, elicited durable responses in patients with advanced, previously treated HER2-mutated non–small cell lung cancer (NSCLC).

This transcript has been lightly edited; captions were auto-generated.

Transcript

At this meeting, you're presenting progression-free survival data and, for the first time, additional results with zongertinib in new groups of patients. Which of the data points offer the most promise for patients with HER2-mutated NSCLC?

For HER2-mutant lung cancer, historically, it's been very hard to develop tyrosine kinase inhibitors, these oral pills that could work for these patients. We and others have run trials before, and, for those patients, the progression-free survival was usually in the range of 2 to 5 months, and the response rate was on the order of 20% to 30% for the most part.

We're excited now, we've got a brand new oral tyrosine kinase inhibitor, zongertinib. The exciting data that we'll be presenting here at the meeting is, first of all, that this drug has a very high response rate in patients with HER2 tyrosine kinase domain mutations who've previously been treated with platinum[-based therapies]. This is a group of patients that has very limited options.

The response rate is 71% that we'll be reporting. We'll also be reporting for the first time that these responses are durable. The duration of response is over 14 months, and the median progression-free survival, how long it takes at least half of the patients for their tumor to start growing again, is 12.4 months, so both of those are greater than a year.

It's very exciting for the first time to have an oral drug where the majority of patients are responding, they're having durable responses, and the toxicity for this drug is very limited; the safety profile is very manageable. Patients are really doing quite well on the drug.

Approximately how many patients who have been previously treated with the approved antibody-drug conjugate for HER2-mutated NSCLC are now in need of a new treatment option? Absent zongertinib, what options would these patients have?

Right now, for patients with HER2 tyrosine kinase domain mutations, there's only one approved targeted agent, and that's trastuzumab deruxtecan. It's an active drug. About 49% of patients respond, median progression-free survival is about 9.9 months, so it's a drug that has clear benefits. It also has side effects associated with it. Those include knocking down blood counts, so neutropenia, and interstitial lung disease.

HER2-mutant lung cancer is about 2% to 4% of non–small cell lung cancer as a whole, so this is a few thousand patients every year that have this mutation and need this treatment. Options for these patients once they've had standard chemotherapy, which has limited efficacy for these patients, are trastuzumab deruxtecan.

If the tumor starts growing after that, the last option is a single-agent chemotherapy called docetaxel. Docetaxel tends to work in 10% to 14% of patients, that's the response rate, so these patients do really have limited options.

With this drug [zongertinib], if it were approved, it would be an alternative to trastuzumab deruxtecan. Given that the drug is oral, highly effective, and has a very favorable safety profile, one imagines that it would be an option many doctors would choose.

Even for patients who had trastuzumab deruxtecan, this could be an option after that. In the Beamion-LUNG 1 study, we present data that for patients who had prior HER2-directed ADCs [antibody-drug conjugates] like trastuzumab deruxtecan or T-DM1 [trastuzumab emtansine], the response rate is 48%, so the drug is still active, even if the patient had prior HER2 ADCs.

How important is it to have an oral therapy option for these patients?

For these patients, having an oral option, I think, is extremely important, especially one that's well tolerated. When patients are getting chemotherapy, or if they're getting a drug like trastuzumab deruxtecan, they're coming in every 2 to 3 weeks typically for treatment. They have to get their blood counts monitored. Often, their white blood cells get very low, they're vulnerable to infection, and there's a lot of side effects that impact their quality of life. Having an oral drug that they just take at home once a day and return for follow-up much less frequently really could improve the quality of life of these patients.