Zongertinib Shows Benefit Across Subgroups in HER2-Mutated NSCLC: John Heymach, MD, PhD

In part 2 of an interview conducted at the American Association for Cancer Research Annual Meeting 2025, 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), discusses the impact of zongertinib, a HER2-targeted tyrosine kinase inhibitor, on subgroups of patients with advanced, previously treated HER2-mutated non–small cell lung cancer. He also highlights the next steps in its clinical development.

Watch part 1 to learn more about the trial's key findings and how zongertinib compares with other treatment options for this patient population.

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

Transcript

The Beamion LUNG-1 study reports that no patients experienced interstitial lung disease. Can you discuss the significance of this result in the safety data?

Antibody-drug conjugates like trastuzumab deruxtecan often have ILD, or interstitial lung disease, as a side effect. For this reason, I think, in the earlier clinical studies, they're very careful about what patients were put on to make sure they didn't have any preexisting lung issues that could compound that.

Patients with lung cancer have a lot of preexisting lung issues, so having an option that has no appreciable risk that we've seen so far of interstitial lung disease is an important thing for these patients.

Can you discuss the significance of the responses among patients with brain metastases?

One thing about patients with HER2 mutations that have non–small cell lung cancer is that they've got a very, very high rate of brain metastases. This really is a tumor type that's very aggressive in that regard. In fact, in the Beamion LUNG-1 study, in cohort 1, almost 40% of patients had brain metastases at the start.

Having activity against these brain metastases is very important for drugs in this class. We present data that patients with brain metastases did have responses to zongertinib. The intracranial response rate for the patients whom we could measure easily by a criteria called the RANO-BM, or RANO-brain metastases criteria, was above 40% for these patients.

The drug clearly has activity. I've had a number of patients myself who've done very well, whose brain tumors responded to this drug. It's an important aspect for being able to successfully treat patients with HER2-mutant non–small cell [lung cancer].

Besides the groups already discussed, are there any subgroup results that are compelling?

We also presented data for the first time on patients who have what are called HER2 non–tyrosine kinase domain [TKD] mutations. Most HER2 mutations are in the tyrosine kinase domain, and that's what this drug blocks, but there are some mutations that occur in other parts of the protein, including the extracellular domain. There's a particular residue, the S310, that's commonly mutated, or in the transmembrane domain.

We consider all these to be non-TKD mutations. This is the largest cohort ever of patients with non-TKD mutations. Now, the response rate for that group is about 30%. If we take those that have known activating mutations, it's about 35%. While that's lower than the TKD group, it's important to keep in mind that the other options for these patients are very limited. Drugs like docetaxel have a 10% to 14% response rate. So, in that setting, that's certainly a clinically meaningful activity.

With zongertinib being under FDA Fast Track and Breakthrough Therapy designations, what are the next steps in clinical development? How soon might this drug be accessible to patients outside of clinical trials?

It's undergoing priority review by the FDA, and the FDA has announced that there's a date in August when decisions will be made about accelerated approval. We're anxiously awaiting and hoping that the drug becomes available to patients.

Now, there's an ongoing study called Beamion LUNG-2 [NCT06151574]. This is for first-line patients who have not been previously treated with chemotherapy, and that's a randomized phase 3 [trial] comparing zongertinib to the standard of care chemoimmunotherapy.

If that study were positive, then zongertinib could be approved as the first drug that you get with HER2 mutations, which would certainly be an exciting development for these patients. So, we eagerly await the results of that; that study is ongoing right now.