Zongertinib for Previously Treated Patients With HER2-Mutant Advanced Non-Small Cell Lung Cancer

Results From the Beamion LUNG-1 Trial 

Joshua Sabari, MD, discusses results from the phase 1a/1b Beamion LUNG 1 trial evaluating zongertinib, a HER2-selective tyrosine kinase inhibitor (TKI), among previously treated patients with HER2-mutant advanced non-small cell lung cancer. For the cohort of patients with tyrosine kinase mutations there was a 71% response rate, with a median progression-free survival of 12.4 months which Dr Sabari called “practice-changing.”

These data were first presented at the American Association for Cancer Research (AACR) Annual Meeting 2025 in Chicago, Illinois, with simultaneously publication in New England Journal of Medicine.

Transcript:

Hello, I'm Dr. Joshua Sabari, thoracic medical oncology at NYU Langone Health and Perlmutter Cancer Center in New York. Today we're going to be discussing an exciting abstract and presentation, as well as simultaneous publication in New England Journal of Medicine, of zongertinib, a HER2-selective TKI. 

The HER2 exon 20 space is an exciting one. We know this is a mutation in non-small cell lung cancer that makes up about 2% to 4% of all patients with lung cancer, more commonly occurring in patients who never smoked, more commonly in the adenocarcinoma histology. And this has been a very difficult to treat mutation. We know it portends poor prognosis in the frontline setting. Historically, patients on chemotherapy with carboplatin-pemetrexed had a median progression-free survival [PFS] about 7 to 8 months. More recently, we saw updated data from a medicine called Enhertu or T-DXd [trastuzumab deruxtecan], a HER2 antibody-drug conjugate [ADC], that showed impressive 55% response rates with a PFS in that 9-month range. 

More recently, we're looking for targeted therapies, TKIs or tyrosine kinase inhibitors, that are truly targeting the kinase domain of HER2 and potentially would have a better toxicity profile. We know that for [T-DXd], one of the most common side effects that we are worried about are the chemotherapy-like hematologic toxicities. But we also do worry about interstitial lung disease. Starting with Zon Gittin, it's really a selective HER2-inhibitor that has very high potency and it spares EGFR, so we don't really potentially see that diarrhea, as well as rash that you'd expect with some of the other HER2/EGFR TKIs. 

The Beamion LUNG-1 study is a phase 1a dose escalation followed by a dose expansion. And what we saw presented at AACR was a dose expansion, the phase 1b, and we saw 3 cohorts presented. We saw cohort 1, which were patients with tyrosine kinase domain mutations, particularly YVMA being the most common mutation. We saw cohort 5, of patients with tyrosine kinase domain mutations who had prior ADC-directed therapy, most commonly with [T-DXd]. That's the current accelerated approval in the second line. And then lastly, we saw cohort 3, which were patients with non-tyrosine kinase domain mutations. Those are extremely rare and much more difficult to treat. 

Starting with the activity in those patients with tyrosine kinase domain mutations, we saw an impressive 71% response rate, with a disease control rate of 96%. The responses occurred early, about 1.5 months in and were durable with a median duration of response of 14.1 months, and really a practice-changing progression-free survival, a median of 12.4 months. This is truly in the realm of a targeted therapy, so response rates north of 70% and a median progression-free survival here north of 12 months. We did see some intracranial activity, overall intracranial activity of 41% with a disease control rate here of 81%. These were patients that did have prior treatment in the study. 

What was the safety profile? We didn't learn any new safety information from what we've seen in the phase 1. Overall, very clean therapy. The adverse event rate leading to discontinuation was very low 3%, and dose reduction only 7%. The most common side effects we saw were grade 1 and 2, diarrhea and rash, and some slight elevations in AST/ALT. And most important, there were no reported cases of drug-related interstitial lung disease. 

When we move to cohort 5, those are patients who've had prior HER2-directed therapy, and particularly we will talk about T-DXd or Enhertu. Twenty-two patients had prior T-DXd treatment. The objective response rate in that patient population receiving zongertinib was an impressive 41% in all-comers who were previously treated, response rate of 48% with a disease control rate of 97%, making me feel confident that this therapy has activity even in patients who were previously treated. 

And then lastly, in cohort 3, these are the patients with non-TKI mutations, the non-YVMA. These are very rare alterations. Response rates were much lower, about 30% with a disease control rate of 65%. But this is the largest data set to date of these patients being treated in this population. 

So, really excited about the data. Also looking forward to the Beamion LUNG-2 study, which is the phase 3 randomized trial of zongertinib at 120 mg daily versus standard of care. Thank you for your attention.

Source:

Heymach JV, Ruiter G, Ahn M-J, et al. Zongertinib in previously treated HER2-mutant non–small-cell lung cancer. N Eng J Med. Published online: April 28, 2025. doi:10.1056/NEJMoa2503704