At ESMO 2025 I was honoured and privileged to present results from cohort 2 of the Beamion LUNG-1 trial. This was looking at patients with HER2 mutant non-small cell lung cancer with advanced stage. We know that HER2 mutant non-small cell lung cancer is an aggressive disease with patients having a reasonable propensity to brain metastases and a poorer survival than we would usually see. HER2 mutations occur in up to 4% of patients with advanced non-small cell lung cancer.
This trial was evaluating the clinical efficacy and safety of zongertinib. Zongertinib is a specifically designed irreversible inhibitor of HER2; it’s a TKI kinase inhibitor of HER2. It’s irreversible and specifically designed to be sparing of EGFR. That’s important because it’s therefore designed to minimise the EGFR-associated toxicities.
We know at the moment that the first-line space in HER2 mutant non-small cell lung cancer the standard of care currently is chemotherapy with or without immunotherapy. So I presented the data on the ongoing Beamion LUNG-1 trial, this is an ongoing phase I trial. In part Ia we dose escalated patients with HER2 altered tumours up to 360mg daily without maximum tolerated dose being identified. There was then a period of dose optimisation and after dose optimisation 120mg once daily was chosen as the optimised dose to take forward in further expansion cohorts.
There have been a number of other expansion cohorts which have been ongoing and several of these cohorts, including cohort 1, resulted in the regulatory approval of zongertinib for HER2 tyrosine kinase domain mutant non-small cell lung cancer in the FDA and also, in fact, in other jurisdictions, including China and Japan.
At the ESMO meeting I was delighted and honoured to present data from cohort 2. Cohort 2 is the expansion cohort of patients with untreated, advanced non-small cell lung cancer with tyrosine kinase domain mutations in HER2. The primary endpoint of the study was objective response rate by BICR and the inclusion criteria for the study were patients with advanced non-small cell lung cancer with tyrosine kinase domain mutations in HER2. They had to have measurable disease outside the brain. Patients with asymptomatic, untreated brain metastases were also allowed to be enrolled.
When we looked at the baseline characteristics of the cohort population, a total of 74 patients were enrolled into the study. There was an even gender balance between males and females. About one third of the population had smoked, so there’s a history of smoking. One third of the population had a history of brain metastases as well.
Importantly, when we look at the distribution of HER2 genotypes within the cohort, we can see that two thirds of the population had the classical, typical YVMA exon 20 insertion and the remaining one third were a wide diversity of other mutation subtypes.
Now, when we look at the primary endpoint of the study, objective response rate by BICR, this was met with a 76% confirmed BICR response rate with 96% of patients achieving disease control. When we look at the waterfall plot every single patient had some evidence of tumour shrinkage on the waterfall plot and, importantly, the clinical benefit of tumour shrinkage was achieved regardless of whether the patient had a YVMA mutation or not.
When we looked at the swimmers plot to get a better granularity on what the responses were like, we could see several things. Not only were the responses durable but, importantly, responses were rapid. In fact, the median time to response was at the time of the first CT scan. In fact, anecdotally patients start feeling better within a week to 15 days of starting the treatment.
The other endpoints that are important are the secondary endpoints, including duration of response and progression free survival. These have not yet been met and after a median follow-up of 8.7 months for duration of response the median has not yet been met. After a median follow-up of 11 months for progression free survival the median progression free survival has not yet been met. So this very much bodes well for time to event endpoints.
Of course, the efficacy needs to be evaluated in the context of safety. With safety we already have data on zongertinib in the relapsed patient population, this was presented by Dr Heymach previously from cohort 1 and is also published in New England. That has underpinned the regulatory approval in the US. What we demonstrated in cohort 2, these untreated patients, was that the distribution of treatment-related adverse events was very similar to what we’ve seen before with no new concerns or safety signals. Most of the adverse events that we saw were actually grade 1 or grade 2, we had no grade 4 or grade 5 treatment related adverse events. Only 9% of patients needed to discontinue zongertinib because of treatment-related adverse events.
In summary, we identified that in this group of patients that were untreated for advanced HER2 mutant non-small cell lung cancer, zongertinib was highly effective with a response rate in the high 70s, disease control rate in the high 90s, every single patient having some form of tumour shrinkage, regardless of the presence of the YVMA mutation or a different type of mutation, and an adverse event profile which is very similar to what we’ve seen before and mostly low-grade, grade 1, grade 2 adverse events.
This drug is being further evaluated in the ongoing randomised phase III trial Beamion LUNG-2. This is a confirmatory phase III trial in which patients with untreated HER2 mutant non-small cell lung cancer are being randomised to receive either zongertinib as the same dose, 120mg once daily, or the current standard of care – chemotherapy with or without immunotherapy. I encourage all of you to propose your patients for this trial at your nearest trial centre.
