Zongertinib Research Could Represent Next Wave in HER2-Mutated NSCLC Management

Effective frontline treatment of patients with HER2-mutated non–small cell lung cancer (NSCLC) will require comprehensive HER2 testing and further research to pinpoint the efficacy and safety of HER2-targeted therapies in development in this setting, according to Christina S. Baik, MD, MS.

“For identifying patients with HER2-mutated NSCLC, we would use a next-generation sequencing [NGS] assay, which would test for HER2 and all other actionable alterations to identify the subtype of lung cancer,” Baik said in an interview with OncLive^®. “That would be the best way to test for the HER2 mutation. However, also remember to test [for HER2 expression] using immunohistochemistry [IHC], which is a separate test from NGS assays.”

In the interview, Baik expanded on the types of HER2 testing that should be performed in all patients with NSCLC, notable aspects of the AE profile of the HER2-targeted TKI zongertinib (BI 1810631), and the design of the ongoing phase 3 Beamion LUNG-2 trial (NCT06151574).

Beamion LUNG-2 is evaluating zongertinib vs pembrolizumab (Keytruda) plus platinum-pemetrexed chemotherapy in patients with HER2-mutant NSCLC.¹ Progression-free survival serves as the primary end point. Key secondary end points include overall response rate (ORR), overall survival, duration of response, symptoms, and quality of life outcomes.

Previously, findings from the phase 1a/2b Beamion LUNG-1 trial (NCT04886804) demonstrated that zongertinib generated an ORR of 74% and a disease control rate of 91% among 23 efficacy-evaluable patients with HER2-mutant NSCLC.² Two dose-limiting toxicities were observed during the maximum tolerated dose evaluation period: grade 3 decreased platelet counts and grade 3 diarrhea.

Baik is an associate professor in the Clinical Research Division at Fred Hutchinson Cancer Center, as well as the clinical research director of Thoracic, Head and Neck Oncology at University of Washington Medicine and an associate professor in the Division of Hematology and Oncology at the University of Washington School of Medicine in Seattle.

OncLive: What are some of the current treatment challenges for patients with HER2-mutant NSCLC?

Baik: There are currently several areas of unmet need. Number one is that we do not yet have a [frontline] targeted therapy for this patient population. For example, for patients with lung cancer [harboring] EGFR mutations, we know there’s a targeted therapy [available] and we start with that [in the frontline]. We don’t have such an oral targeted therapy [for patients harboring] HER2 mutations. I’m hoping that will change in the near future, but a huge unmet need is that there are no available [HER2]-targeted therapies that we can start with [in the first line]. There is a targeted therapy—fam-trastuzumab deruxtecan-nxki [Enhertu]—a HER2-directed antibody-drug conjugate [ADC] that is effective in HER2-mutated lung cancer, but we give it in the second-line setting.

The second unmet need is that we do not fully understand the role of immunotherapy in patients with HER2-mutated NSCLC. Do we need to add immunotherapy to chemotherapy or use immunotherapy by itself? There are some data, but not robust data, [that address these questions so far].

What is the standard practice for HER2 testing in NSCLC?

There are 2 types of HER2 tests, and it’s important to clarify between those. There is the HER2 mutation, which we would see [based on] a change in genetic testing. Often, we can identify [HER2 mutations] through an NGS assay. These are usually insertion mutations in [HER2] exon 20, for example, as well as other point mutations. The second type of test is IHC. This is used to test for protein overexpression of HER2 and is different from mutation testing.

What is your advice for streamlining HER2 testing expectations between medical oncologists and pathologists?

Communication and workflow are specific to each institution. What’s done in 1 institution is not necessarily the same for another institution, or even for private practices that will use a third-party lab. That’s the challenge behind this.

At the University of Washington, we have tried to create a workflow so that all patients with NSCLC undergo molecular testing up-front when they’re first diagnosed, which would include HER2 mutational testing; we are working on getting HER2 IHC testing as well for all patients. [However, this testing requires] close communication with the pathologist to set the workflow.

Although a HER2-directed TKI is not yet approved for patients with HER2-mutated NSCLC, what should be known about the adverse effect (AE) profile of this class of agents?

The AEs will be specific to the drug that gets approved. The oral targeted agent that is furthest along in [development is] zongertinib. [This agent is] not yet FDA approved, but there are good data to show that it’s effective in patients with HER2-mutated NSCLC. Intracranial responses have been observed as well.

[Regarding] zongertinib, some of the common AEs have been diarrhea, gastrointestinal AEs, and transaminitis. [However, transaminitis] is not unique to this drug; transaminase is a common toxicity [associated with] all different TKIs. [Overall], I don’t think we can generalize [the AE profile of zongertinib] for all future HER2 inhibitors.

How might dose adjustment help mitigate some of the AEs seen with zongertinib?

There’s more to learn about the drug as we gather more clinical experience. What we have now is based on what’s been publicly presented in the [Beamion LUNG-1] trial, and the AEs appear to be dose related. However, the severity of AEs can vary by patient. [If a patient has severe diarrhea], for example, dose reduction helps. A lot of these AEs are dose dependent, similar to many other TKIs.

What are the design and rationale of the ongoing phase 3 Beamion LUNG-2 trial?

That study is evaluating zongertinib treatment-naive patients [with HER2-mutated advanced NSCLC] to determine whether this drug will be better than the current standard of care [SOC], which is chemotherapy plus immunotherapy. We do not fully know whether patients with HER2-mutated NSCLC benefit from immunotherapy as much as those who may not have a HER2 mutation or any other oncogenes or oncogene drivers. That said, [immunotherapy] is still considered a SOC [for these patients].

The control arm [of Beamion LUNG-2] is chemoimmunotherapy, which is being compared with zongertinib in the first-line setting. Crossover [is allowed], meaning that if patients are randomly assigned to receive chemoimmunotherapy and their disease progresses, they can [switch to receive] zongertinib. This trial may give us a definitive answer regarding the role of zongertinib in the first-line setting.

What are the key things to know regarding the current state of treating HER2-mutated NSCLC and where ongoing research could take the treatment paradigm?

Make sure [HER2 is] being tested for. Whatever assay you’re using, make sure HER2 is called out and that [it is being] tested for along with the other actionable alterations that can make a huge difference [in determining treatment] for patients. Remember that HER2 IHC testing, or even HER2 fluorescence in situ hybridization testing for [HER2] amplification, is not going to detect the HER2 mutation. Make sure all these different types of HER2 alterations have been tested for.

Secondly, we have a HER2-directed ADC for patients [with HER2-mutated disease] in the later-line setting. However, we have exciting data with zongertinib, as well as other HER2[-targeted therapies]. This field will continue to move forward and evolve in the years to come.

References

1. Beamion LUNG-2: a study to test whether zongertinib (BI 1810631) helps people with advanced non-small cell lung cancer with HER2 mutations compared with standard treatment. ClinicalTrials.gov. Updated November 1, 2024. Accessed November 1, 2024. https://clinicaltrials.gov/study/NCT06151574
2. Heymach J, Opdam F, Barve MA, et al. Phase Ia/Ib trial of zongertinib (BI 1810631), a HER2-specific tyrosine kinase inhibitor (TKI), in patients (pts) with HER2 aberration-positive solid tumors: updated phase Ia data from Beamion LUNG-1, including progression-free survival (PFS) data. J Clin Oncol. 2024;42(suppl 16):abstr 8514. doi:10.1200/JCO.2024.42.16_suppl.8514