Martin Dietrich, MD, PhD, discusses how zongertinib offers a new targeted option for HER2-mutant NSCLC, yielding durable responses and strong CNS activity.
The FDA approval of zongertinib (Hernexeos) has introduced a novel, precision-targeted treatment approach for patients with HER2-mutant non–small cell lung cancer (NSCLC), a biologically aggressive subtype often associated with high rates of central nervous system (CNS) metastases and limited response to immunotherapy, according to Martin Dietrich, MD, PhD.
HER2-mutant NSCLC shares key molecular features with EGFR-driven disease, including low immunogenicity and poor responsiveness to checkpoint inhibitors, leaving chemotherapy as the historical mainstay of treatment.
Zongertinib’s Activity in HER2+ NSCLC
Evaluable patients who had received prior platinum-based chemotherapy and had not been previously treated with a HER2-targeted TKI or antibody-drug conjugate (ADC; n = 71) achieved an overall response rate (ORR) of 75% (95% CI, 63%-83%); 58% of patients achieved a duration of response (DOR) lasting at least 6 months.1,2 Among those who had received both platinum-based chemotherapy and a prior HER2-targeted ADC (n = 34), the ORR was 44% (95% CI, 29%-61%), and 27% of patients achieved a DOR lasting at least 6 months.1
In an interview with OncLive®, Dietrich expanded on the meaningful clinical activity observed with zongertinib in both treatment-naive and previously treated patients with HER2-mutant NSCLC, highlighting the agent’s strong intracranial efficacy, durable responses, and favorable safety profile. He also discussed how these findings could support integrating zongertinib as a targeted option earlier in the treatment sequence—a question being addressed in the ongoing phase 3 Beamion LUNG-2 trial (NCT06151574), which aims to further define the agent’s role within HER2-directed treatment paradigms.
Dietrich currently serves as a medical oncologist with The US Oncology Network Cancer Care Centers of Brevard, practicing in Rockledge, Florida. He is also an assistant professor of internal medicine at the University of Central Florida in Orlando.
Dietrich: HER2-mutant NSCLC is one of the most aggressive and brain-metastatic subsets of lung cancer, and it is difficult to treat. It shares several biological features with EGFR-mutated disease, so we see limited efficacy with immunotherapies. The datasets are small, but what we know so far is that immunotherapy [in HER2-mutant disease] seems to produce response rates similar to [those in] EGFR-[mutant disease, which are] low. We’re mainly dependent on chemotherapy in this context, so introducing the first targeted therapy, [zongertinib], for HER2-mutant NSCLC is exciting.
The Beamion LUNG-1 study evaluated zongertinib at 120 mg daily in a multi-cohort design.2 In cohort 1—the most relevant group, which included patients with tyrosine kinase domain [TKD] mutations, the most common subtype—the ORR was 75%.1,2 We’ve seen strong correlations [between this agent and] intracranial response in other datasets, and the durability [of response] was good. Adjusted for underlying genetic background, the median DOR and estimated progression-free survival were both well above 1 year, which is encouraging in a pretreated subset.
In other cohorts, such as cohort 3 and cohort 5, responses were observed in patients with non-TKD mutations and in those previously treated with fam-trastuzumab deruxtecan-nxki [Enhertu], with response rates of approximately 30% to 40%. This provides proof of concept that these patients can benefit from targeted therapy. Ideally, we want to offer targeted agents as early as possible, given their [association with] improved quality of life, strong efficacy, and favorable safety profiles.
[Zongertinib] is the first HER2-targeted therapy that effectively captures the most common exon 20 insertion mutations in HER2 [with a high degree of specificity] and minimal overlap with EGFR inhibition. [Because of that], we’re not seeing many on-target adverse effects in the skin or gastrointestinal tract, which is positive.
These data are currently strongest for the second line and beyond, [where zongertinib is currently] approved. [However,] the ongoing Beamion LUNG-2 trial will serve as a confirmatory study, comparing the phase 3 KEYNOTE-189 trial [NCT02578680] regimen [of pembrolizumab (Keytruda) plus chemotherapy] against zongertinib in the first-line setting.
I’m not overly enthusiastic about that trial because the platinum/pemetrexed/pembrolizumab control arm hasn’t been validated in the HER2-mutant subset. [That study] is more of an extrapolation from the broader adenocarcinoma paradigm. Still, we’ll have to see how the FDA decides, how guidelines [evolve], and how [insurance providers] will implement [coverage for] the drug. Overall, it’s exciting to finally have a HER2-targeted agent that delivers high efficacy, CNS activity, and a favorable safety profile.
