Zongertinib and the next chapter of human epidermal growth factor receptor 2-targeted therapy in non-small-cell lung cancer

Human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC) has long presented a paradox: a well-defined oncogenic driver with historically limited therapeutic options. In a recent New England Journal of Medicine (NEJM) study, Heymach et al. report early clinical results of zongertinib, a novel, highly selective HER2 tyrosine kinase inhibitor (TKI) designed to target these molecular alterations with improved tolerability in the phase I Beamion LUNG-1 study (1).

Although HER2 alterations occur in only 2–4% of NSCLC cases, they define a biologically distinct subset (2-4). The most common mutations are in-frame insertions within exon 20 of the tyrosine kinase domain (TKD), which stabilize the receptor’s active conformation and drive constitutive downstream signaling independent of ligand binding (5). In contrast to HER2 amplification or overexpression, which are established therapeutic targets in breast and gastric cancers (5), these kinase-domain mutations have been particularly challenging to inhibit with earlier HER2-directed antibodies or pan-human epidermal growth factor receptor (HER) TKIs, as those agents achieved limited efficacy and considerable off-target toxicity (6-12).

The antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) has recently transformed this landscape, achieving regulatory approval and meaningful clinical benefit in HER2-mutant NSCLC. Nevertheless, safety concerns such as interstitial lung disease (ILD) and uncertainty regarding the durability of clinical benefit—particularly progression-free survival (PFS)—relative to other HER2-targeted strategies, both of which are being evaluated in randomized trials including DESTINY-Lung04 (NCT05048797), continue to highlight the need for complementary HER2-targeted approaches (13,14). Within this evolving paradigm, zongertinib emerges as a next-generation TKI with the potential to further expand the therapeutic repertoire for patients with HER2-mutant NSCLC, pending confirmation in randomized studies.

Beamion LUNG-1 provides some of the strongest early clinical evidence to date that selective HER2 inhibition can achieve substantial and potentially durable activity in NSCLC with HER2 kinase-domain mutations. In cohort 1 (n=75; TKD mutation without prior ADC therapy) treated with 120 mg of zongertinib once daily, the confirmed objective response rate (ORR) reached 71% [95% confidence interval (CI): 60–80; P<0.001 vs. ≤30% benchmark]. The median duration of response (DoR) was 14.1 months (95% CI: 6.9 to not evaluable) with a median PFS of 12.4 months (95% CI: 8.2 to not evaluable) at the November 2024 cutoff. These outcomes compare favorably with prior HER2-directed therapies and represent a meaningful therapeutic advance for this molecular subset in the context of early-phase evaluation. In addition, other TKIs are in clinical development for HER2-mutant NSCLC, including the epidermal growth factor receptor (EGFR)/HER2-targeted agent sevabertinib, which has received U.S. Food and Drug Administration (FDA) approval in previously treated HER2-mutant NSCLC (15).

In historical context, earlier pan-HER TKIs such as poziotinib and pyrotinib produced ORRs of <40% in HER2 exon 20-mutant NSCLC, with median PFS <7.5 months and frequent EGFR-mediated toxicities, including rash and diarrhea, that limited long-term dosing. T-DXd subsequently improved efficacy, achieving ORR of 55–60% with median PFS of 8–9 months, but at the cost of clinically meaningful ILD risk and without prospective, systematic assessment of intracranial activity. Against this backdrop, zongertinib demonstrates a differentiated profile, with a confirmed ORR exceeding 70% and median PFS of 12.4 months in patients without prior exposure to a HER2-directed ADC, meaningful prospectively assessed intracranial activity, and an absence of treatment-related ILD.

Efficacy extended to patients previously treated with ADCs. In cohort 5 (n=31; TKD mutation and prior HER2-directed ADC), 48% of patients (95% CI: 32–65) had tumors that achieved a response at a median follow-up of 6.8 months (95% CI: 5.5–8.5). Among the 22 patients with prior T-DXd exposure, the ORR was 41% (95% CI: 23–61), with a median DoR of 5.3 months (95% CI: 2.8 to not evaluable) and median PFS 6.8 months (95% CI: 5.4 to not evaluable). Although the median durations of benefit trended shorter than in ADC-naïve populations, these findings demonstrate clinically significant activity in a heavily pretreated, ADC-experienced setting and indicate limited cross-resistance between HER2-directed ADCs and small-molecule HER2 inhibitors.

In the exploratory cohort 3, which included patients with non-TKD HER2 mutations, a response was seen in 6 patients (30%; 95% CI: 15–52). Responses occurred across multiple non-TKD mutation subtypes, suggesting potential, albeit variable, sensitivity to HER2 inhibition. The median DoR and PFS were not yet mature at the time of data cutoff, warranting continued follow-up to clarify durability in this biologically heterogeneous group.

Crucially, zongertinib also showed intracranial efficacy. Among 27 patients evaluable by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, the confirmed intracranial ORR was 41% (95% CI: 25–59%), underscoring meaningful central nervous system (CNS) penetration—a long-standing limitation of many earlier HER2-targeted agents. However, longer follow-up will be required to define durability of intracranial control. In parallel, several next-generation HER2-targeted TKIs designed to improve CNS penetration are in development (e.g., ORIC-114, NVL-330, IAM1363) (16-18).

The safety profile of zongertinib further differentiates it from earlier agents. Across all cohorts, grade ≥3 treatment-related adverse events occurred in 17% of patients in cohort 1, 3% in cohort 5, and 25% in cohort 3. The most frequent high-grade events were elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Notably, no cases of treatment-related ILD or deaths occurred.

The investigators prospectively enrolled patients across three clinically and biologically defined cohorts. The design enabled evaluation of zongertinib in both treatment-naïve and post-ADC settings. It also allowed assessment of activity in rarer, non-canonical mutations. The study’s rigorous dose-finding phase established a 120 mg daily regimen that achieved sustained target inhibition with manageable tolerability, supporting long-term oral administration.

Pharmacologically, zongertinib was engineered to achieve potent HER2 inhibition with minimal EGFR cross-reactivity. This design resulted in pronounced on-target efficacy 71% objective responses in cohort 1, without the dose-limiting rash and diarrhea that historically curtailed pan-HER TKIs such as poziotinib or pyrotinib. The absence of treatment-related ILD further differentiates zongertinib from HER2-directed ADCs, particularly T-DXd, where ILD remains a clinically significant concern. Prospective intracranial evaluations further strengthen the assessment of CNS activity in HER2-mutant disease.

Although the trial population was dominated by canonical exon 20 insertions (A775_G776insYVMA and related variants), the inclusion of non-TKD mutations broadens biological insight, suggesting that zongertinib’s activity may extend beyond the most common exon 20 subtype. Taken together, the consistency of efficacy across treatment contexts, measurable CNS penetration, and a favorable safety profile highlight a therapeutic profile that could meaningfully shift the management of HER2-mutant NSCLC.

Despite its rigor, the Beamion-LUNG-1 trial remains an open-label, multicohort, single-arm phase I study designed to establish proof of concept rather than comparative efficacy, and its findings should be interpreted accordingly. As such, the impressive response rates should be interpreted cautiously until validated in randomized settings. Cohort sizes were modest (75, 31, and 20 patients), yielding wide CIs, and a median follow-up of only 10–12 months limits conclusions regarding durability and overall survival. The post-ADC cohort was composed almost exclusively of patients previously treated with T-DXd, which strengthens clinical relevance but limits generalizability beyond T-DXd-exposed populations. The study lacked translational correlations, such as serial plasma sequencing or on-treatment biopsies, to confirm target engagement, and did not report post-progression molecular analyses to elucidate mechanisms of acquired resistance. As with other HER2-directed TKIs, resistance to zongertinib is expected to develop over time; however, whether this occurs via secondary HER2 mutations or off-target pathways remains unclear. Collectively, these considerations highlight the necessity for larger, controlled trials incorporating comprehensive molecular profiling to define the long-term and comparative impact of zongertinib in HER2-mutant NSCLC.

While the trial encompassed several HER2 mutation subtypes, its molecular representation was dominated by canonical exon 20 insertions, which accounted for roughly three-quarters of enrolled patients. Responses were concentrated within this group, consistent with zongertinib’s design as a selective inhibitor of HER2 kinase-domain mutations. Cohort 3 included patients with non-TKD alterations such as L755P and G776V, but numbers were small and efficacy was less consistent, making variant-specific activity difficult to define. Consequently, these findings primarily reflect outcomes in the prevalent exon 20 insertion subtype rather than the broader HER2-altered NSCLC landscape, which also includes amplification, protein overexpression, and co-mutated tumors.

Building on these insights, future development of zongertinib should incorporate longitudinal tissue and plasma sequencing to delineate resistance mechanisms and inform rational combination strategies, such as pairing with ADCs or agents targeting downstream HER2 signaling pathways. Clinically relevant priorities include defining on-target secondary HER2 kinase-domain mutations, activation of bypass pathways involving parallel receptor tyrosine kinases or downstream effectors (e.g., MET, KRAS, PI3K alterations) and phenotypic shifts such as epithelial-mesenchymal transition or histologic transformation that may reduce HER2 dependence. The evaluation of predictive biomarkers beyond mutation status, including variant-specific sensitivity, HER2 amplification and protein expression, allelic fraction, and co-mutation context, and dynamic circulating tumor DNA (ctDNA) kinetics remains critical for refining patient selection and optimizing sequencing strategies across HER2-targeted modalities. Intracranial outcomes also represent a critical frontier: although Beamion LUNG-1 demonstrated a 41% confirmed intracranial response rate among 27 evaluable patients, limited follow-up leaves the durability of CNS control and any potential prophylactic activity uncertain.

Given that ADCs exhibit limited blood-brain barrier penetration, whereas TKIs may offer earlier intracranial control but are susceptible to eventual resistance, randomized phase 3 trials incorporating translational and CNS endpoints, including serial ctDNA monitoring, resistance genotyping, and prospective intracranial assessments, will be essential to define zongertinib’s optimal sequencing and clarify whether selective HER2 inhibition should be positioned alongside or before ADC therapy as a foundational component of treatment for HER2-mutant NSCLC. The ongoing phase 3 Beamion LUNG-2 trial (NCT06151574) is evaluating the efficacy and safety of first-line zongertinib as compared with the standard of care in patients with unresectable, locally advanced, or metastatic HER2-mutant nonsquamous NSCLC.

Beamion LUNG-1 positions zongertinib as an emerging benchmark for selective HER2 inhibition in NSCLC, within the limitations of a phase I, single-arm study. With confirmed responses exceeding 70% in TKD disease, encouraging intracranial activity, and an absence of treatment-related ILD, it demonstrates that precise molecular targeting of HER2 can translate into clinically meaningful benefit. These results distinguish the selective HER2-targeted zongertinib from prior pan-HER TKIs and provide proof that potency and selectivity can coexist with tolerability. Nonetheless, several important questions remain: the durability of benefit beyond 1 year, mechanisms of resistance, and optimal strategies for integrating this agent with ADCs or other systemic therapies. Ongoing and planned randomized studies will clarify whether zongertinib should be administered before, after, or in combination with ADC therapy. Should these findings be validated in the randomized setting, selective HER2 blockade has the potential to become a foundational component of care for this previously treatment-limited population, transforming HER2-mutant NSCLC into a disease characterized by effective, biomarker-driven precision therapy. Currently, several HER2-targeted TKIs and ADCs are under clinical development, offering a promising future for a patient subgroup that until recently had very limited therapeutic options. Ongoing randomized studies will define their roles in the first-line treatment of advanced NSCLC, and additional studies are underway to evaluate HER2-targeted strategies in earlier-stage disease, where targeted therapies have already been established for other oncogenic drivers such as EGFR and anaplastic lymphoma kinase (ALK).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Shanghai Chest. The article has undergone external peer review.

Peer Review File: Available at https://shc.amegroups.com/article/view/10.21037/shc-2025-1-7/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://shc.amegroups.com/article/view/10.21037/shc-2025-1-7/coif). F.R.H. has participated in ad hoc compensated scientific advisory boards for AstraZeneca/Daiichi, Bristol Myers Squibb, Regeneron, Henlius/Fosun, OncoHost, Natera, Agilent/Dako, Nectin Therapeutics, Genentech/Roche, Danaher Diagnostics, Amgen, and Novocure. F.R.H. has received payments for professional activities from Beijing Capstone Management Consulting (June 2025), DXY Education, Hengzhou (November 2025), and Regeneron. F.R.H. reports a patent titled “EGFR protein- and gene copy number as predictive biomarkers for EGFR-directed therapies” through the University of Colorado. F.R.H. has participated in data safety monitoring or advisory board activities for Henlius/Fosun and is a member of the Board of Directors of CHOSA Oncology AB. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in Previously Treated HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med 2025;392:2321-33. [Crossref] [PubMed]
2. Hong L, Patel S, Drusbosky LM, et al. Molecular landscape of ERBB2 alterations in 3000 advanced NSCLC patients. NPJ Precis Oncol 2024;8:217. [Crossref] [PubMed]
3. Kato Y, Udagawa H, Matsumoto S, et al. Efficacy of immune checkpoint inhibitors plus platinum-based chemotherapy as 1st line treatment for patients with non-small cell lung cancer harboring HER2 mutations: Results from LC-SCRUM-Asia. Lung Cancer 2024;197:107992. [Crossref] [PubMed]
4. Waliany S, Nagasaka M, Park L, et al. Real-World Prevalence, Treatment Patterns, and Outcomes for Patients With HER2 (ERBB2)-Mutant Metastatic Non-Small Cell Lung Cancer, From a US-Based Clinico-Genomic Database. Cancer Med 2024;13:e70272. [Crossref] [PubMed]
5. Zeng J, Ma W, Young RB, et al. Targeting HER2 genomic alterations in non-small cell lung cancer. J Natl Cancer Cent 2021;1:58-73. [Crossref] [PubMed]
6. Riudavets M, Sullivan I, Abdayem P, et al. Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations. ESMO Open 2021;6:100260. [Crossref] [PubMed]
7. Cornelissen R, Prelaj A, Sun S, et al. Poziotinib in Treatment-Naive NSCLC Harboring HER2 Exon 20 Mutations: ZENITH20-4, A Multicenter, Multicohort, Open-Label, Phase 2 Trial (Cohort 4). J Thorac Oncol 2023;18:1031-41. [Crossref] [PubMed]
8. Song Z, Li Y, Chen S, et al. Efficacy and safety of pyrotinib in advanced lung adenocarcinoma with HER2 mutations: a multicenter, single-arm, phase II trial. BMC Med 2022;20:42. [Crossref] [PubMed]
9. Zhou C, Li X, Wang Q, et al. Pyrotinib in HER2-Mutant Advanced Lung Adenocarcinoma After Platinum-Based Chemotherapy: A Multicenter, Open-Label, Single-Arm, Phase II Study. J Clin Oncol 2020;38:2753-61. [Crossref] [PubMed]
10. Liu SM, Tu HY, Wei XW, et al. First-line pyrotinib in advanced HER2-mutant non-small-cell lung cancer: a patient-centric phase 2 trial. Nat Med 2023;29:2079-86. [Crossref] [PubMed]
11. Elamin YY, Robichaux JP, Carter BW, et al. Poziotinib for Patients With HER2 Exon 20 Mutant Non-Small-Cell Lung Cancer: Results From a Phase II Trial. J Clin Oncol 2022;40:702-9. [Crossref] [PubMed]
12. Le X, Cornelissen R, Garassino M, et al. Poziotinib in Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial. J Clin Oncol 2022;40:710-8. [Crossref] [PubMed]
13. Smit EF, Felip E, Uprety D, et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol 2024;25:439-54. [Crossref] [PubMed]
14. U.S. Food and Drug Administration. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. 2022. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung
15. U.S. Food and Drug Administration. FDA grants accelerated approval to sevabertinib for non-squamous non-small cell lung cancer. 2025. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sevabertinib-non-squamous-non-small-cell-lung-cancer
16. Pharmaceuticals O. ORIC Pharmaceuticals Announces First Patients Dosed Across Three Expansion Cohorts in Phase 1b Trial of ORIC-114 in Patients with Mutated NSCLC. 2025. Available online: https://investors.oricpharma.com/news-releases/news-release-details/oric-pharmaceuticals-announces-first-patients-dosed-across-three/
17. Le X, Piotrowska Z, Spira AI, et al. NVL-330, a selective HER2 tyrosine kinase inhibitor, in patients with advanced or metastatic HER2-altered non-small cell lung cancer: The phase 1 HEROEX-1 study. J Clin Oncol 2025;43:TPS8665. [Crossref] [PubMed]
18. Adjei AA, Wong K-K, Koehler M, et al. IAM1363-01: A phase 1/1b study of a selective and brain-penetrant HER2 inhibitor for HER2-driven solid tumors. J Clin Oncol 2024;42:TPS3186.