HER2

  • Human epidermal growth factor receptor 2 (HER2); erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERB-B2)
  • Gene Location: chromosome 17 (17q12)

HER2 Biology

  • Discovered in 1984, the HER2 oncogene is located on chromosome 17q12 and encodes a transmembrane tyrosine kinase receptor that is part of the epidermal growth factor receptor family.1,2

Etiology and Epidemiology

HER2 Mutations/Amplifications in NSCLC:

  • HER2 (ERBB2) mutations and amplifications have been identified in 2% to 4% of NSCLC.3,4
  • HER2-mutant NSCLC represents a heterogenous disease group, found in both smokers and nonsmokers.
  • Patients with HER2 mutations typically exhibit a worse prognosis than do patients with EGFR and ALK mutations, partially because their disease cannot yet be treated with a highly selective, targeted therapy.
  • De novo HER2 mutations are usually mutually exclusive with other driver genes, and predominantly occur in the kinase domain.3
  • HER2 mutations primarily involve insertion or duplication events in exon 20 and other activating mutations, and they are associated with responsiveness to anti-HER2 targeted therapy.3,4
  • HER2-mutated NSCLC demonstrates a propensity for brain metastases during treatment, with subtype HER2 YVMA insertion showing a particularly higher estimated 12-month brain metastasis incidence when compared with the group not having this insertion.3,5

HER2 Overexpression in NSCLC:

  • HER2 overexpression, specifically the IHC 3+ population, is presented in approximately 1-5% of patients with NSCLC.6
  • Patients with HER2 score 3 staining exhibit a poorer prognosis and reduced 5-year survival compared to those with scores of 0–2, underscoring HER2 overexpression (score 3) as an adverse prognostic factor in adenocarcinoma.7

HER2 Testing

When to Test:

  • All patients with advanced or metastatic lung adenocarcinoma should undergo broad molecular profiling at diagnosis.6
  • Broad molecular profiling should also be considered for those with advanced or metastatic lung squamous cell carcinoma at diagnosis. In early-stage disease, testing at diagnosis should include assessment of PD-L1, EGFR, and ALK.6

Available Testing Methods:

  • NGS-based testing is considered the most effective method for detecting a wide range of genomic ERBB2 (HER2) alterations; however, Sanger sequencing and targeted PCR approaches are also options.6
  • Immunohistochemistry (IHC) is the recommended method for assessing HER2 overexpression.6

Guideline Recommendations for Testing:

  • Based on clinical trial data and FDA approval of fam-trastuzumab deruxtecan-nxki (T-DXd), the NCCN NSCLC Panel advises testing for HER2 mutations in all patients with metastatic nonsquamous NSCLC or NSCLC not otherwise specified (NOS).6
  • Testing for HER2 mutations may also be considered for patients with metastatic squamous cell carcinoma.6
  • With the tumor-agnostic approval of T-DXd, guidelines now recommend biomarker testing for HER2 overexpression using IHC in patients with adenocarcinoma, large cell carcinoma, NSCLC not otherwise specified (NOS), and squamous cell carcinoma.6
  • HER2 IHC testing should be performed at some point during the course of disease progression, with careful consideration of tissue preservation when determining timing.6

HER2 Targeted Therapy

Approved Agents:

  • On August 11, 2022, the US Food & Drug Administration (FDA) granted accelerated approval to T-DXd for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.8
  • Accelerated approval was granted based on findings from DESTINY-Lung02, marking the first approval for HER2-mutated NSCLC.8
  • Alongside this approval, the FDA also sanctioned Life Technologies Corporation’s Oncomine™ Dx Target Test (tissue) and Guardant Health, Inc.’s Guardant360® CDx (plasma) as Enhertu's companion diagnostics, stipulating that tumor tissue testing is recommended if no mutation is detected with plasma-based testing.8
  • On August 8, 2025, the US Food and Drug Administration (FDA) granted accelerated approval to zongertinib for adult patients with unresectable or metastatic non-squamous non–small cell lung cancer (NSCLC) whose tumors harbor HER2 (ERBB2) tyrosine kinase domain–activating mutations following prior systemic therapy. On February 26, 2026, the FDA granted accelerated approval to zongertinib for an expanded indication for adults with unresectable or metastatic non-squamous NSCLC whose tumors have HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-authorized test.12
  • Accelerated approval was granted based on findings from Beamion-Lung1 objective response rate and duration of response.12
  • Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.12

Tumor Agnostic Approvals:

  • On April 5, 2024, the Food and Drug Administration granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.9
  • Efficacy was evaluated in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831).9

Trastuzumab Deruxtecan (T-DXd)11:

  • FDA-Approved Indication:
    • Adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA approved test, and who have received a prior systemic therapy.
    • Adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.
  • Mechanism of Action:
    • Trastuzumab deruxtecan (T-DXd) is a HER2-directed ADC consisting of a humanized anti-HER2 IgG1 antibody linked to the topoisomerase I inhibitor payload, deruxtecan, via a cleavable tetrapeptide linker.
    • Upon binding HER2 on tumor cells, T-DXd undergoes internalization and intracellular linker cleavage, thereby releasing the DXd payload and subsequently causing DNA damage and apoptotic cell death.
  • Drug Information:
  • Patient Resources:

Zongertinib13:

  • FDA-Approved Indication:
    • Adult patients with unresectable or metastatic non-squamous NSCLC whose tumors have HER2 (ERBB2) tyrosine kinase domain activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.
    • This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
  • Mechanism of Action:
    • Zongertinib is a kinase inhibitor of human epidermal growth factor receptor 2 (HER2). In vitro, zongertinib inhibited phosphorylation of HER2, downstream signaling of HER2 (phosphorylation of ERK), and proliferation of lung cancer cells harboring HER2 tyrosine kinase domain activating mutations.
    • In vivo, zongertinib demonstrated anti-tumor activity in mouse xenograft models of NSCLC harboring HER2 tyrosine kinase domain activating mutations.
  • Drug Information:
  • Patient Resources:

References

  1. Rubin I and Yarden, Y. The basic biology of HER2. Ann Oncol. 2001;12(supp1):S3-S8. doi:10.1093/annonc/12.suppl_1.s3
  2. Schechter AL, Stern DF, Vaidyanathan L, et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984;312(5994):513‐516. doi:10.1038/312513a0
  3. Yu X, Ji X, Su C. HER2-altered non-small cell lung cancer: biology, clinicopathologic features, and emerging therapies. Front Oncol. 2022;12:860313. doi:10.3389/ fonc.2022.860313
  4. Pillai RN, Behera M, Berry LD, et al. HER2 mutations in lung adenocarcinomas: a report from the Lung Cancer Mutation Consortium. Cancer. 2017;123(21):4099-4105. doi:10.1002/cncr.30869
  5. Yang S, Wang Y, Zhao C, et al. Exon 20 YVMA insertion is associated with high incidence of brain metastasis and inferior outcome of chemotherapy in advanced non-small cell lung cancer patients with HER2 kinase domain mutations. Transl Lung Cancer Res. 2021;10(2):753-765. doi:10.21037/tlcr-20-559
  6. Uzunparmak B, Haymaker C, Raso G, Masciari S, Wang L, Lin H, Gorur A, Kirby B, Cimo AM, Kennon A, Ding Q, et al. HER2-low expression in patients with advanced or metastatic solid tumors. Ann Oncol. 2023 Nov;34(11):1035-1046. doi: 10.1016/j.annonc.2023.08.005
  7. Takenaka M, Hanagiri T, Shinohara S, et al. The prognostic significance of HER2 overexpression in non-small cell lung cancer. Anticancer Res. 2011 Dec;31(12):4631-6
  8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Non-small cell lung cancer, version 3.2024. Accessed March 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  9. FDA. FDA grant accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. US FDA. Updated August 16, 2022. Accessed March 18, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung
  10. FDA.gov. FDA grant accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. Updated April 5, 2024. Accessed April 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
  11. ENHERTU (fam-trastuzumab deruxtecan-nxki). Prescribing information. Daiichi Sankyo Inc; February 2024. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true
  12. U.S. FDA grants accelerated approval to Boehringer’s HERNEXEOS® as first orally administered targeted therapy for previously treated patients with HER2-mutant advanced NSCLC. Press Release. August 8, 2025 https://www.boehringer-ingelheim.com/us/media/press-releases/hernexeos-zongertinib-tablets-gains-accelerated-approval
  13. HERNEXEOS (zongertinib). Prescribing information. Boehringer Ingelheim; August 2025. https://pro.boehringer-ingelheim.com/us/products/hernexeos/bipdf/hernexeos-prescribing-information

Additional Reading

Ren S, Wang J, Ying J, et al. Consensus for HER2 alterations testing in non-small-cell lung cancer. ESMO Open. 2022;7(1):100395. doi:10.1016/j.esmoop.2022.100395

Zhao J, Xia Y. Targeting HER2 alterations in non-small-cell lung cancer: a comprehensive review. JCO Precis Oncol. 2020;4:411-425. doi:10.1200/PO.19.00333

Vathiotis IA, Bafaloukos D, Syrigos KN, Samonis G. Evolving treatment landscape of HER2-mutant non-small cell lung cancer: trastuzumab deruxtecan and beyond. Cancers (Basel). 2023;15(4):1286.doi:10.3390/cancers15041286