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 (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 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

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

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

Tumor Agnostic Approval:

  • In April of 2023, T-DXd was granted accelerated approval for previously treated unresectable or metastatic HER2+ (IHC 3+) solid tumors with no satisfactory alternative treatment options, marking it as the first tumor-agnostic approved ADC.9
  • Accelerated approval was based on findings from three clinical trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831).9

Mechanism of Action:

  • T-DXd is a HER2-directed antibody-drug conjugate (ADC) consisting of a humanized anti-HER2 IgG1 antibody linked to the topoisomerase I inhibitor payload, deruxtecan, via a cleavable tetrapeptide linker.7
  • Upon binding of 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.7

Learn more about Fam-Trastuzumab Deruxtecan-nxki (T-DXd) >

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. 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
  7. 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
  8. ENHERTU (fam-trastuzumab deruxtecan-nxki). Prescribing information. Daiichi Sankyo Inc; February 2024. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true
  9. 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

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