HER2
Human epidermal growth factor receptor 2 (HER2); erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERB-B2)
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 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
In the 2023 update to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in NSCLC, new testing recommendations for HER2 mutations were introduced.4 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. 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). Testing for HER2 mutations may also be considered for patients with metastatic squamous cell carcinoma.
HER2 Targeted Therapy
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 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. 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.
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. Accelerated approval was based on findings from three clinical trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831).9
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). Package insert. Daiichi Sankyo Inc; February 2024.
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
