Background: HER2 is part of the ERBB receptor tyrosine kinase family. Also known as ERBB2, HER2 does not have its own ligand binding domain, therefore it cannot bind growth factors. Alterations in the HER2 gene lead to hyperactivation triggering multiple signaling pathways, including MAPK and PI3K/AKT, resulting in uncontrolled cell proliferation, transformation and oncogenesis. HER2 alterations occur through three potential mechanisms: gene mutation, amplification and protein overexpression. HER2 amplifications occur in less than 15% patients with NSCLC. HER2 mutations are seen in 2% to 6% of EGFR/KRAS/ALK-negative NSCLC. While targeted therapies have been successful in breast cancer, they have not proven effective in NSCLC.
- Clinical Features Associated: females, Asian ethnicity, minimal/no smoking history, adenocarcinoma histology, CNS involvement reported in up to 47% of patients
Detection Methods: FISH, IHC, RT-PCR, NGS
Most Common Alterations:
- HER2 Mutations:
- HER2 mutations are found in 1% to 4% of patients with NSCLC. The most common mutations occur in exon 20 which resemble EGFR 20-activating mutations
- YMVA exon 20 mutations, insertion of three to 12 base pairs resulting in duplication or insertion of amino acids, account for 80% to 90% of all HER2 mutations and are the focus of HER2-directed therapies.
- Point mutations in exon 20, L755S and G776C, account for 8% to 10% of HER2 mutations.
- Mutations found in conjunction with other driver mutations, including EGFR, ALK and ROS, should be treated differently. Additional rare mutations have been identified (G660D, R678Q, E693 and Q709L) but their prognostic value remains unclear.
- Current Diagnostic Methods: NGS, RT-PCR, and qPCR
- HER2 Gene Amplification:
- Amplifications have been identified in 2% to 5% of treatment-naive NSCLC patients and 13% in those patients who progressed on prior EGFR TKI therapy. Prognosis for patients with HER2 amplification remains unclear, with some studies suggesting shorter OS
- Current Diagnostic Methods: FISH, NGS, ELISA, and RT-PCR
- HER2 Overexpression:
- Overexpression is found in 2% to 30% of patients with NSCLC and has been shown to be associated with worse survival especially in early-stage NSCLC
- Current Diagnostic Methods: IHC, qPCR and RT-PCR
FDA-Approved Targeted Therapies:
- Trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo):
- HER2-directed antibody drug-conjugate received FDA approval in 2020 for patients with HER2 mutant metastatic NSCLC who have progressed on platinum-based chemotherapy treatment. Approval was based on the DESTINY-Lung01 multicenter phase 2 study of patients with HER2-mutant or HER2 overexpression unresectable and metastatic NSCLC. At the time of approval, an ORR of 72.7% was found with a median PFS of 11.3 months
- Most Common Adverse Events: nausea, anemia, decreased appetite, decreased neutrophil, hair loss
- Poziotinib (Spectrum Pharmaceuticals):
- Irreversible TKI targets EGFR and HER2 exon 20 mutations received fast-track designation from the FDA in 2021 for patients with NSCLC with HER2 exon 20 mutations. Designation was granted based on two studies. Single-centered phase 2 trial of heavily pretreated NSCLC patients with either EGFR or HER2 mutations found an ORR of 42% with median PFS of 5.6 months in the HER2 mutant cohort. The single center ZENITH20 trial included patients with NSCLC with mutations in exon 20 in either EGFR or HER2. At a median follow up of 8.3 months, an ORR of 27.8% was found with a disease control rate of 70% and median PFS of 5.5 months
- Most Common Adverse Events: rash, diarrhea, inflamed or sore mouth
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