HER2 in Non-Small Cell Lung Cancer (NSCLC): Evolution of the Therapeutic Landscape and Emerging Drugs-A Long Way to the Top

Abstract

Non-small-cell lung cancer (NSCLC) can harbour different HER2 alterations: HER2 protein overexpression (2-35%), HER2 gene amplification (2-20%), and gene mutations (1-4%). The discovery of the HER2 gene in the 1980s raised great expectations for the treatment of several tumours. However, it was only in 2004 that HER2 mutations were identified, and they currently represent a key druggable target in NSCLC. Despite numerous strengths, there is only one FDA/EMA-approved targeted therapy, an antibody-drug conjugate (ADC) called trastuzumab deruxtecan for pretreated patients with HER2 mutant NSCLC. In the first-line treatment, the standard of care (SoC) remains chemotherapy with or without immunotherapy. In the past, pan-HER tyrosine kinase inhibitors (TKIs) were extensively studied with poor results. But, two newly developed HER2-specific TKIs with low EGFR WT inhibition (BAY2927088 and zongertinib) reported encouraging results and received the breakthrough therapy designation from the FDA. Ongoing clinical trials are investigating new agents. This review focuses on HER2 alterations. Additionally, the anti-HER2 therapies explored so far will be discussed in detail, including the following: HER2 inhibitors (pan-inhibitors and selective inhibitors), monoclonal antibodies (mAbs), and ADCs. A section of this paper is dedicated to the role of immunotherapy in HER2-altered NSCLC. The last section of this paper focuses on the drugs under development and their challenges.

Keywords: ADC; ERBB2; HER2; NSCLC; adenocarcinoma; antibody–drug conjugate; immunotherapy; targeted therapy; tyrosine kinase inhibitor.

Figure 1

Intracellular molecular pathways due to the activation of the HER2 protein, a transmembrane receptor, after its hetero- or homo-dimerization: MAPK/ERK pathway, PIK3/AKT/mTOR pathway, and JAK/STAT pathway. Abbreviations: EGFR = epidermal growth factor receptor; HER 2/3/4 = human epidermal growth factor receptor-2/3/4; P = phosphate; L = ligand; Ras = rat sarcoma virus proteins; Braf = serine/threonine-protein kinase B-Raf (v-Raf murine sarcoma viral oncogene homolog B); MEK = mitogen-activated protein kinase; ERK = extracellular-signal-regulated kinases; GRB2: growth-factor-receptor-bound protein 2; SOS = son-of-sevenless protein; PIK3 = phosphatidylinositol 3-kinases; AKT = protein kinase B (also called PKB); mTOR = mechanistic/mammalian target of rapamycin. JAK = Janus kinase. STAT = signal transducer and activator of transcription; PLC-γ = phospholipase C-gamma; PKC = Protein Kinase C; c-Fos = cellular oncogene fos; c-Jun = cellular homolog of the viral oncoprotein v-Jun; c-Myc = homology with the viral gene v-myc; CREB = cAMP Response Element-Binding Protein; S6K = Ribosomal protein S6 Kinase; FoXK1 = Forkhead box protein K1. Created using biorender.com.

Figure 2

HER2 mutations (considering only in oncogenic and likely oncogenic mutations) reported in 35 NSCLC studies in a large public database (cbioportal). (A) Representation of these mutations in the tyrosine-kinase domain (TKD), extracellular domain (ECD), and transmembrane domain (TMD). (B) Graphical representation of the frequency of the most representative mutations for each HER2 domain (TKD, ECD, TMD). Abbreviations: TKD: tyrosine-kinase domain, ECD = extracellular domain, TMD = transmembrane domain. Created using biorender.com.

Figure 3

Illustration of type of HER2 tyrosine-kinase inhibitors (TKIs) explored in HER2-mutated NSCLC. (A) Two of various pan-HER TKIs (afatinib and poziotinib). (B) Two of many dual EGFR/HER2 TKIs: pyrotinib and BAY2927088. (C) Two new selective HER2 TKIs: zongertinib and ELVN-002. Legend: yellow stars: promising drugs for which phase I/II data are published; purple star: drug for which phase I trial is ongoing. Abbreviations: TKIs: tyrosine-kinase inhibitors. ELVN: Eleven-Nineteen-Leukemia Protein IN-2. Created using biorender.com.

Figure 4

Illustration of antibody–drug conjugates (ADCs) investigated in HER2-altered NSCLC. (A) Trastuzumab emtamsine (TDM1), a second-generation ADC. (B) Trastuzumab deruxtecan (TDXd), a third-generation ADC (C) Trastuzumab rezetecan (SHR-A 1811), another third-generation ADC. Created using biorender.com.