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.

Epidermal growth factor receptor (EGFR) mutations occur in approximately 10–20% of Caucasian and up to 50% of Asian patients with oncogene-addicted non-small cell lung cancer (NSCLC). Most frequently, alterations include exon 19 deletions and exon 21 L858R mutations, which confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). In the last decade, the third-generation EGFR-TKI osimertinib has represented the first-line standard of care for EGFR-mutant NSCLC. However, the development of acquired mechanisms of resistance significantly impacts long-term outcomes and represents a major therapeutic challenge. The mesenchymal–epithelial transition (MET) gene amplification and MET protein overexpression have emerged as prominent EGFR-independent (off-target) resistance mechanisms, detected in approximately 25% of osimertinib-resistant NSCLC. Noteworthy, variability in diagnostic thresholds, which differ between fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) platforms, complicates its interpretation and clinical applicability. To address MET-driven resistance, several therapeutic strategies have been explored, including MET-TKIs, antibody–drug conjugates (ADCs), and bispecific monoclonal antibodies, and dual EGFR/MET inhibition has emerged as the most promising strategy. In this context, the bispecific EGFR/MET antibody amivantamab has demonstrated encouraging efficacy, regardless of MET alterations. Furthermore, the combination of the ADC telisotuzumab vedotin and osimertinib has been associated with activity in EGFR-mutant, c-MET protein-overexpressing, osimertinib-resistant NSCLC. Of note, several novel agents and combinations are currently under clinical development. The success of these targeted approaches relies on tissue re-biopsy at progression and accurate molecular profiling. Yet, tumor heterogeneity and procedural limitations may challenge the feasibility of re-biopsy, making biomarker-agnostic strategies viable alternatives.