Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC

•EGFR and HER2 exon 20 mutations are intrinsically resistant to available EGFR TKIs and anti-HER2 agents in metastatic NSCLC.•Novel drugs that overcome steric resistance have been tested in clinical trials in this population, with promising results.•These advances may revolutionize the therapeutic landscape of this particular oncogene-driven NSCLC subtype. Approximately 4% of epidermal growth factor receptor (EGFR)−mutated non-small cell lung cancer (NSCLC) present EGFR exon 20 in-frame insertions, accounting for 0.3 %–3.7 % of NSCLC. In addition, 2 %–4 % of patients with NSCLC harbor human epidermal growth factor receptor 2 gene (HER2) mutations, being the 90 % of them exon 20 insertions. These mutations confer intrinsic resistance to available EGFR tyrosine kinase inhibitors (TKIs) and anti-HER2 treatments, as they result in steric hindrance of the drug-binding pocket. Therefore, no targeted therapies have been approved for NSCLC patients with EGFR or HER2 exon 20- activating mutations to date and remain an unmet clinical need. Promising efforts to novel treatment development have been made. Early data provide encouraging activity of novel drugs targeting EGFR and HER2 mutations in metastatic NSCLC. In this review we will summarize all the data reported to date about these driver molecular alterations and potential targeted therapies.