Non-small Cell Lung Cancer with EGFR or HER2 Exon 20 Insertion Mutations: Diagnosis and Treatment Options

Molecular testing is performed upon diagnosis of non-small cell lung cancer (NSCLC) because of the large success of targeted therapies for oncogenic mutations. Epidermal growth factor receptor (EGFR) mutations are the most commonly identified mutation in NSCLC, and EGFR exon 20 insertion mutations (exon20ins) are the third most common mutation in EGFR following EGFR exon 19 deletions and exon 21 L858R mutations. EGFR exon20ins have regularly demonstrated resistance to classical EGFR inhibition. Two treatments-mobocertinib and amivantamab-have recently been the first drugs to be approved by the US Food and Drug Administration (FDA) for treatment of lung cancers with these mutations following platinum-based therapy. Research surrounding these two drugs demonstrates strong efficacy, but with an intense array of side effects. Another targetable driver mutation is the human epidermal growth factor receptor 2 (HER2) exon20ins, representing approximately 2-3% of NSCLC patients. This mutation has been heavily studied in vitro as well as clinically, and trastuzumab deruxtecan was just recently granted accelerated FDA approval based on the high efficacy demonstrated in the Destiny-Lung01 study. However, similar to their EGFR counterparts, HER2 inhibitors also have evidence of toxicity in clinical studies. In this paper, we discuss the limited response of EGFR and HER2 exon20ins to a wide range of standard treatment regimens, such as platinum-based chemotherapy and classic EGFR tyrosine kinase inhibitors, as well as immunotherapy. We also review recently approved and upcoming targeted therapeutic options, considering what research is presently being done regarding efficacy and the reduction of side effects, as well as the agents' risks and benefits for incorporation into an approved treatment regimen.