Spotlight on Mobocertinib (TAK-788) in NSCLC with EGFR Exon 20 Insertion Mutations

The EGFR exon 20 insertion ( EGFR ex20ins) mutations are the third most common EGFR mutations seen in non-small cell lung cancer (NSCLC). More than 50 variants of EGFR ex20ins mutations have been identified with A767_V769dupASV being the most common variant across multiple surveys. Treatment with currently available EGFR tyrosine kinase inhibitors (TKIs) including osimertinib is generally ineffective. Amivantamab (JNJ-372), a bispecific monoclonal antibody against EGFR and MET, has recently been approved by the US FDA for patients with advanced or metastatic NSCLC harboring EGFR ex20ins mutations after disease progression on platinum-based chemotherapy. Among all the TKIs in clinical development, mobocertinib (TAK-788) has been granted priority review by the FDA for the same indication as amivantamab. Here, we provide a concise review on mobocertinib, with a focus on its chemical structure, preclinical data, and phase 1/2 trial results. Future directions will likely focus on combination approach such as TKI plus chemotherapy in the first-line setting, designing drugs with CNS activity, and exploring disease characteristics of various EGFR ex20ins mutation variants and how they may affect treatment response.