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

The EGFR exon 20 insertion (EGFRex20ins) mutations are the third most common EGFR mutations seen in non-small cell lung cancer (NSCLC), constituting up to 12% of NSCLC cases harboring EGFR mutations.1 This molecular alteration is characterized by in-frame insertions and/or duplications clustered between codons 762 and 774, resulting in constitutive activation of the EGFR pathway.2,3 More than 50 variants of EGFRex20ins mutations have been identified with A767_V769dupASV (ASV) being the most common variant across multiple The EGFR exon 20 insertion (EGFRex20ins) mutations are the third most common EGFR mutations seen in non-small cell lung cancer (NSCLC). More than 50 variants of EGFRex20ins 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 EGFRex20ins 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 EGFRex20ins mutation variants and how they may affect treatment response.