Uncommon epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) pose therapeutic challenge due to limited response to EGFR tyrosine kinase inhibitors (TKIs). This study presents preclinical evidence and mechanistic insights into the combination of lazertinib, a third-generation EGFR-TKI
and amivantamab, an EGFR-MET bispecific antibody, for treating NSCLC with uncommon EGFR mutations. The lazertinib-amivantamab combination demonstrates significant antitumor activity in patient-derived models with uncommon EGFR mutations either before treatment or after progressing on EGFR-TKIs. Lazertinib enhances the inhibitory capacity of amivantamab by increasing its on-target expression. Notably, the combination surpasses afatinib, a first-line treatment for uncommon EGFR mutations in NSCLC, in terms of in vivo efficacy. Promising clinical activity is also observed in two case studies of patients treated with this combination (NCT04077463). Our findings highlight the potential of the lazertinib-amivantamab combination as a therapeutic strategy for uncommon EGFR mutations, an area of unmet medical need, and support further clinical investigation.