Amivantamab Induces Immune-Mediated Cytotoxicity in Mesothelioma Through EGFR and MET Engagement

Introduction: Diffuse pleural mesothelioma (DPM) is a lethal malignancy with no approved therapies directly targeting tumor cells. Based on reports that EGFR and MET are frequently expressed in DPM, we sought to systematically assess their co-expression and determine the preclinical activity of amivantamab, a bispecific antibody that targets EGFR and MET. Methods: We evaluated EGFR and MET expression in patient cohorts and cell lines using transcriptomic analysis, immunohistochemistry, and biochemical assays. The mechanistic actions of amivantamab, including receptor internalization, signaling blockade, and immune-mediated cytotoxicity, were assessed using in vitro co-culture systems with peripheral blood mononuclear cells and natural killer (NK) cells. In vivo efficacy was evaluated in mesothelioma patient-derived xenograft models using immunodeficient mice reconstituted with human NK cells. Results: Transcriptomic and single-cell RNA-sequencing analyses of DPM patient cohorts revealed frequent co-expression of EGFR and MET, predominantly in malignant cells. Immunohistochemical analyses confirmed EGFR and MET protein expression across mesothelioma histologic subtypes. In vitro, amivantamab preferentially bound to DPM cells, inhibited ligand-induced EGFR and MET signaling, and promoted receptor internalization. Co-culture experiments demonstrated that amivantamab induced dose-dependent cytotoxicity through NK cell–mediated antibody-dependent cellular cytotoxicity. In multiple mesothelioma patient-derived xenograft models, the combination of amivantamab and NK cells significantly reduced tumor growth without overt toxicity. Conclusions: Amivantamab demonstrates robust preclinical antitumor activity in mesothelioma, primarily through innate immune–mediated cytotoxicity associated with EGFR and MET engagement. These findings support the clinical evaluation of bispecific EGFR/MET-targeting antibodies in mesothelioma.