Amivantamab Shows Preclinical Immune-Mediated Activity in Mesothelioma Through Dual EGFR/MET Targeting
Key Insights
Amivantamab, a bispecific antibody targeting EGFR (search) and MET, demonstrated preclinical antitumor activity in diffuse pleural mesothelioma (search) through dual receptor blockade and natural killer cell-mediated ADCC.
EGFR (search) and MET were found to be frequently co-expressed in malignant mesothelioma cells across transcriptomic, single-cell RNA sequencing, and immunohistochemistry analyses.
In patient-derived xenograft models reconstituted with human natural killer cells, amivantamab significantly reduced tumor growth without overt toxicity, with one model showing 89.1% tumor growth inhibition.
Amivantamab, a bispecific antibody designed to simultaneously target both EGFR (search) and MET, has demonstrated promising preclinical antitumor activity in diffuse pleural mesothelioma (search), according to a new study published in the Journal of Thoracic Oncology. The findings suggest that dual receptor targeting combined with immune effector cell engagement may offer a novel therapeutic avenue for one of the most difficult-to-treat thoracic malignancies.
Diffuse pleural mesothelioma (search) remains a biologically complex and aggressive cancer arising from the pleural lining of the lung. Despite advances in systemic therapy, treatment options designed to directly target tumor-cell vulnerabilities remain limited, and resistance to both chemotherapy and immunotherapy is common.
EGFR (search) and MET Are Frequently Co-Expressed in Mesothelioma
The study evaluated EGFR (search) and MET expression across mesothelioma patient cohorts and cell lines using transcriptomic analysis, single-cell RNA sequencing, immunohistochemistry, and biochemical assays. Results showed frequent co-expression of both receptors, predominantly in malignant tumor cells rather than in surrounding nonmalignant tissue. Protein expression of EGFR and MET was confirmed across mesothelioma histologic subtypes.
This co-expression pattern supports the biological rationale for dual receptor targeting. Rather than relying on inhibition of a single pathway, amivantamab may simultaneously interfere with two relevant signaling axes implicated in cellular proliferation, survival, migration, and treatment resistance.
Amivantamab Blocks Signaling and Promotes Receptor Internalization
In vitro experiments demonstrated that amivantamab preferentially bound to diffuse pleural mesothelioma (search) cells. The antibody inhibited ligand-induced signaling through both EGFR (search) and MET pathways and promoted internalization of both receptors. Receptor internalization may reduce the availability of EGFR and MET at the cell surface, while signaling inhibition may limit downstream proliferative and survival cascades.
However, direct signaling blockade represented only one component of the observed antitumor effect. The most striking findings involved immune-mediated cytotoxicity.
NK Cell-Mediated ADCC Emerges as Central Mechanism
When mesothelioma cells were cultured with peripheral blood mononuclear cells or natural killer (NK) cells, amivantamab induced dose-dependent cytotoxicity. The data indicate that antibody-dependent cellular cytotoxicity (ADCC) was a major mechanism of action. ADCC occurs when an antibody binds tumor cells and recruits immune effector cells, particularly NK cells, through Fc receptor interactions, enabling direct killing of antibody-coated tumor cells.
This mechanism may be especially relevant in mesothelioma, where receptor expression alone may not be sufficient for durable tumor control. The study suggests amivantamab may act through a combination of dual EGFR (search) and MET signaling blockade, receptor internalization, NK cell recruitment, and ADCC.
Patient-Derived Xenograft Models Confirm Tumor Growth Suppression
In patient-derived xenograft models using immunodeficient mice reconstituted with human NK cells, the combination of amivantamab and NK cells significantly reduced tumor growth across multiple models. One representative model showed tumor growth inhibition of 89.1%. No overt toxicity was reported.
These results reinforce that amivantamab's preclinical activity in mesothelioma may depend substantially on immune-cell participation rather than receptor blockade alone.
Clinical Rationale and Limitations
EGFR (search) expression in mesothelioma has been recognized for years, but EGFR-targeted therapies have not consistently produced meaningful clinical benefit. One potential explanation is that simply inhibiting receptor signaling may be insufficient. Amivantamab differs from conventional targeted therapies through its dual-targeting design and capacity to recruit immune effector cells.
The study adds to growing interest in biomarker-informed and immune-engaging treatment strategies for mesothelioma. EGFR (search) and MET co-expression could become relevant biomarkers for future clinical studies.
Important limitations must be acknowledged. This was a preclinical study conducted in cell culture systems and patient-derived xenograft models, not in patients treated in a prospective clinical trial. The efficacy of amivantamab in mesothelioma, the optimal patient population, the relevance of EGFR (search) and MET expression levels, and the safety of this approach in clinical practice remain unknown. Human NK cell-reconstituted mouse models cannot fully reproduce the complexity of the human tumor microenvironment.
Future Directions
The study supports further evaluation of amivantamab in diffuse pleural mesothelioma (search). Future clinical research may need to explore whether EGFR (search) and MET co-expression predicts benefit, the role of histologic subtype, the contribution of NK cell activity and the immune microenvironment, potential combinations with chemotherapy or immune checkpoint inhibition, and biomarkers associated with resistance to EGFR/MET dual targeting.
The findings also raise a broader question for mesothelioma research: could treatment strategies that combine receptor targeting with innate immune activation improve outcomes in a disease with limited tumor-directed options? Clinical trials will be required to determine whether the preclinical activity translates into clinically meaningful response rates, progression-free survival, overall survival, or improved quality of life.