Immunological effects of amivantamab in EGFR or MET-expressing non-small cell lung cancer

Background: Epidermal growth factor receptor ( EGFR ) mutations represent one of the most frequent oncogenic driver in non-small cell lung cancer (NSCLC). Amivantamab, a bispecific antibody targeting EGFR and MNNG HOS Transforming (MET), has demonstrated clinical benefit in EGFR -mutant NSCLC through dual blockade, but its immunological role in human clinical specimens, especially tumor-infiltrating lymphocytes (TILs), has not been directly evaluated. Methods: We analyzed surgically resected tumor samples from 40 patients with NSCLC to investigate immune responses and their associations with EGFR and MET expression. TILs were characterized by flow cytometry (FCM) and immunohistochemistry (IHC). To assess the immunomodulatory potential of amivantamab, fresh tumor digests containing live tumor cells and TILs were cultured ex vivo with CD3 and CD28 stimulation in the absence or presence of amivantamab, followed by FCM. EGFR and MET expression were also evaluated by IHC. Results: EGFR mutations and high EGFR protein expression were associated with a trend toward reduced CD8⁺ T-cell and dendritic cell (DC) infiltration. In ex vivo TIL assays, exposure to amivantamab significantly activated CD8⁺ T cells, such as programmed cell death-1 expression and cytokine production, and promoted DC maturation. These effects were most pronounced in tumors with high EGFR or MET protein expression rather than EGFR mutations. Conclusions: This study provides the first direct evidence from ex vivo fresh TIL assays using human NSCLC clinical specimens that amivantamab can activate immune responses. EGFR and MET expression may serve as potential biomarkers for amivantamab-induced immune responses.