Efficacy of amivantamab, a bi-specific antibody targeting EGFR and MET, in ALK-rearranged non-small-cell lung cancer cell lines

Background: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective in treating ALK-rearranged non-small-cell lung cancer (NSCLC). However, at least 40% of patients develop acquired resistance during treatment. Adaptive or acquired resistance to ALK TKIs could be mediated through epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling. Sixteen percent of acquired resistance cases are linked to bypass signaling. Methods: In this study, we evaluated the effects of amivantamab, a bi-specific antibody targeting both EGFR and MET, on ALK-rearranged NSCLC cells. We investigated the effect of amivantamab on the ALK-rearranged NSCLC cell lines H3122, ABC-19, and ABC-11. Results: Combining alectinib with amivantamab resulted in greater inhibition of cell growth inhibition in H3122 and ABC-19 cells compared to alectinib alone, but not in ABC-11 cells. EGFR TKI erlotinib showed similar efficacy in H3122 and ABC-19 cells, whereas MET TKI tepotinib was ineffective in both, suggesting that the efficacy of amivantamab is through EGFR inhibition. Unlike H3122 and ABC-19 cells, ABC-11 cells were resistant to EGFR/MET signaling inhibition. Interestingly, amivantamab enhanced alectinib efficacy against ABC-11 cells in the presence of peripheral blood mononuclear cells (PBMCs), despite showing no effect alone without PBMCs, suggesting action through non-signal inhibitory mechanisms. Finally, we treated alectinib-resistant cellswith alectinib, with or without amivantamab, and found that amivantamab restored the sensitivity of these cells to alectinib. Conclusion: The bi-specific antibody amivantamab, which targets EGFR and MET, enhanced the efficacy of alectinib through both signal and non-signal inhibitory mechanisms in ALK-rearranged NSCLC cells.