Overcoming EGFR Resistance: The Therapeutic Potential of MCLA-129 in NSCLC

Non-small cell lung cancer (NSCLC) is a prevalent cancer type with a significant percentage of patients having epidermal growth factor receptor (EGFR) mutations. These individuals initially respond to tyrosine kinase inhibitors (TKIs) but often experience relapse. Resistance to EGFR TKIs is frequently associated with upregulation of the c-MET growth factor pathway, with Met amplification detected in a subset of resistant tumors. A functional screen was conducted to identify bispecific antibodies (bAbs) that target both EGFR and c-MET, leading to the selection of MCLA-129. This bAb was derived from immunized MeMo mice and was evaluated in a xenograft NSCLC model.

A diverse panel of over 400 bAbs was tested for their ability to inhibit the proliferation of N87 cells stimulated by EGF and/or HGF. Five bAbs showed efficacy comparable to a combination of cetuximab and a MetMab analog. MCLA-129 was further characterized and demonstrated potent inhibitory activity against NSCLC cell lines with an EGFR exon 19 deletion. The presence of HGF counteracted the inhibitory effects of EGFR TKIs, but the combination of MCLA-129 with these TKIs restored growth inhibition.

MCLA-129 also showed significant anti-tumor activity in a genetically engineered mouse model, where it induced tumor regression and slowed regrowth post-treatment. This effect was further enhanced when combined with erlotinib. Importantly, MCLA-129's therapeutic effect was observed without relying on antibody-dependent cellular cytotoxicity (ADCC) and was not seen in mice treated with erlotinib alone or with a bivalent c-MET antagonist.

In a model of acquired resistance to EGFR TKIs, MCLA-129, when added to erlotinib, resulted in immediate and sustained tumor inhibition. The study suggests that MCLA-129 has the potential to overcome c-MET-mediated resistance to EGFR TKIs both in vitro and in vivo, and its activity surpasses that of other biologics targeting EGFR and c-MET without functional immunity. These findings warrant further clinical evaluation of MCLA-129 for NSCLC patients who develop resistance to EGFR-targeted therapies.