Abstract B33: The oligoclonal antibody MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancer cells harboring EGFR extracellular domain mutations

Abstract The anti-EGFR antibodies cetuximab and panitumumab are used to treat ‘RAS’ wild type colorectal cancers (CRCs), but their efficacy is limited by development of drug resistance. At relapse, approximately 20% of tumors carry EGFR extracellular domain (ECD) mutations (S492R, R451C, S464L, G465R, G465E, K467T, I491M) that impair antibody binding. We find that these EGFR genetic variants are effectively targeted by the oligoclonal anti-EGFR antibody MM-151. Both EGFR mediated signaling and proliferation of colorectal cancer (CRC) cells carrying EGFR ECD mutations are impaired by MM-151. Notably, EGFR extracellular domain mutations, which are found in circulating free tumor DNA (ctDNA) of CRC patients who relapsed upon anti-EGFR antibodies treatment, decline during MM-151 therapy. In conclusion, MM-151 based therapy may be valuable for the treatment of secondary resistance to cetuximab and panitumumab driven by EGFR ECD mutations. Further prospective clinical evaluation is warranted.