Abstract LB-B05: MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancer cells harboring EGFR extracellular domain mutations

Abstract

Abstract Cetuximab and panitumumab are monoclonal anti-EGFR antibodies (moAbs) currently used for the treatment of ‘RAS’ wild type colorectal cancers (CRC). Development of acquired resistance almost invariably limits the efficacy of these agents. At relapse, about 20% of tumors treated with cetuximab and panitumumab carry EGFR extracellular domain (ECD) mutations (S492R, R451C, S464L, G465R, G465E, K467T, I491M), which impair antibody binding. We postulated that mCRC patients who become resistant to cetuximab or panitumumab due to the emergence of EGFR ECD mutations may still benefit from further line of treatment with EGFR blockade. We observed that the EGFR ECD variants are effectively targeted by the oligoclonal anti-EGFR antibody MM-151. MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. We have analyzed liquid biopsies of 11 CRC patients that developed resistance to previous treatment with cetuximab and were then enrolled in the first MM-151 phase I study. Longitudinal profiling of circulating cell-free tumor DNA (ctDNA) samples collected during MM-151 treatment revealed a decrease of EGFR ECD mutant levels that paralleled the response as measured by radiological methods.In conclusion, we provide mechanistic evidence for the efficacy and use of MM-151 as a therapeutic opportunity for patients whose tumors develop EGFR ECD mutations as the prevalent mechanism of acquired resistance to cetuximab or panitumumab treatment. Citation Format: Sabrina Arena, Giulia Siravegna, Benedetta Mussolin, Jeffrey D. Kearns, Beni B. Wolf, Sandra Misale, Luca Lazzari, Andrea Bertotti, Livio Trusolino, Alex A. Adjei, Clara Montagut, Federica Di Nicolantonio, Rachel Nering, Alberto Bardelli. MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancer cells harboring EGFR extracellular domain mutations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B05.