Frequency of S492R mutations in the epidermal growth factor receptor: analysis of plasma DNA from patients with metastatic colorectal cancer treated with panitumumab or cetuximab monotherapy. Issue 10 (2nd October 2020)

• Record Type: Journal Article
• Authors: Price, Timothy; Ang, Agnes; Boedigheimer, Michael; Kim, Tae Won; Li, Jin; Cascinu, Stefano; Ruff, Paul; Satya Suresh, Attili; Thomas, Anne; Tjulandin, Sergei; Peeters, Marc
• Is Part Of: Cancer biology & therapy. Volume 21:Issue 10(2020)
• Page Start: 891
• Page End: 898
• Publication Date: 2020-10-02
• Subjects: Colorectal cancer -- gene mutations -- resistance -- cetuximab -- panitumumab -- anti–epidermal growth factor receptor; 616.99406
• DOI: 10.1080/15384047.2020.1798695
• Languages: English
• ISSNs: 1538-4047

Abstract

ABSTRACT: Background: Antibodies against epidermal growth factor receptor (EGFR), panitumumab, a fully human monoclonal antibody, and cetuximab, a human/mouse chimeric monoclonal antibody, have shown clinical efficacy in metastatic colorectal cancer (mCRC). In the phase 3 noninferiority ASPECCT (ClinicalTrials.gov, NCT01001377) study, panitumumab was demonstrated to be noninferior to cetuximab and provided a similar overall survival benefit for patients with chemotherapy-refractory wild-type KRAS exon 2 mCRC. However, some patients eventually develop resistance to anti-EGFR therapy. EGFR p.S492R mutation was previously identified as conferring resistance to cetuximab, but not to panitumumab. Methods: This biomarker study analyzed plasma samples from ASPECCT collected at both baseline and posttreatment. Results: No EGFR p.S492R mutations were identified at baseline; however, after treatment the EGFR p.S492R mutation was detected in 1% of patients treated with panitumumab versus 16% of those treated with cetuximab, supporting that, in a large population, this mutation is more likely to be induced by cetuximab than by panitumumab. There were, however, no significant differences in progression-free survival or overall survival between patients who were wild-type compared with those with the S492R mutation within the cetuximab arm or the overall population. Conclusions: These results may support targeting treatment to small patient subgroups based on the presence of emerging EGFR mutations and provide a molecular rationale for rechallenging with a different anti-EGFR agent in patients who develop resistance. Prospective studies are needed to evaluate the efficacy of panitumumab in the EGFR p.S492R mutant population.