Publication for CCTG CO17 Loree JM, Dowers A, Tu D, Jonker D, Edelstein DL, Quinn H, Holtrup F, Price T, Zalcberg JR, Moore MJ, Karapetis CS, Callaghan CJ, Waring P, Kennecke HF, Hamilton SR, Kopetz S. Expanded low allele frequency RAS and BRAF V600E testing in metastatic colorectal cancer as predictive biomarkers for cetuximab in the randomized CO.17 trial (ONLINE). Clin Cancer Res clincanres, 2020. http://clincancerres.aacrjournals.org/content/early/2020/10/21/1078-0432.CCR-20-2710.abstract RATIONALE: Monoclonal antibodies, such as cetuximab, can target tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Best supportive care is the use of drugs and other treatments to improve the quality of life of patients. Combining cetuximab with best supportive care may slow the growth of the tumor and help patients live longer and more comfortably. It is not yet known whether cetuximab combined with best supportive care is more effective than best supportive care alone in treating metastatic epidermal growth factor receptor-positive colorectal cancer. PURPOSE: This randomized phase III trial is studying cetuximab and best supportive care to see how card card-body bg-light well they work compared to best supportive care alone in treating patients with metastatic epidermal growth factor receptor-positive colorectal cancer. RESULTS: KRAS, NRAS, and BRAF mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival (OS) (HR 0.51, 95% CI 0.32-0.81, P=0.004) and progression free survival (PFS) (HR 0.25, 95% CI 0.15-0.41, P<0.0001) compared to BSC in RAS/BRAF wild type patients. Cetuximab did not improve OS/PFS for KRAS, NRAS, or BRAF mutated tumors and tests of interaction confirmed expanded KRAS (P=0.0002) and NRAS (P=0.006) as predictive, while BRAF mutations were not (P=0.089). BEAMing identified 14% more tumors as RAS mutant than Sanger sequencing and cetuximab lacked activity in these patients. Mutations at MAF<5% were noted in 6/242 patients (2%). One patient with a KRAS A59T mutation (MAF=2%) responded to cetuximab. More NRAS than KRAS mutations were low MAF (OR 20.50, 95% CI 3.88-96.85, P=0.0038). Conclusions: We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal RAS/BRAF alterations are uncommon and remain of indeterminate significance.
