Novel Approach for Clinical Validation of the cobas KRAS Mutation Test in Advanced Colorectal Cancer

AIM: Our objective was to assess the performance of the cobas test versus comparators for KRAS mutation status and predicting clinical response to anti-epidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC samples from 398 patients from Roche study NO16968 (XELOXA) and 82 supplemental samples were tested with the cobas(®) KRAS mutation test (cobas test), the therascreen(®) KRAS RGQ PCR kit test (therascreen test), and Sanger sequencing as the reference method for detecting mutations in codons 12/13. RESULTS: For 461 eligible samples, the cobas test, therascreen test, and sequencing had invalid results for 5.2, 10.8, and 2.6 % of specimens, respectively. Valid cobas and therascreen test results had similar KRAS mutation-positive rates (37.3 vs. 36.3 %, respectively); sequencing was 28.5 %. Positive and negative percent agreement (PPA/NPA) between the cobas test and sequencing was 96.9 % (95 % confidence interval [CI] 92.2–98.8), and 88.7 % (95 % CI 84.7–91.8), respectively. PPA/NPA between the cobas and therascreen tests was 93.3 % (95 % CI 88.1–96.3) and 96.5 % (95 % CI 93.5–98.1), respectively. Bridging analysis from NCIC-CO.17 and NCT00113763 using the cobas test yielded modeled hazard ratios for overall survival and progression-free survival (PFS) of 0.558 (95 % CI 0.422–0.752) and 0.413 (95 % CI 0.304–0.550), respectively, for cetuximab and 0.989 (95 % CI 0.778–1.299) and 0.471 (95 % CI 0.360–0.626), respectively, for panitumumab, demonstrating significant efficacy in the KRAS-negative population for PFS. CONCLUSION: The cobas test showed similar accuracy to the therascreen test for detecting KRAS mutations and could appropriately identify mCRC patients ineligible for anti-EGFR therapy as demonstrated by bridging analysis results. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40291-016-0193-4) contains supplementary material, which is available to authorized users.