Activity of EGFR inhibition in atypical (non-V600E) BRAF-mutated metastatic colorectal cancer.

Abstract

596 Background: Atypical BRAF mutations (a BRAF) represent a rare molecular subtype of metastatic colorectal cancer (mCRC), distinct from BRAFV600E (class I). Preclinical data categorizes a BRAF into class II (intermediate-high kinase activity without RAS dependency) and III (low kinase activity, RAS dependent), however the clinical impact regarding these functional classes is unknown. Methods: We retrospectively analyzed 2,084 mCRC patients (pts) at MD Anderson Cancer Center (MDACC) to identify a BRAF and BRAFV600E. Clinicopathologic features were compared by chi-square or fisher’s exact test. Overall survival (OS) calculated utilizing Kaplan-Meier method and log-rank test. Statistical tests were two-sided. Results: a BRAF occurred in 36 mCRC pts (1.7%; 95% CI 1.2-2.4): 22 class III, 10 class II, 4 unclassified. The most common class II and class III BRAF codons were 469 (60%) and 594 (59%), respectively . Median OS (mOS) for a BRAF mCRC was 39.4 months (mo), without difference between class III and II. 19/36 (53%) were left sided primary tumors and 24/36 (67%) were microsatellite stable. BRAFV600E occurred in 221 mCRC pts (10.6%; 95% CI 9.3-12.0) with a mOS of 21.0 mo. In contrast to BRAFV600E which is mutually exclusive with RAS mutations, 12 pts with a BRAF were RAS mutants (class III, 7/21 [33%], class II 5/10 [50%]). Among a BRAF RAS wt pts, 11 (50%) received anti-EGFR monoclonal antibodies (mAb) (class III 7/14 [50%], class II 3/5 [60%]). There were no responses, and only three pts (all class III) achieved stable disease as best response. Median time on therapy was 4 months. Class II RAS wt pts treated with anti-EGFR mAb had mOS of 31.7 mo versus 46.8 mo for those not exposed (HR 2.0; 95% CI 0.3-15.9). Class III RAS wt pts treated with anti-EGFR mAB had mOS of 44.2 mo versus 45.7 mo for those not treated (HR 0.80; 95% CI 0.2-2.6). Conclusions: a BRAF mCRC appear to manifest improved clinical outcomes as previously reported. Despite this, the efficacy of anti-EGFR therapy appears limited in class II and III patients. Future efforts are needed to establish the predictive impact of functional classes on anti-EGFR efficacy and to design novel therapeutic strategies for a BRAF mCRC.