Abstract 4126: Treatment and survival of patients with de novo metastatic colorectal cancer (mCRC) rested for KRAS, NRAS or BRAF mutations
Authors: Booker Ben D. , Markt Sarah C. , Schumacher Fredrick R. , Rose Johnie , Cooper Greg S. , Selfridge J Eva , Koroukian Siran M. 
Published: June 2022

Abstract
Study Purpose: Molecular profiling of RAS (KRAS, NRAS) and BRAF mutations in mCRC is recommended by national guidelines to inform targeted treatment. The purpose of this study was to determine whether results of genomic testing are associated with receipt of targeted therapy (i.e. VEGFi and EGFRi), and whether receipt of first-line targeted therapy is associated with survival among patients with mCRC.
Methods: Using the nationwide de-identified electronic health record-derived Flatiron Health database, we included 10,168 patients with de novo mCRC diagnosed between 2013-2020 and tested for at least one of the above biomarkers at any time. We used multivariable Cox proportional hazards regression models, beginning follow-up at date of metastatic diagnosis and continued until death or end of follow-up, adjusted for age, sex, race/ethnicity, mutation status (mutant vs. wild type (WT)), tumor site (colon vs. rectum), mismatch repair (MMR), comorbidities, ECOG status, payer type, and first-line (1L) treatment, to investigate the associations between: 1) mutation status and 1L treatment; and 2) 1L treatment and overall survival.
Results: Overall, 9.5% did not have documented 1L treatment. Among patients with 1L treatment documented (n=9,202), the most common were FOLFOX+VEGFi (36.3%), followed by FOLFOX alone (15.8%), single-agent capecitabine (7.2%), and FOLFIRI+VEGFi (5.0%). After adjusting for treatment, patients with KRAS, NRAS, and BRAF mutant tumors had worse survival than those WT for all three: (HR: 1.32, 95% confidence interval: 1.23-1.42), (HR: 1.23, 95% CI: 1.04-1.47), and (HR: 1.77, 95% CI: 1.57-2.00), respectively. Of patients with RAS mutations, 59.8% received VEGFi, regardless of chemotherapy backbone. Contrary to outcomes reported from clinical trials, we observed similar survival in patients treated with VEGFi, compared to those without (HR: 1.03, (0.95-1.12)). Among patients with RAS WT tumors, 51.6% received VEGFi, but had no survival benefits (HR:1.06 (0.96-1.17)). About 1% of patients RAS mutant and 15.9% of RAS WT tumors received EGFRi regardless of chemotherapy backbone, and experienced better survival than those treated with VEGFi (HR: 0.88 (0.77-1.00). We observed no differences in survival by treatment among those with BRAF mutations.
Conclusions: Treatment with VEGFi was common. However, contrary to survival data from clinical trials, which exclude vulnerable populations, patients treated with VEGFi did not experience survival benefits, highlighting the importance of examining survival outcomes in routine clinical care. In patients with RAS WT tumors, treatment with EGFRi was associated with improved survival compared with those treated with VEGFi. Future studies should incorporate tumor sidedness and contraindications to determine appropriateness of treatment with VEGFi or EGFRi in patients with mCRC.
Citation Format: Ben D. Booker, Sarah C. Markt, Fredrick R. Schumacher, Johnie Rose, Greg S. Cooper, J Eva Selfridge, Siran M. Koroukian. Treatment and survival of patients with de novo metastatic colorectal cancer (mCRC) rested for KRAS, NRAS or BRAF mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4126.