Dynamics in treatment response and disease progression of metastatic colorectal cancer (mCRC) patients with focus on BRAF status: Analysis of untreated RAS-wildtype mCRC patients receiving FOLFOXIRI either with or without panitumumab in the VOLFI trial (AIO KRK0109).

Abstract

e16055 Background: In patients with mCRC, dynamics of response and disease progression may play a critical role in the understanding of long-term outcome. Depth of response (DpR), time to DpR and post-DpR survival represent innovative endpoints to evaluate response and disease dynamics. Methods: We evaluated DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR image to tumor progression or death), and post-DpR overall survival (pOS = DpR image to death) with special focus on BRAF mutational status in 66 patients. Results: BRAF wildtype (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (-57.6% vs. -40.8%, p = 0.013) with a comparable time to DpR (BRAF-WT 4.0 (95% CI 3.1-4.4) months vs. BRAF-MT 3.9 months (95% CI 2.5-5.5), p = 0.8852). pPFS was 6.5 (95% CI 4.7-8.4) versus 2.6 (95% CI 1.0-3.9) months in favor of BRAF-WT patients (HR: 0.24 (95% CI 0.11-0.53; p < 0.001). This also transferred into a significant difference in pOS (33.6 (95% CI 30.0-42.1) versus 5.4 (95% CI 4.7-16.1) months, HR: 0.27 (95% CI 0.13- 0.55); p < 0.001). Further data including primary tumor site will be presented at the meeting. Conclusions: BRAF-MT patients treated within the VOLFI-trial derive a less profound response to treatment as compared to BRAF-WT patients. The substantial difference in outcome according to BRAF status is evident after achievement of deepest response with BRAF-MT patients hardly deriving any further disease control beyond DpR. This is reflected by pPFS and pOS. Our observations hint towards aggressive tumor evolution in patients with BRAF-MT-tumors which may already be molecularly detectable at time of DpR. These findings somehow challenge the currently practiced aggressive treatment strategy of FOLFOXIRI-based 1st-line regimens as they may stimulate treatment resistance and suggest that close monitoring of BRAF-MT patients may include the continuous monitoring of clonal evolution.