Dynamics in treatment response and disease progression of metastatic colorectal cancer (mCRC) patients with focus on BRAF status and primary tumor location: analysis of untreated RAS-wild-type mCRC patients receiving FOLFOXIRI either with or without panitumumab in the VOLFI trial (AIO KRK0109)

Abstract

Purpose In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints. Methods We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), 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 status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively. Results BRAF wild-type (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 [4.0 (95% CI 3.1-4.4) vs. 3.9 (95% CI 2.5-5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9-8.0) versus 2.6 (95% CI 1.2-4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11-0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0-41.3) vs. 5.4 (95% CI 5.0-5.9) months; HR 0.27 (95% CI 0.13-0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site. Conclusions BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.

Panitumumab Plus Fluorouracil and Folinic Acid Versus Fluorouracil and Folinic Acid Alone as Maintenance Therapy in RAS Wild-Type Metastatic Colorectal Cancer: The Randomized PANAMA Trial (AIO KRK 0212)

“… 25 , 28 , 29 However, it could be argued that induction therapy involving an anti-EGFR antibody reaches the maximum depth of response after a median of 3-4 months and the induction interval might be considered adequate from a biologic standpoint. 13 , 32 Furthermore, the evaluation of maintenance efficacy only in patients who actually underwent maintenance therapy was not consistently conducted in other maintenance therapy trials. 22 - 25 , 29 , 31 , 33 …”

“…25,28,29 However, it could be argued that induction therapy involving an anti-EGFR antibody reaches the maximum depth of response after a median of 3-4 months and the induction interval might be considered adequate from a biologic standpoint. 13,32 Furthermore, the evaluation of maintenance efficacy only in patients who actually underwent maintenance therapy was not consistently conducted in other maintenance therapy trials. [22][23][24][25]29,31,33 Third, the PANAMA trial included subgroups of patients with right-sided primary tumor location, BRAF-mutated tumors, and/or microsatellite instability-high tumors who are not ideal candidates for anti-EGFR antibody-based first-line therapy.…”

Response and Disease Dynamics in Untreated Metastatic Colorectal Cancer With Bevacizumab-Based Sequential vs. Combination Chemotherapy—Analysis of the Phase 3 XELAVIRI Trial

“…In general, time to DpR does not seem to be a specifically sensitive endpoint in the context of the specific trial regimens and the molecular subgroups of mCRC. However, it might be noted that the time to DpR appears longer in the XELAVIRI trial as compared to other recent trials, maybe reflecting the limited frequency of trial dropouts due to secondary resectability of tumors (3,22).…”

“…22.2%; p < 0.001; female: -34.0% vs. -24.4%; p = 0.13) and rate of ETS [male: 64.8% vs. and Supplementary Figure A.2. Within the different molecular subgroups and genders, the time to DpR was comparable.…”