MAVERICC, a Randomized, Biomarker-stratified, Phase II Study of mFOLFOX6-Bevacizumab versus FOLFIRI-Bevacizumab as First-line Chemotherapy in Metastatic Colorectal Cancer

Abstract

MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC). MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/β-actin mRNA expression level and region. Of 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS [HR = 0.79; 95% CI (confidence interval): 0.61-1.01; = 0.06] and OS (HR = 0.76; 95% CI: 0.56-1.04; = 0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR = 0.84; 95% CI: 0.56-1.26; = 0.40; OS, HR = 0.80; 95% CI: 0.51-1.26; = 0.33). Across treatment groups, high plasma VEGF-A levels (>5.1 pg/mL) were observed with shorter PFS (HR = 1.19; 95% CI: 0.93-1.53; = 0.17) and significantly shorter OS (HR = 1.64; 95% CI: 1.20-2.24; < 0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable with those reported previously. First-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these bevacizumab-containing regimens.

Impact of Prior Bevacizumab Treatment on VEGF-A and PlGF Levels and Outcome Following Second-Line Aflibercept Treatment: Biomarker Post Hoc Analysis of the VELOUR Trial

“…The fact that high baseline VEGF-A and PlGF levels in patients treated with placebo are associated with poor outcomes is supported by previous reports (42)(43)(44). High VEGF-A serum levels (>5.1 pg/mL) at baseline were associated with worse OS and PFS in patients with mCRC who received either mFOLFOX6 or FOLFIRI with first-line bevacizumab (44). In contrast, a study of 813 patients with mCRC who received bevacizumab did not identify a link between poor response to bevacizumab and high VEGF-A expression in the tumor by IHC, and this may be an important factor that differentiates this study from the studies reporting VEGF-A serum levels, including the one presented here (45).…”

“…The fact that high baseline VEGF-A and PlGF levels in patients treated with placebo are associated with poor outcomes is supported by previous reports (42)(43)(44). High VEGF-A serum levels (>5.1 pg/mL) at baseline were associated with worse OS and PFS in patients with mCRC who received either mFOLFOX6 or FOLFIRI with first-line bevacizumab (44).…”

Comprehensive review of targeted therapy for colorectal cancer

“…191 Two independent trials stated no difference in terms of efficacy against metastatic CRC between FOLFOX and FOLFIRI combined with bevacizumab. 192,193 Yet interestingly, a bevacizumab-containing regimen seemed to have better efficacy with the triplet FOLFOXIRI regimen than FOLFIRI alone (PFS: 12.3 vs. 9.7 months; HR: 0.77; p = 0.006; OS: 29.8 vs. 25.8 months; HR: 0.80; p = 0.03), although the latter doublet regimen had fewer adverse reactions according to the TRIBE trial. 187 In addition to first-line application of bevacizumab, various trials have validated its efficacy in the second-line setting.…”

AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta‐analysis using TRIBE, MAVERICC and FIRE3

“…The study subjects were 884 patients with mCRC treated with chemotherapy. The patients underwent FOLFIRI, mFOLFOX6 or FOLFOXIRI combined with bevacizumab or cetuximab as the first‐line chemotherapy in three prospective phases II or III clinical trials: TRIBE (NCT00719797), MAVERICC (NCT01374425) and FIRE‐3 (NCT00433927) . In TRIBE, patients underwent either FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab; in MAVERICC, either FOLFIRI plus bevacizumab or mFOLFOX6 plus bevacizumab; in FIRE3, either FOLFIRI plus bevacizumab or FOLFIRI plus cetuximab (detailed in Supporting Information Methods).…”

“…The study subjects were 884 patients with mCRC treated with chemotherapy. The patients underwent FOLFIRI, mFOLFOX6 or FOLFOXIRI combined with bevacizumab or cetuximab as the firstline chemotherapy in three prospective phases II or III clinical trials: TRIBE (NCT00719797), 15 MAVERICC (NCT01374425) 16 and FIRE-3 (NCT00433927). 17 18 Patients without sufficient peripheral whole blood samples for analysis were excluded (the inclusion/exclusion criteria is shown in Supporting Information Fig.…”