A phase II trial of 1st-line modified-FOLFOXIRI plus bevacizumab treatment for metastatic colorectal cancer harboring RAS mutation: JACCRO CC-11

Abstract

FOLFOXIRI plus bevacizumab is considered a standard initial therapy for metastatic colorectal cancer (mCRC). However, few prospective trials have evaluated triplet therapy plus bevacizumab in patients with RAS mutant mCRC. Patients with an age of 20 to 75 years, and unresectable, measurable tumors harboring RAS mutation were given first-line treatment with bevacizumab (5 mg/kg on day 1) plus modified-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, and fluorouracil 2400 mg/m2 as a 46-h continuous infusion on day 1, repeated every 2 weeks). The primary endpoint was the objective response rate (ORR) as evaluated by an external review board. Progression-free survival (PFS), overall survival, early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. Among 64 patients who were enrolled between October 2014 and August 2016, 62 were evaluable for efficacy (right-sided tumors in 27%). ORR and disease control rate were 75.8% (95% confidence interval [CI] 65.1-86.5) and 96.8%, respectively. ETS was 73.8%, and median DpR was 49.2%. Median PFS was 11.5 (95% CI 9.5-14.0) months as of the cut-off date of September 2017. Adverse events of grade 3 or 4 were neutropenia (54%), hypertension (32%), diarrhea (13%), anorexia (11%), peripheral neuropathy (2%), and febrile neutropenia (5%). In conclusion, this prospective trial demonstrated for the first time that FOLFOXIRI plus bevacizumab is an active first-line treatment for patients with RAS mutant mCRC. Modified-FOLFOXIRI plus bevacizumab might become an alternative regimen of triplet chemotherapy for mCRC in Japan.

FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: the randomised phase III VISNÚ-1 trial

“…The subgroup analysis of PFS from our study showed that FOLFOXIRI-bevacizumab was superior in all patient subgroups, with the exception of those with PI3K- mutated tumours (n=43) or right-sided tumours (n=93), thus confirming the benefit of intensified therapy across a range of prognostic factors among patients with ≥3 CTC/7.5 mL blood. These subgroups included patients with RAS -mutated tumours (HR 0.80; 95% CI 0.56 to 1.16), and are consistent with a recent meta-analysis 17 and phase II study 18 supporting the first-line use of FOLFOXIRI-bevacizumab in RAS -mutated tumours. A positive effect of FOLFOXIRI-bevacizumab was also evident in patients with BRAF mutations (HR 0.83; 95% CI 0.37 to 1.86), although the effect size for this subgroup was smaller than reported in the TRIBE study (HR=0.55).…”

The Evolving Biomarker Landscape for Treatment Selection in Metastatic Colorectal Cancer

“…2) [3, 35], but has limitations. Specifically, RAS mutations may be associated with lesser benefit from chemotherapy plus bevacizumab compared with RAS wild type (WT) mCRC [36–38], although the recent JACCRO CC-11 trial suggests that first-line mFOLFOXIRI (leucovorin, 5-FU, oxaliplatin, irinotecan) plus bevacizumab is effective for patients with RAS -mutated mCRC [39]. Treatment with aflibercept or ramucirumab (in combination with FOLFIRI) may be efficacious as second-line therapies for patients with RAS -mutated mCRC [3, 40].…”

Safety and effectiveness of FOLFOXIRI plus molecular target drug therapy for metastatic colorectal cancer: A multicenter retrospective study

“…Regarding the use of modified FOLFOXIRI therapy, there was no difference in toxicity between non-homozygous and homozygous polymorphisms. Thus, modified FOLFOXIRI therapy can be possibly performed safely [4].…”

“…The FOLFOXIRI therapy has a promising antitumor activity. However, due to its toxic side effects, several clinical trials were conducted for dose optimization [4]. In addition, there are antibodies approved for mCRC treatment, the anti-vascular endothelial growth factor (VEGF) antibodies (bevacizumab, ramucirumab, aflibercept) and the anti-epidermal growth factor receptor (EGFR) antibodies (cetuximab, panitumumab) used in mCRC with wild-type RAS gene.…”