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

Hironaga Satake,Masahito Kotaka,Yutaro Kubota,Yuji Miyamoto,Kazuma Kobayashi,Masahiro Takeuchi,Yu Sunakawa,Wararu Ichikawa,Takashi Sekikawa,Manabu Shiozawa,Masashi Fujii,Hiroshi Nakayama,Masahiro Gotoh,Akinori Takagane,Akitaka Makiyama,Masato Nakamura,Misuzu Mori

doi:10.18632/oncotarget.24702

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.

Highlights

Randomized studies in patients with metastatic colorectal cancer, including the TRIBE, STEAM, and CHARTA trials, have demonstrated that bevacizumab combined with infusional fluorouracil/ levofolinate/irinotecan/oxaliplatin (FOLFOXIRI) is more effective than doublet plus bevacizumab treatment and is tolerated as first-line treatment [1,2,3]
The full analysis set consisted of patients, and patients were included in the safety population because 1 of the patients did not meet the eligibility criteria but received the protocol treatment, and another patient did not receive any course of treatment (Supplementary Figure 1)
Our study demonstrated that modifiedFOLFOLXIRI plus bevacizumab was an active first-line treatment in Japanese patients with metastatic colorectal cancer (mCRC) who harbor RAS mutant tumors

Summary

Introduction

Randomized studies in patients with metastatic colorectal cancer (mCRC), including the TRIBE, STEAM, and CHARTA trials, have demonstrated that bevacizumab combined with infusional fluorouracil/ levofolinate/irinotecan/oxaliplatin (FOLFOXIRI) is more effective than doublet plus bevacizumab treatment and is tolerated as first-line treatment [1,2,3]. The randomized phase II STEAM trial of sequential or concurrent FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab in the United States showed comparable results to the TRIBE trial [2]. The molecular sub-analysis of the TRIBE trial demonstrated FOLFOXIRI plus bevacizumab is a feasible treatment option irrespective of RAS or BRAF status [5]; exploratory sub-analyses of randomized trials according to RAS showed inconsistent results for efficacy of triplet plus bevacizumab regimen in RAS mutant tumors [2, 6]. Few studies prospectively evaluated the FOLFOXIRI plus bevacizumab regimen for RAS mutant mCRC

Methods

Results

Conclusion