A RANDOMIZED head-to-head comparison in patients with advanced colorectal cancer found that a regimen of FOLFOXIRI (fluorouracil/leucovorin, oxaliplatin, irinotecan) plus bevacizumab (Avastin) was more effective than a regimen of FOLFOX (fluorouracil/leucovorin, oxaliplatin) plus bevacizumab as first-line treatment. The results of the multicenter German AIO KRK 0209 (“CHARTA”) trial were initially presented at the 2017 Gastrointestinal Cancers Symposium by Hans-Joachim Schmoll, MD, PhD, of the University Hospital in Halle, Germany.1 Updated results of this phase II trial were presented in a poster session at the 2017 ASCO Annual Meeting.2 To better select patients with the best chance of benefit from the FOLFOXIRI plus bevacizumab regimen, a combined prognostic and predictive classification was proposed by the investigators.
In the study of 242 evaluable patients, researchers compared outcomes with FOLFOX plus bevacizumab vs FOLFOXIRI plus bevacizumab. FOLFOXIRI plus bevacizumab was administered at the same dose and schedule as in the TRIBE study,3 with 25% dose reduction in cycles 1 and 2 allowed. The arms were balanced for baseline characteristics, including KRAS and BRAF status and sidedness of the primary tumor.
“These data further support the efficacy and good tolerability of [FOLFOXIRI/bevacizumab] for the first-line treatment of patients with these eligibility criteria."— Hans-Joachim Schmoll, MD, PhD
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“FOLFOX/bevacizumab is one of the most commonly used first-line treatments in advanced colorectal cancer but has limited activity. We hypothesized that the regimen of FOLFOXIRI plus bevacizumab might be superior to [FOLFOX/bevacizumab],” Dr. Schmoll said. “TRIBE investigated FOLFIRI/bevacizumab plus oxaliplatin and found superior outcomes in all parameters. The CHARTA trial also met its primary endpoint of significantly improved progression-free survival at 9 months with [FOLFIRI/ bevacizumab plus oxaliplatin].”
Patients underwent 6 months of induction chemotherapy, then maintenance therapy with capecitabine plus bevacizumab for a maximum of 12 months. Upon disease progression, patients were treated at the investigator’s discretion. The primary endpoint was progression-free survival at 9 months (prespecified level of statistical significance was P < .1).
FOLFOXIRI/BEVACIZUMAB significantly improved progression-free survival at 9 months: 68%, vs 56% with FOLFOX/bevacizumab (P = .085). Median progression-free survival was 12 months and 10 months, respectively, representing a 20% reduction in risk with FOLFOXIRI (hazard ratio [HR] = 0.7). Response rates were 70% and 60%, respectively (P = .16), Dr. Schmoll reported. By RAS mutation status and site of tumor, FOLFOXIRI/bevacizumab’s effect was greatest in RAS wild-type tumors.
The overall survival data from the CHARTA trial were presented at the 2017 ASCO Meeting. At the time of analysis, median survival was 28 months for FOLFOXIRI/bevacizumab and 24 months for FOLFOX/bevacizumab (hazard ratio [HR] = 0.88; P = .39), with the curves separating early in favor of the FOLFOXIRI/bevacizumab regimen and with partial crossover occurring beyond 2 years. “The improvement in progression-free survival and response rate is similar to that seen in TRIBE, although not significantly so, very likely due to the lower number of patients,” Dr. Schmoll said.
In TRIBE, after a median follow-up of 26.6 months, median progression-free survival was 12.2 months with FOLFOXIRI/bevacizumab compared with 9.7 months with FOLFIRI/ bevacizumab (HR = 0.73; P = .0012). Median overall survival was 29.8 and 25.8 months, respectively (HR = 0.80, P = .03), and response rates were 65% and 53% (P = .006).
“The protocol was well tolerated, without an increase in clinically relevant toxicity in this mixed patient population, including patients up to 82 years of age,” he reported. The main difference in toxicity was more diarrhea with the FOLFOXIRI/bevacizumab regimen (54% vs 40% for all grades, and 15% vs 12% for grades 3 and 4) and more hematologic toxicity. The Quality of Life–Global Health Scores were slightly better in patients receiving FOLFOXIRI/ bevacizumab.
“These data further support the efficacy and good tolerability of [FOLFOXIRI/bevacizumab] for the first-line treatment of patients with these eligibility criteria,” Dr. Schmoll said. ■
DISCLOSURE: Dr. Schmoll has received honoraria form Roche, GSK, and Servier; served as a consultant or advisor to Roche, Bayer, and GSK; received research funding from Roche and GSK; and received travel expenses from Roche, Bayer, Servier, and GSK.
1. Schmoll H-J, Garlipp B, Junghanss C, et al: CHARTA: FOLFOX + bevacizumab +/- irinotecan in advanced colorectal cancer—Final results of the randomized phase II trial of the AIO (KRK 0209). 2017 Gastrointestinal Cancers Symposium. Abstract 658. Presented January 21, 2017.
2. Schmoll H-J, Meinert FM, Cygon F, et al: “CHARTA”: FOLFOX/bevacizumab vs FOLFOXIRI/bevacizumab in advanced colorectal cancer—Final results, prognostic and potentially predictive factors from the randomized phase II trial of the AIO. 2017 ASCO Annual Meeting. Abstract 3533. Presented June 3, 2017.
3. Cremolini C, Loupakis F, Antoniotti C, et al: FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: Updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol 16:1306-1315, 2015.
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