BARCELONA, Spain-The FOLFOXIRI regimen in combination with bevacizumab has become a standard option in first-line treatment of colorectal cancer.
Now, results of a phase II trial now suggest that 4 months of induction therapy with a modified FOLFOXIRI (mFOLFOXIRI) regimen plus the epidermal growth factor receptor (EGFR) inhibitor cetuximab followed by cetuximab maintenance is feasible and has relevant activity in colorectal cancer. The researchers also report a high surgical conversion rate, which they say may positively affect overall survival results, though those data are not mature.
The data were presented at the recent European Society of Medical Oncology World Congress on Gastrointestinal Cancer by Carlotta Antoniotti, MD, a medical oncologist in the Department of Translational Research at the University of Pisa, Italy (Abstract O-011).
The phase II randomized MACBETH trial was conducted by the Gruppo Oncologico Nord Ovest cooperative group.
MACBETH patients, all with RAS/BRAF wildtype metastatic colorectal cancer, were treated with FOLFOXIRI plus cetuximab followed by either maintenance with cetuximab or maintenance with the vascular endothelial growth factor inhibitor bevacizumab.
Antoniotti reported similar overall response rates for the two study arms: 92 percent for the cetuximab-containing arm and 89 percent for the bevacizumab-containing arm. But the curative resection rate for the cetuximab-containing arm was significantly higher, 45.8 percent versus 29.8 percent for the bevacizumab-containing arm.
As background for this trial, Antoniotti said an upfront intensified treatment with the triplet FOLFOXIRI in combination with bevacizumab has been shown to be a valid therapeutic option in selected patients with metastatic colorectal adenocarcinoma (N Engl J Med 2014;371:1609-18).
The combination of triple chemotherapy regimens with an anti-EGFR agent reported promising activity but with some safety concerns in phase II trials, mainly grade-3/4 diarrhea in 25-94 percent of patients (BMC Cancer 2014;14:521).
Study Methodology
Between November 2011 and February 2015, 323 patients from 21 Italian centers were screened. Out of 143 randomized patients, 116 were RAS/BRAF wildtype and were therefore included in the modified intent-to-treat.
The trial arms were well balanced. Patients had unresectable colorectal cancer previously-untreated for metastatic disease, with RAS and BRAF wildtype mutations. Adjuvant oxaliplatin-containing chemotherapy was allowed if more than 12 months had elapsed between the end of adjuvant treatment and relapse.
Patients were age 18 to 75 years of age. Of note, patients were eligible for the trial if they had ECOG performance status of two or less, but performance status had to be zero if between 71-75 years.
The modified FOLFOXIRI regimen comprises irinotecan 130 mg/m2, followed by oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and 5FU 2400 mg/m2 by continuous infusion over 48 hours (The "classic" FOLFOXIRI regimen uses irinotecan 165 mg/m2 and 5FU 3200 mg/m2).
Arm A with cetuximab included 59 patients, median age 61 years; 86 percent had synchronous metastases but only 10 percent had prior adjuvant chemotherapy; and 59 percent had a resected primary tumor.
Arm B with bevacizumab included 57 patients, median age 59 years. Eighty-two percent had synchronous metastases and 14 percent had prior adjuvant chemotherapy. Fifty-eight percent had a resected primary tumor.
The mFOLFOXIRI-cetuximab induction regimen was administered for up to eight cycles. Arm A then received maintenance cetuximab until progression, while Arm B received maintenance bevacizumab until progression.
Results, Toxicity
Both study arms had relevant activity with similar responses.
The complete response rate in Arm A was 5 percent versus 4 percent in Arm B, while the partial response rates were 63 percent and 72 percent respectively. Adding the rates of complete and partial response and stable disease, the disease control rates were 92 percent for Arm A and 89 percent for Arm B.
R0/R1/R2 surgery was 45.8 percent for Arm A versus 29.8 percent for Arm B, for a combined rate of 37.9 percent for all 117 patients. In the liver-only subgroup, R0/R1/R2 rates were 71.4 percent for Arm A and 58.3 percent for Arm B, for a combined rate of 65.4 percent.
In secondary surgery, Arm A had a 32.2 percent R0 rate versus 22.8 percent for Arm B, for a combined rate of 27.6 percent. In secondary surgery for the liver-only subgroup, the rates of R0 were 53.6 percent versus 45.8 percent respectively, for a rate of 50.0 percent for all patients.
According to Antoniotti, neutropenia and diarrhea were the major adverse events. The rates of grade-3/4 diarrhea were 20.3 percent for Arm A and 15.8 percent for Arm B, for a combined rate of 18.1 percent.
The rates of grade-3/4 neutropenia were 28.8 percent for Arm A and 33.3 percent for Arm B, for a combined rate of 31.0 percent. And rates of grade-3/4 febrile neutropenia were 3.4 percent for Arm A and 1.8 percent for Arm B, for a combined rate of 2.6 percent.
Robert H. Carlson is a contributing writer.