Dirk Arnold, MD
Two active maintenance regimens following disease stabilization with standard induction therapy demonstrated superior disease-free outcomes compared with no treatment in patients with metastatic colorectal cancer (mCRC), according to findings of a phase III trial (AIO KRK 0207) presented at the 16th World Congress on Gastrointestinal Cancer on June 28, 2014, in Barcelona. Patients who received maintenance treatment with fluoropyrimidines plus bevacizumab or bevacizumab monotherapy experienced progression-free survival (PFS).
The optimal strategy for maintenance following combination chemotherapy that includes bevacizumab has remained unsettled. Dirk Arnold, MD, director, department of Medical Oncology, Tumour Biology Centre in Freiburg, Germany and colleagues evaluated whether maintenance with no therapy or bevacizumab monotherapy was non-inferior to fluoropyrimidines plus bevacizumab following successful induction treatment.
“Progression-free survival was improved with active maintenance treatment but it is too soon to tell if there is an effect on overall survival,” said Arnold.
The trial enrolled 840 patients with mCRC who received 24 weeks of induction treatment with fluoropyrimidines, oxaliplatin, and bevacizumab. After completing this treatment, 473 patients who did not experience disease progression were randomized into one of the following arms: Arm A, standard maintenance treatment with fluoropyrimidines and bevacizumab (n= 141); arm B, bevacizumab monotherapy (n= 153); or arm C, no treatment (n= 153). The initial induction therapy regimen would be re-administered if any patients exhibited disease progression.
The primary endpoint of the trial was time to failure of strategy (TFS), which included the time of first induction treatment and duration of maintenance until disease progression.
Sample size was calculated using a one-sided alpha of 0.0125 and power of 80% for a conclusion of non-inferiority of maintenance compared with the fluoropyrimidines and bevacizumab, arm. Secondary endpoints included time to first progression (PFS1) and overall survival (OS).
Following initial induction therapy, the response rate [RR=complete response (CR) + partial response (PR)] was 60% in arm A and B versus 59% in arm C. The best response of stable disease was reported for 40% of patients in arms A and B versus 41% of patients in arm C.
After being assigned to a maintenance strategy, patients achieved median PFS1 in arms A, B, and C of 6.2, 4.8 and 3.6 months (A versus C, hazard ratio [HR] =0.64, 95% CI 0.50 – 0.82; and B versus C, HR=0.49, 95% CI 0.38 – 0.63 (P
< .0001)], respectively.
PFS1 from start of induction was 11.7 months, 10.2 months and 9.0 months in arms A, B, and C, respectively (P
TFS favored arm A over arm C, HR=1.22, 95% CI 0.96-1.57, P = .11), but did not reach statistical significance. No statistically significant difference was observed between arms A and B in TFS (HR=0.98; 95% CI 0.76-1.28, P
Few patients terminated maintenance because of unacceptable toxicity; 8%, 5% and 1% of patients in arms A, B, and C discontinued for this reason. However 58%, 79%, and 86% of patients in arms A, B. and C discontinued because of disease progression.
The re-induction rate was low overall at 37%; upon first progression only 24% of patients in arm A and 47 % of patients in both arms B and C, received re-induction.
Rates for grades 1, 2, and 3 toxicity during maintenance were similar across all 3 arms.
After 200 documented events, preliminary OS was 23.4 months from randomization, without significant difference between treatment arms (P
The researchers concluded that bevacizumab alone is non-inferior to bevacizumab combined with fluoropyrimidines as maintenance but no active maintenance is inferior to combination maintenance. In addition, immediate re-induction rates upon first progression were too low to accept this strategy.
“I suspect, but we do not know, that irinotecan toxicity was a factor in patients’ decisions to forego re-induction therapy,” Arnold remarked.
The AIO study group has received an unrestricted grant from Roche.
Arnold et al. A Phase III Trial of Fluoropyrimidines (FP) Plus Bevacizumab (BEV) or no Treatment as Maintenance Strategy Following a Standard Combination of FP, Oxaliplatin (OXO), and BEV as First-line Treatment for Patients With Metastatic Colorectal Cancer (mCRC). Presented at: the ESMO 16th World Congress on Gastrointestinal Cancer; June 25-28, 2014; Barcelona, Spain. Abstract AIO KRK 0207.
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