High-Dose FOLFIRI plus Bevacizumab in the Treatment of Metastatic Colorectal Cancer Patients with Two Different UGT1A1 Genotypes: FFCD 0504 Study

Abstract

High-dose FOLFIRI has an acceptable safety profile and promising efficacy. UDP-glucuronosyltransferase: (UGT1A1) polymorphism may be predictive of toxicity and efficacy of irinotecan. This phase II study aimed to evaluate the combination of high-dose FOLFIRI plus bevacizumab in patients with previously untreated metastatic colorectal cancer (MCRC) based on their UGT1A1 genotype. Patients with the UGT1A1 à 1/ à 1 (group 1) or à 1/ à 28 (group 2) genotype received bevacizumab plus high-dose FOLFIRI every 2 weeks. Using the Bryant and Day design with objective response rate and toxicity as the primary endpoints, 54 patients in each group were required with a planned interim analysis after inclusion of 17 patients per group. We planned to stop the trial at the interim analysis if 7 patients exhibited an objective response (OR) and/or !3 patients exhibited severe toxicity. At the interim analysis, ORs were higher than the number expected: 52.9% (group 1) and 58.8%

UGT1A1 Allele Test Not Only Minimizes the Toxicity But Also Maximizes the Therapeutic Effect of Irinotecan in the Treatment of Colorectal Cancer: A Narrative Review

“…In the single-arm trials, three studies from Europe directly used high dose irinotecan according to the guidance of UGT1A1 genotypes (23,25,26), while two studies from Asia used the dose escalation of irinotecan (24,27). A prospective study was about high dose FOLFIRI (260 mg/ m 2 ) combined with local surgery and radiofrequency ablation for the unresectable liver metastases from CRC patients with UGT1A1 *1/*1 or *1/*28 (23).…”

“…In the single-arm trials, three studies from Europe directly used high dose irinotecan according to the guidance of UGT1A1 genotypes ( 23 , 25 , 26 ), while two studies from Asia used the dose escalation of irinotecan ( 24 , 27 ).…”

“…There were five single-arm (23)(24)(25)(26)(27) trials and four double-arm trials (28)(29)(30)(31) on the application of FOLFIRI regimen containing high dose irinotecan under the guidance of genotypes in mCRC patients with UGT1A1 *1/*1 or *1/*28. The characteristics and results of these studies are shown in Tables 2, 3, respectively.…”

An expansion study of genotype-driven weekly irinotecan and capecitabine in combination with neoadjuvant radiotherapy for locally advanced rectal cancer with UGT1A1 *1*1 genotype

“…However, in a subsequent phase II study, although high-dose FOLFIRI plus bevacizumab achieved an expected overall response rate in UGT1A1 *1*1 and *1*28 patients, it was stopped at the interim analysis because the number of unacceptable toxicities was higher than the number defined in the stopping rules in the statistical analysis plan (⩾20%). 20 It suggested that the escalated irinotecan dose required more evidence for validation.…”

Genotypes Affecting the Pharmacokinetics of Anticancer Drugs

“…Patients with the *28/*28 genotype were excluded [43]. Recently, it was demonstrated that high-dose irinotecan (260 mg/m 2 ) FOLFIRI combined with bevacizumab did not improve the overall response rate in metastatic colorectal cancer patients with the *1/*1 or *1/*28 genotype [44]. Whether irinotecan dose escalation in wild-type UGT1A1 patients contributes to improved clinical outcome is therefore questionable.…”