Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer

Abstract

confers a higher risk of toxicity in patients treated with irinotecan. Patients with and genotypes might tolerate higher than standard doses of irinotecan. We aimed to identify the MTD of irinotecan in patients with metastatic colorectal cancer (mCRC) with and genotypes treated with FOLFIRI plus bevacizumab, and to determine whether bevacizumab alters irinotecan pharmacokinetics. Previously untreated patients with mCRC (25 ; 23) were given FOLFIRI plus bevacizumab every 2 weeks. The irinotecan dose was escalated using a 3 + 3 design in each genotype group as follows: 260, 310, and 370 mg/m The MTD was the highest dose at which <4/10 patients had a dose-limiting toxicity (DLT). Pharmacokinetics of irinotecan and SN-38 were measured on days 1 to 3 (without bevacizumab) and 15 to 17 (with bevacizumab). For patients, 2 DLTs were observed among 10 patients at 310 mg/m, while 370 mg/m was not tolerated (2 DLTs in 4 patients). For patients, 2 DLTs were observed among 10 patients at 260 mg/m, while 310 mg/m was not tolerated (4 DLTs in 10 patients). Neutropenia and diarrhea were the most common DLTs. Changes in the AUCs of irinotecan and SN-38 associated with bevacizumab treatment were marginal. The MTD of irinotecan in FOLFIRI plus bevacizumab is 310 mg/m for patients and 260 mg/m for patients. Bevacizumab does not alter the pharmacokinetics of irinotecan. The antitumor efficacy of these genotype-guided doses should be tested in future studies of patients with mCRC treated with FOLFIRI plus bevacizumab..

Cost Evaluation of Irinotecan‐Related Toxicities Associated With the UGT1A1*28 Patient Genotype

“…Newer biologics are now used in all the patients treated for mCRC disease, in association with chemotherapy, in developed countries. However, FOLFIRI is still a highly used, standard backbone chemotherapy in patients with mCRC, and UGT1A1*28 has been demonstrated to impact the toxicity risk also in patients treated with the combination regimens . Only future studies designed to unravel pharmacodynamic interactions between chemotherapy and biologics will assess the impact of *28 genotype on the toxicity management costs of the combination regimens.…”

Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

“…Despite the establishment of these guidelines, UGT1A1 genotyping is currently not routinely performed [ 282 ], which could be explained by the fact that prospective studies evaluating the clinical effects of genotype-directed dosing are scarce. Most likely, reduction of the irinotecan dose to prevent toxicity in carriers of UGT1A1*1/*28 and UGT1A1*28/*28 is indeed useful since the maximum tolerated dose of irinotecan was lower in these patients relative to wild-type patients [ 283 ].…”

North Central Cancer Treatment Group N0543 (Alliance): A phase 2 trial of pharmacogenetic‐based dosing of irinotecan, oxaliplatin, and capecitabine as first‐line therapy for patients with advanced small bowel adenocarcinoma

“…A triplet combination of oxaliplatin, irinotecan, and 5‐FU has demonstrated a survival benefit in patients with pancreatic and colorectal cancers . UDP glucuronosyltransferase family 1 member A1 ( UGT1A1 ), the metabolic enzyme involved in the clearance of SN‐38, the active metabolite of irinotecan, has common polymorphisms in the number of TA repeats (6 vs 7), and affects the toxicity profile of irinotecan (including risk of neutropenia and diarrhea) and its efficacy . A 7/7 genotype is perhaps best known as the most common cause of Gilbert syndrome, a generally asymptomatic indirect hyperbilirubinemia .…”