Regorafenib Plus FOLFIRI With Irinotecan Dose Escalated According to Uridine Diphosphate Glucuronosyltransferase 1A1 Genotyping in Patients With Metastatic Colorectal Cancer

Abstract

We analyzed the results of previously treated patients with metastatic colorectal cancer (mCRC) who received regorafenib plus FOLFIRI with the irinotecan dose escalation on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping. Thirteen patients with previously treated mCRC were subjected to UGT1A1 genotyping between October 2013 and June 2015 and were administered regorafenib plus FOLFIRI with irinotecan dose escalation. Patients with UGT1A1*1/*1 and *1/*28 genotypes were administered 180 mg/m2 of irinotecan, whereas those with the UGT1A1*28/*28 genotype were administered 120 mg/m2 of irinotecan. For all patients, the irinotecan dose was increased by 30 mg/m2 every two cycles until grade ≥3 adverse events or severe adverse events developed, following which the dose was reverted to and maintained at the previously tolerated level. The oral regorafenib dose was adjusted to 120 mg/day daily. The median follow-up period was 10.0 months (1.0-21.0 months). The disease control rate was 69.2%, whereas the median progression-free survival and overall survival were 9.5 and 13.0 months, respectively. Our findings indicate that regorafenib plus FOLFIRI with irinotecan dose escalation based on UGT1A1 genotyping in previously treated patients with mCRC and with UGT1A1*1/*1 and UGT1A1*1/*28 genotypes is clinically effective and yields improved oncological outcomes.

Multicenter, randomized, double‐blind phase 2 trial of FOLFIRI with regorafenib or placebo as second‐line therapy for metastatic colorectal cancer

“…Using a continuous dosing schedule, a small observational study reported similar grade 3 or higher adverse events in 71%, though with higher incidences of severe hand-foot syndrome (61%) and mucositis (38%). 15 Together, these studies all suggest full-dose FOL-FIRI and regorafenib, even on an intermittent schedule, are not tolerable for most patients. Certainly, the need for dose reduction and higher rates of discontinuation for toxicity in the regorafenib arm of our study likely explain why, despite increased clinical activity as evidenced by the higher response rate, there was only a small effect on PFS as well as no survival benefit from the addition of regorafenib.…”

“…The reason for the discrepancy in the SN‐38 AUC is uncertain, and it may well be due to chance because of the small number of studied patients in each report. Using a continuous dosing schedule, a small observational study reported similar grade 3 or higher adverse events in 71%, though with higher incidences of severe hand‐foot syndrome (61%) and mucositis (38%) . Together, these studies all suggest full‐dose FOLFIRI and regorafenib, even on an intermittent schedule, are not tolerable for most patients.…”

Oncologic Outcomes in Metastatic Colorectal Cancer with Regorafenib with FOLFIRI as a Third- or Fourth-Line Setting

“…On the contrary, clinical presentations in patients with UGT1A1 *1/*28 vary individually, but these patients generally tolerate the recommended initial irinotecan dose of 180 mg/m 2 [34]. However, patients with the homozygous UGT1A1 *1/*1 genotype are more resistant to irinotecan-associated AEs and could tolerate an irinotecan dose as high as 260 mg/m 2 in previous observational studies [12], [35]. As the result, for patient safety and treatment efficacy of irinotecan dose-escalated FOLFIRI, UGT1A1 genotyping was carried out before treatment was initiated.…”

“…HFSR is the most commonly encountered grade ≥3 AE associated with regorafenib, and it leads to dose reduction or interruption of treatment [4], which may impair the efficacy of regorafenib. Moreover, the incidence of HFSR is more frequent in the Asian population [37], and modification of the dosing schedule from 160 mg once daily for 3 weeks in a 4-week cycle to 120 mg daily for 4 weeks with the same accumulated dose of 3360 mg in a single cycle still yielded high rates of grade 3 HFSR, which recovered earlier than with the original dosing schedule though [12]. A dose reduction from 160 to 120 mg for 3 weeks in a 4-week cycle greatly reduced the occurrence of grade 3 HFSR (75% vs. 16.7%) with comparable DCR (60% vs. 58.3%) in a Japanese study [6].…”

“…However, UGT1A1 genotyping also predicts the maximum dose of irinotecan that can be tolerated and enables dose adjustment of irinotecan [9], [10], [11]. We previously introduced dose-reduced regorafenib combined with dose-adjusted irinotecan based on individual UGT1A1 genotyping along with 5-fluorouracil (5-FU) plus leucovorin (FOLFIRI regimen) with satisfactory oncological results [12].…”