Oncological Outcomes of Patients with Peritoneal Metastasis–only Colorectal Cancer Treated with First-line Bevacizumab and FOLFIRI through Irinotecan Dose Escalation According to UGT1A1 Polymorphism: Compared to Liver Metastasis–only, and Lung Metastasis–only

Background:The prognosis of metastatic colorectal cancer (mCRC) depends on the metastatic site and systemic therapy regimen. Peritoneal metastases are associated with a relatively unfavorable prognosis among patients with mCRC. In this article, we present the treatment outcomes of patients with peritoneal carcinomatosis (PC)–only, liver metastasis (LiM)–only, and lung metastasis (LuM)–only CRC.Methods:Overall, 206 mCRC patients with single-site metastasis and who had received treatment from January 2014 to December 2018 were recruited. Among 206 patients with mCRC, 15 had PC-only mCRC, 145 had LiM-only mCRC, and 46 had LuM-only mCRC. They attended regular follow-ups until November 2020, and the median follow-up period was 24.7 months (5.1–41.3 months). Patients’ characteristics, including clinical data, gene mutation profiles, and clinical outcomes, were evaluated. All patients with PC-only CRC were treated with first-line bevacizumab and FOLFIRI, and the irinotecan dose escalation depended on UGT1A1 polymorphism.Results:Of the 206 patients, no statistical difference was observed between the PC-only, LiM-only, and LuM-only groups in terms of age, primary tumor location, RAS mutation status, BRAF mutation status, and epidermal growth factor receptor overexpression (all P > 0.05). KRAS mutations were detected in two (16.7%) patients with PC-only CRC, 39 (36.4%) patients with LiM-only CRC, and 12 (36.4%) patients with LuM-only CRC. NRAS mutations were detected in one (8.3%) patient with PC-only CRC, six (7.3%) patients with LiM-only CRC, and two (7.1%) patients with LuM-only CRC. BRAF mutations were detected in two (15.4%) patients with PC-only CRC, seven (6.9%) patients with LiM-only CRC, and one (2.9%) patient with LuM-only CRC. Patients with PC-only CRC had a median progression-free survival (mPFS) of 18.0 months and a median overall survival (mOS) of 24.6 months. Patients with LiM-only or LuM-only CRC had mPFS of 18.2 and 26.6 months and mOS of 25.0 and 44.5 months, respectively. No significant differences regarding PFS and OS (both P > 0.05) between the three groups of patients with mCRC were observed.Conclusions:A PC-only status is considered to be a challenge in the treatment of patients with mCRC. Our study revealed that in patients with PC-only mCRC had a higher incidence of BRAF mutations, and treatment of first-line bevacizumab and FOLFIRI through irinotecan dose escalation according to UGT1A1 polymorphism could confer such patients with comparable outcomes to that of patients with LiM-only and LuM-only mCRC. However, further prospective randomized trials on patients with peritoneal metastatic mCRC should be conducted to verify the findings of this retrospective study.

UGT1A1 Polymorphism for Irinotecan Dose Escalation in Patients with BRAF-Mutated Metastatic Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI

Background. Patients with metastatic colorectal cancer (mCRC) and BRAF V600E mutation have a poor prognosis, with a median progression-free survival (PFS) of only 5–7 months after initial therapy. The current standard first-line chemotherapy for these patients includes FOLFOX or FOLFIRI plus bevacizumab. In this study, we explored the effects and oncological outcomes of UGT1A1 polymorphism for irinotecan escalation in patients with BRAF-mutated mCRC. Patients and Methods. This retrospective study included 17 patients with BRAF-mutated mCRC between April 2016 and December 2019. UGT1A1 genotyping was performed on all patients prior to initiating bevacizumab plus FOLFIRI chemotherapy. The primary endpoint was PFS, and the secondary endpoints were toxicity, response rate, disease control rate, and overall survival (OS). Results. Fifteen and two patients had UGT1A1 1∗/1∗ and 1∗/28∗, respectively. Eight underwent irinotecan dose escalation with tolerable adverse effects (AEs), and nine maintained an irinotecan dose of 180 mg/m2 or required deescalation to 150 mg/m2 due to intolerable AEs. After a median follow-up period of 15.7 (range, 3–54) months, the median PFS and OS were 9.4 and 15.7 months, respectively. Grade 3/4 AEs were observed in three (6%) patients. The disease control and partial response rates were 64.7% and 11.8%, respectively, indicating that most patients (14, 82.3%) could maintain this as a first-line line therapy with stable disease or proceed to second-line therapy if disease progression occurred, thereby maintaining acceptable performance status. Conclusions. The oncological outcomes of patients with BRAF-mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a first-line therapy are acceptable with tolerable AEs; this may be a feasible treatment option in such patients. Pretherapeutic UGT1A1 genotyping-guided dose adjustment can achieve favorable outcomes.

SFCE-RAPIRI Phase I Study of Rapamycin Plus Irinotecan: A New Way to Target Intra-Tumor Hypoxia in Pediatric Refractory Cancers

Hypoxic environment is a prognostic factor linked in pediatric cancers to a worse outcome, favoring tumor progression and resistance to treatments. The activation of mechanistic Target Of Rapamycin (mTor)/hypoxia inducible factor (HIF)-1 pathway can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a phase I trial associating both drugs in pediatric refractory/relapsing solid tumors. Patients were enrolled according to a 3 + 3 escalation design with ten levels, aiming to determine the MTD (maximum tolerated dose) of rapamycin plus irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m2/day), associating biweekly intravenous irinotecan (125 to 240 mg/m2/dose). Toxicities, pharmacokinetics, efficacy analyses, and pharmacodynamics were evaluated. Forty-two patients, aged from 2 to 18 years, were included. No MTD was reached. Adverse events were mild to moderate. Only rapamycin doses of 1.5 mg/m2/day reached over time clinically active plasma concentrations. Tumor responses and prolonged stable disease were associated with a mean irinotecan area under the curve of more than 400 min.mg/L. Fourteen out of 31 (45.1%) patients had a non-progressive disease at 8 weeks. Most of them were sarcomas and brain tumors. For the phase II trial, we can then propose biweekly 125 mg/m2 irinotecan dose with a pharmacokinetic (PK) follow-up and a rapamycin dose of 1.5 mg/m2/day, reaching a blood concentration above 10 g/L.

Real-world outcomes associated with liposomal irinotecan dose reductions in metastatic pancreatic ductal adenocarcinoma

Aim: This study sought to understand the association between liposomal irinotecan dose reductions (DRs) and clinical outcomes among patients with metastatic pancreatic ductal adenocarcinoma. Materials & methods: A retrospective study of adult patients with metastatic pancreatic ductal adenocarcinoma treated with liposomal irinotecan in the Flatiron Health database was conducted to assess treatment and clinical outcomes. Results: DRs occurred in 28.4% of the 320 patients in the study. Patients with DRs had longer overall survival (7.7 [95% CI: 6.2–10.2]) vs 3.6 [3.2–4.1] months) and time to discontinuation (4.2 [3.0–4.9] vs 1.4 [1.0–1.5] months) than patients without DRs. Results were consistent in a validation analysis requiring three cycles of treatment. Conclusion: Liposomal irinotecan DRs were associated with improved clinical outcomes compared with patients without DRs.

Dosage Adjustment of Irinotecan in Patients with UGT1A1 Polymorphisms: A Review of Current Literature

Objective: To review available literature regarding pharmacogenomics (PGx) effects on the metabolism of irinotecan by the UGT1A1 gene and the resulting dose adjustments based on PGx genetic variant. Summary: Irinotecan is a chemotherapy agent commonly used in treatment of various cancers such as metastatic colorectal cancer (mCRC) and others. The extent of decreased function of UGT1A1 varies based on genotype so irinotecan dose adjustments may be needed. Those with UGT1A1 homozygous *28/*28 genotype may experience 70% reduction in activity, while heterozygous genotypes with *1/*28 may only experience 30% loss. UGT1A1*6 variants may also play a role in decreased function. The incidence of *28 and *6 alleles varies among ethnic populations resulting in the need for dosage adjustments to avoid toxicities. Conclusion: These findings add to a growing body of literature that suggest patients with UGT1A1 *28 or *6 variant alleles benefit from lower doses of irinotecan. However, due to the heterogeneity of currently available studies, more evidence that investigates various regimens in different patient populations is needed to determine the most appropriate dosing strategies. Although other factors, as well as efficacy considerations will likely influence clinical decision making, genotype may be an important factor when determining dose. Review Article

Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1genotyping in previous treated metastatic colorectal cancer patients:study protocol for a randomized controlled trial

Background Regorafenib is an oral multikinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor, and monoclonal antibodies targeting epidermal growth factor receptor. A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in a 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) regimen on the basis of an individual uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. The aim of this study is to address the efficacy and safety of a dose-adjusted combination of regorafenib and FOLFIRI for patients with mCRC. Methods A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose-escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival, and the secondary endpoints are overall survival, disease control rate, time to progression, and duration of treatment. Safety assessments will also be recorded. Discussion Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidence regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC. Trial registration ClinicalTrials.gov, NCT03880877. Prospectively registered on 19 March 2019.

Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1 genotyping in previous treated metastatic colorectal cancer patients: study protocol for a randomized controlled trial

Background Regorafenib is an oral multi-kinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor (VEGF), and monoclonal antibodies targeting epidermal growth factor receptor (EGFR). A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in FOLFIRI regimen on basis of individual uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. This study is trying to address the efficacy and safety of dose adjusted combination of regorafenib and FOLFIRI for patients with mCRC. Methods A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival (PFS) and the secondary endpoints are overall survival (OS), disease control rate (DCR), time to progression (TTP), and duration of treatment (DoT). Safety assessments are recorded as well. Discussion Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidences regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC.

Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1 genotyping in previous treated metastatic colorectal cancer patients: study protocol for a randomized controlled trial

Background Regorafenib is an oral multi-kinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor (VEGF), and monoclonal antibodies targeting epidermal growth factor receptor (EGFR). A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in FOLFIRI regimen on basis of individual uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. This study is trying to address the efficacy and safety of dose adjusted combination of regorafenib and FOLFIRI for patients with mCRC. Methods A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival (PFS) and the secondary endpoints are overall survival (OS), disease control rate (DCR), time to progression (TTP), and duration of treatment (DoT). Safety assessments are recorded as well. Discussion Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidences regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC.

Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1 genotyping in previous treated metastatic colorectal cancer patients: study protocol for a randomized controlled trial

Background Regorafenib is an oral multi-kinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor (VEGF), and monoclonal antibodies targeting epidermal growth factor receptor (EGFR). A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in FOLFIRI regimen on basis of individual uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. This study is trying to address the efficacy and safety of dose adjusted combination of regorafenib and FOLFIRI for patients with mCRC. Methods A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival (PFS) and the secondary endpoints are overall survival (OS), disease control rate (DCR), time to progression (TTP), and duration of treatment (DoT). Safety assessments are recorded as well. Discussion Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidences regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC.