A phase II trial of UGT1A1 genotype-guided FOLFIRI plus bevacizumab as first-line therapy for advanced, unresectable colorectal cancer.

Autor: Sanoff HK; Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, United States.; Division of Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27514, United States., Deal AM; Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, United States., Patel J; Levine Cancer Center, Charlotte, NC 28204, United States., Sorah JD; Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, United States.; Division of Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27514, United States., Gaddy J; Division of Oncology, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, United States., O'Neil B; Community Health System, Indianapolis, IN 46250, United States., Turk A; Division of Hematology/Oncology, Indiana University, Indianapolis, IN 46202, United States., Irvin W; Bon Secours Cancer Institute, Richmond, VA 23114, United States., Boles J; UNC Rex Hematology/Oncology, Raleigh, NC 27607, United States., Lee MS; Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States., McRee A; The Janssen Research and Development, Spring House, PA 19002, United States., Wardell AC; Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, United States., Weck KE; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27514, United States., Basch E; Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, United States.; Division of Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27514, United States., Wood WA; Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27514, United States.; Division of Hematology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27514, United States., Innocenti F; Division of Pharmacotherapy and Experimental Therapeutics, Eschelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27514, United States.
Jazyk: angličtina
Zdroj: The oncologist [Oncologist] 2024 Sep 06; Vol. 29 (9), pp. 786-793.
DOI: 10.1093/oncolo/oyae122
Abstrakt: Background: FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity.
Methods: In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS).
Results: One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia.
Conclusions: A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting.
(© The Author(s) 2024. Published by Oxford University Press.)
Databáze: MEDLINE
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