A multicenter phase II study of personalized FOLFIRI-cetuximab for safe dose intensification.

Abstract

We conducted a multicenter proof of concept phase II trial in patients with advanced colorectal cancer receiving FOLFIRI-cetuximab regimens to explore individual drug tailoring using pharmacogenetics and pharmacokinetics (PK) monitoring. Patients were stratified by their pharmacogenetic/phenotypic status: the irinotecan dose was adjusted according to the number of TA tandem repeats in the UGT1A1 promoter, while the 5-fluorouracil (5-FU) dose was initially adjusted according to dihydropyrimidine dehydrogenase (DPD) activity at initial screening (5-FUODPM Tox) followed by PK-guided dose optimization (5-FUODPM Protocol). An advanced cetuximab PK/pharmacodynamics (PD) study was performed but dosage remained unchanged. Eighty-five patients receiving second-line chemotherapy were enrolled. Mean irinotecan doses at 3 months were 247 ± 50, 210 ± 53 and 140 ± 21 mg/m2 for those with 6/6 (33), 6/7 (26), and 7/7 (7) TATA repeats in the UGT1A1 promoter region, respectively. The 5-FU dose was initially reduced in four patients with DPD deficiency, but mean 5-FU dose at 3 months was 2,412 ± 364 mg/m2 (1,615-3,170 mg/m2). Grade 4 toxicities were not encountered and grade 4 neutropenia occurred in 6.8%, 5.9%, and 0% of patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes. The objective response rate was 25.8% among the 85 patients, 57.3% in patients with tumors wild type (WT) for KRAS, and 25% in those whose tumor harbored a mutant-KRAS. Secondary resection of hepatic metastases was performed in 31.7% of patients. Median progression-free survival (PFS) for all 85 patients was 181 days and 200, 132, and 121 days for patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes, respectively; these differences were not statistically different. In parallel, a strong relationship was shown between cetuximab AUC and regimen efficacy. We conclude that personalized drug tailoring when administering in FOLFIRI + cetuximab allows for safe and efficient individual dose intensification.

• Authors: Michèle Boisdron-Celle, Jean Philippe Metges, Olivier Capitain, Antoine Adenis, Jean Luc Raoul, Thierry Lecomte, You Heng Lam, Roger Faroux, Claude Masliah, Anne Lise Poirier, Virginie Berger, Alain Morel, Erick Gamelin
• Journal: Seminars in oncology (Semin Oncol) Vol. 44 Issue 1 Pg. 24-33 (Feb 2017) ISSN: 1532-8708 [Electronic] United States
• PMID: 28395759 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• KRAS protein, human
• UGT1A1 enzyme
• Glucuronosyltransferase
• Proto-Oncogene Proteins p21(ras)
• Cetuximab
• Leucovorin
• Fluorouracil
• Camptothecin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives)
• Cetuximab (administration & dosage, adverse effects)
• Female
• Fluorouracil (administration & dosage, adverse effects)
• Genotype
• Glucuronosyltransferase (genetics)
• Humans
• Leucovorin (administration & dosage, adverse effects)
• Male
• Middle Aged
• Neoplasms (drug therapy, mortality)
• Precision Medicine
• Proto-Oncogene Proteins p21(ras) (genetics)