title: 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/m2for 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.affiliation: Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France. Electronic address: michele.boisdron@ico.unicancer.fr.
authors.forename: Michèle
authors.initials: M
authors.lastname: Boisdron-Celle
authors.affiliation: CHU Morvan, Brest, France.
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Metges
authors.affiliation: Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Capitain
authors.affiliation: CRLCC Oscar Lambret, Lille, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Adenis
authors.affiliation: CRLCC Centre Paoli - Calmettes, Marseille, France.
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Raoul
authors.affiliation: CHU Trousseau, Tours, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lecomte
authors.affiliation: CH Cholet, France.
authors.forename: You Heng
authors.initials: YH
authors.lastname: Lam
authors.affiliation: CHD Les Oudairies, La Roche sur Yon, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Faroux
authors.affiliation: Clinique Mutualiste de l׳Estuaire Cité Sanitaire, Saint Nazaire, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Masliah
authors.affiliation: Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France.
authors.forename: Anne Lise
authors.initials: AL
authors.lastname: Poirier
authors.affiliation: Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Berger
authors.affiliation: Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Morel
authors.affiliation: Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France.
authors.forename: Erick
authors.initials: E
authors.lastname: Gamelin
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000068818:Cetuximab / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality; D057285:Precision Medicine; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D000068818:Cetuximab; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D002955:Leucovorin; D016283:Proto-Oncogene Proteins p21(ras); D000099148:UGT1A1 Enzyme; C117307:KRAS protein, human
keywords: 5-Fluorouracil dose adaptation; DPD; Dihydropyrimidine deshydrogenase; Dose intensification; Irinotecan