A Triple Combination Tailored Therapy (Folfiri-Cetuximab) for Safe Dose Intensification: A Multicenter Phase II Proof-Of-Concept Study.

Abstract

Introduction: A multicenter phase II trial was conducted to explore individual dose optimization for advanced colorectal cancer patients treated with 5‐Fluorouracil (5‐FU); irinotecan (CPT11) and cetuximab (FOLFIRI‐Cetuximab regimen) using pharmacogenetics and PK‐monitoring approaches. Methods: For dose modifications, patients were stratified by their genetic and/or phenotypic status. CPT11 standard dose (180mg/m2) was adjusted according to UGT1A1∗28 profile (6/6, 6/7 or 7/7 repeats of UGT1A1 TATA box). Conventional initial 5‐FU dose (2400mg/m2) was adapted before the first cycle according to dihydropyrimidine dehydrogenase (DPD) deficiency screening by 5‐FUODPMToxTM, then the dose optimization was PK‐guided by 5‐FUODPMProtocolTM for the following cycles. Cetuximab PK was performed but dosage remained unchanged. Results: A total of 104 patients were enrolled. Mean CPT11 doses at 3 months were: 256 + /‐50 mg/m2 for 6/6 (58), 184 + /‐53 mg/m2 for 6/7 (38) and 127 + /‐14 mg/m2 for 7/7 (8) patients. Initial 5‐FU dose was reduced (>20%) for 5.8% of patients (5 DPD deficient patients and 1 elderly patient). Throughout the entire treatment, the mean dose of 5‐FU was 722 mg/m2 to 4117 mg/m2. No grade 4 diarrhea was seen, whereas grade 4 neutropenia was noted only in 6/6 patients (5.2%) and 6/7 patients (7.9%). Among the 87 evaluable patients for response, we observed an objective response rate of 32.2%, and disease control of all subgroups (6/6, 6/7 or 7/7) was more than 71%. 40 patients (38.4%) were able to have a secondary resection, even in 2nd line chemotherapy. No difference in median PFS was observed in the three UGT1A1 subgroups (199 days for 6/6, 6/7 and 7/7 genotypes). A relationship was shown between cetuximab AUC and regimen efficacy. Conclusion: Pharmacogenetics and pharmacokinetic monitoring allows safe dose intensification, able to enhance efficacy and limit toxicity compared to conventional BSA dosing. Partial DPD deficiency is not a contraindication to 5‐FU provided that the dose is PK‐guided. PK‐guided cetuximab intensification warrants further investigation.