Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'aquila, Italy
Gemma Bruera , Silvia Massacese , Francesco Pepe , Umberto Malapelle , Antonella Dal Mas , Eugenio Ciacco , Giuseppe Calvisi , Paolo Marchetti , Giancarlo Troncone , Maurizio Simmaco , Enrico Ricevuto
Background: Intensive triplet chemotherapy/bevacizumab significantly increased MCRC outcome. Phase II study investigated safety/activity of FIr-C/FOx-C triplet/cetuximab (CET) in first-line RAS wild-type and prediction of individual limiting toxicity syndromes (LTS) by pharmacogenomic biomarkers. Methods: Simon two-step design: p0 70%, p1 85%, power 80%, α5%, β20%; projected ORR I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-timed-flat-infusion 900 mg/m2 d1-2,8-9,15-16,22-23; irinotecan (CPT-11) 160 mg/m2 d1,15, oxaliplatin 80 mg/m2 d8,22; CET 400 then 250 mg/m2 d1,8,15,22; every 28d. Toxicity, individual LTS evaluated, compared by chi-square test; activity/efficacy by log-rank. 5-FU/CPT-11 pharmacogenomic biomarkers, 5-FU degradation rate (5-FUDR), SNPs ABCB1, CYP3A4, DYPD, UGT1A1 evaluated in patients with LTS and at recommended dose. Results: Enrolled: 29 patients < 75 years, primary/intermediate CIRS; from 04/2014 KRAS/NRAS wild-type; median age 59; 7 young-elderly (yE) 24%; 7 liver-limited (L-L) 24%. Recommended CPT-11/5-FU 120/750 mg/m2. Primary endpoint met: OR 14/18 78% as-treated, confirmed in preliminary phase II 17/23 74% intent-to-treat. Liver metastasectomies 14%, 57% L-L. At median follow-up 18 months, PFS 12, OS 23 months. At recommended doses, received DI > 80%; G3-4 toxicities: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS 19 (65.5%), 83% yE. LTS prevalently multiple (ms) vs single site (59 vs 7% p 0.006). Reduced FUDR 56%, SNPs CYP3A4 22%, UGT1A1 71%, > 2 positive pharmacogenomics biomarkers 78% prevalently in patients with gastrointestinal LTS. Conclusions: Intensive first-line FIr-C/FOx-C at recommended doses is tolerable, highly effective in RAS wild-type. Reduced FUDR, CYP3A4, UGT1A1 SNPs may predict individual LTS-ms to select fit patients. Prospective studies personalized by toxicity biomarkers will confirm efficacy. Clinical trial information: Numero EudraCT 2009-016793-32.
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