Abstract A052: Predictive wild-type RAS/BRAF and pharmacogenetic biomarkers drive selection of metastatic colorectal cancer patients fit for intensive first-line FIr-C/FOx-C schedule adding cetuximab to triplet chemotherapy

Autor: Giuseppe Calvisi, Gemma Bruera, Maurizio Simmaco, Antonella Dal Mas, Corrado Ficorella, Enrico Ricevuto, Silvia Massacese, Eugenio Ciacco
Rok vydání: 2018
Předmět:
Zdroj: Molecular Cancer Therapeutics. 17:A052-A052
ISSN: 1538-8514
1535-7163
DOI: 10.1158/1535-7163.targ-17-a052
Popis: Background: Intensive-first line bevacizumab (BEV) addition to triplet chemotherapy significantly increased clinical outcome in metastatic colorectal cancer (MCRC) patients. Cetuximab (CET) addition to doublet chemotherapy significantly increased clinical outcome in RAS wild-type MCRC. This phase II study investigated safety and activity of FIr-C/FOx-C schedule of weekly CET added to triplet chemotherapy in first line RAS wild-type MCRC. Methods: The phase II study was planned according to Simon two-step design: delta 15% (p0 70%, p1 85%), power 80%, α 5%, β 20%; projected objective responses (ORR), I step 14/19 patients. FIr-C/FOx-C schedule: 5-fluorouracil (5-FU) 12h-timed-flat-infusion 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; associated to weekly alternating irinotecan (CPT-11) 160 mg/m2, days 1,15 or oxaliplatin (OXP) 80 mg/m2, days 8, 22; CET 400 mg/m2 loading dose, then 250 mg/m2 days 1,8,15,22; every 4 weeks. Toxicity and limiting toxicity syndromes (LTS) were evaluated and compared using chi-square test; activity and efficacy using log-rank test. 5-FU degradation rate (5-FUDR) and single nucleotide polymorphisms (SNP) of 4 genes (DYPD, CYP3A4, ABCB1, UGT1A1) involved in metabolism of 5-FU and CPT-11 were evaluated in individual patients showing LTS and at the recommended doses as predictive biomarkers of toxicity. Results: Twenty-nine consecutive patients 80% for each drug and cumulative G3-4 toxicities in 13 patients were: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%. LTS, consisting of the LT, associated or not to G2 or other LT, were observed overall in 19 patients (65.5%), 83% in yE. LTS were prevalently multiple than single site (59% versus 7%, chi square 7.703, p = 0.006). Reduced FUDR, CYP3A4 and UGT1A1 SNPs, also frequently associated, were particularly observed in patients showing gastrointestinal LTS, while not in patients without LTS. Conclusion: Intensive first-line FIr-C/FOx-C regimen at the modified recommended doses is tolerable and highly effective in RAS wild-type MCRC patients, with significantly increased LTS multiple sites, justifying careful selection of fit patients using a panel of 5 predictive biomarkers of 5-FU and CPT11 toxicity. Citation Format: Gemma Bruera, Silvia Massacese, Antonella Dal Mas, Corrado Ficorella, Eugenio Ciacco, Giuseppe Calvisi, Maurizio Simmaco, Enrico Ricevuto. Predictive wild-type RAS/BRAF and pharmacogenetic biomarkers drive selection of metastatic colorectal cancer patients fit for intensive first-line FIr-C/FOx-C schedule adding cetuximab to triplet chemotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A052.
Databáze: OpenAIRE
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