A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma
| Autor: | Sanaa Tahiri, Amir Ali Talasaz, Elizabeth Dito, R. Kate Kelley, Anna Ong, W. Michael Korn, Andrew H. Ko, Ryan Courtin, Eric A. Collisson, Tanios Bekaii-Saab, Nancy M. Joseph, Regina Linetskaya, Jessica Van Ziffle, Olga M. Mirzoeva, Margaret A. Tempero, Peter Kuhn, Alan P. Venook, Sharvina Ziyeh |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Oncology Cancer Research Pathology medicine.medical_treatment Drug Resistance Kaplan-Meier Estimate Neoplastic Cells 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols 80 and over Circulating Clinical endpoint Molecular Targeted Therapy Cancer EGFR inhibitors Aged 80 and over DNA Neoplasm Middle Aged Neoplastic Cells Circulating 5.1 Pharmaceuticals 6.1 Pharmaceuticals 030220 oncology & carcinogenesis Retreatment Adenocarcinoma Female Erlotinib Development of treatments and therapeutic interventions medicine.drug Adult medicine.medical_specialty Clinical Trials and Supportive Activities Oncology and Carcinogenesis Article Erlotinib Hydrochloride Pancreatic Cancer 03 medical and health sciences Rare Diseases Clinical Research Pancreatic cancer Internal medicine medicine Humans Oncology & Carcinogenesis Neoplasm Staging Aged Chemotherapy business.industry Evaluation of treatments and therapeutic interventions DNA medicine.disease Pancreatic Neoplasms Clinical trial 030104 developmental biology Drug Resistance Neoplasm Selumetinib Neoplasm Benzimidazoles Digestive Diseases business Biomarkers |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research, vol 22, iss 1 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-15-0979 |
| Popis: | Purpose: On the basis of preclinical evidence of synergistic activity between MEK and EGFR inhibitors in pancreatic ductal adenocarcinoma (PDAC), we evaluated the safety and efficacy of selumetinib, a MEK1/2 inhibitor, plus erlotinib in patients with previously treated advanced PDAC. Experimental Design: In this single-arm phase II trial, eligible patients received the combination of erlotinib 100 mg plus selumetinib 100 mg daily in 3-week cycles. Study assessments included measurement of clinical outcomes, with a primary endpoint of overall survival, and exploration of potential molecular predictors of treatment benefit. Results: Forty-six patients were enrolled and received a median of two cycles (range, 1–7). Although no objective responses were observed, 19 patients (41%) showed evidence of stable disease for ≥6 weeks, and 13 of 34 patients (38%) had a CA19-9 decline ≥50%. Median progression-free survival was 1.9 months [95% confidence interval (CI), 1.4–3.3 months], with a median overall survival of 7.3 months (95% CI, 5.2–8.0 months). Common adverse events included rash, diarrhea, and nausea/vomiting. Patients with tumors exhibiting an epithelial phenotype (demonstrated by a high level of E-cadherin expression) were more likely to be sensitive to study treatment. Tumor-derived DNA was detectable in plasma from the majority of patients using next-generation digital DNA sequencing, and its relative abundance correlated with tumor burden. Conclusions: A therapeutic strategy of dual targeted inhibition of the MEK and EGFR pathways shows modest antitumor activity in pancreatic cancer. Specific molecular subtypes may derive greatest benefit from this combination. Further exploration, both with more potent MEK inhibitors and in molecularly enriched patient subsets, is warranted. Clin Cancer Res; 22(1); 61–68. ©2015 AACR. |
| Databáze: | OpenAIRE |
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