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Clin Cancer Res. 2016 Jan 1;22(1):61-8. doi: 10.1158/1078-0432.CCR-15-0979. Epub 2015 Aug 6.

A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma.

Author information

1
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. andrewko@medicine.ucsf.edu.
2
Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
3
Department of Pathology, University of California San Francisco, San Francisco, California.
4
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
5
Guardant Health, Inc., Redwood City, California.
6
University of Southern California, Los Angeles, California.

Abstract

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.

PMID:
26251290
PMCID:
PMC4703532
DOI:
10.1158/1078-0432.CCR-15-0979
[Indexed for MEDLINE]
Free PMC Article

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