A multicenter, open-label phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma

Andrew H. Ko, Tanios Bekaii-Saab, Jessica Van Ziffle, Olga M. Mirzoeva, Nancy M. Joseph, Amir Ali Talasaz, Peter Kuhn, Margaret A. Tempero, Eric A. Collisson, R. Kate Kelley, Alan P. Venook, Elizabeth Dito, Anna Ong, Sharvina Ziyeh, Ryan Courtin, Regina Linetskaya, Sanaa Tahiri, W. Michael Korn

Research output: Contribution to journalArticle

41 Citations (Scopus)

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 nextgeneration 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.

Original languageEnglish (US)
Pages (from-to)61-68
Number of pages8
JournalClinical Cancer Research
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

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Phase II Clinical Trials
Mitogen-Activated Protein Kinase Kinases
Adenocarcinoma
Drug Therapy
Confidence Intervals
Survival
Cadherins
Exanthema
Tumor Burden
Pancreatic Neoplasms
DNA Sequence Analysis
Nausea
Disease-Free Survival
Vomiting
Diarrhea
Neoplasms
Research Design
Therapeutics
Phenotype
Safety

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A multicenter, open-label phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma. / Ko, Andrew H.; Bekaii-Saab, Tanios; Van Ziffle, Jessica; Mirzoeva, Olga M.; Joseph, Nancy M.; Talasaz, Amir Ali; Kuhn, Peter; Tempero, Margaret A.; Collisson, Eric A.; Kelley, R. Kate; Venook, Alan P.; Dito, Elizabeth; Ong, Anna; Ziyeh, Sharvina; Courtin, Ryan; Linetskaya, Regina; Tahiri, Sanaa; Korn, W. Michael.

In: Clinical Cancer Research, Vol. 22, No. 1, 01.01.2016, p. 61-68.

Research output: Contribution to journalArticle

Ko, AH, Bekaii-Saab, T, Van Ziffle, J, Mirzoeva, OM, Joseph, NM, Talasaz, AA, Kuhn, P, Tempero, MA, Collisson, EA, Kelley, RK, Venook, AP, Dito, E, Ong, A, Ziyeh, S, Courtin, R, Linetskaya, R, Tahiri, S & Korn, WM 2016, 'A multicenter, open-label phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma', Clinical Cancer Research, vol. 22, no. 1, pp. 61-68. https://doi.org/10.1158/1078-0432.CCR-15-0979
Ko, Andrew H. ; Bekaii-Saab, Tanios ; Van Ziffle, Jessica ; Mirzoeva, Olga M. ; Joseph, Nancy M. ; Talasaz, Amir Ali ; Kuhn, Peter ; Tempero, Margaret A. ; Collisson, Eric A. ; Kelley, R. Kate ; Venook, Alan P. ; Dito, Elizabeth ; Ong, Anna ; Ziyeh, Sharvina ; Courtin, Ryan ; Linetskaya, Regina ; Tahiri, Sanaa ; Korn, W. Michael. / A multicenter, open-label phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 1. pp. 61-68.
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T1 - A multicenter, open-label phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma

AU - Ko, Andrew H.

AU - Bekaii-Saab, Tanios

AU - Van Ziffle, Jessica

AU - Mirzoeva, Olga M.

AU - Joseph, Nancy M.

AU - Talasaz, Amir Ali

AU - Kuhn, Peter

AU - Tempero, Margaret A.

AU - Collisson, Eric A.

AU - Kelley, R. Kate

AU - Venook, Alan P.

AU - Dito, Elizabeth

AU - Ong, Anna

AU - Ziyeh, Sharvina

AU - Courtin, Ryan

AU - Linetskaya, Regina

AU - Tahiri, Sanaa

AU - Korn, W. Michael

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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 nextgeneration 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.

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