A phase i study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer

Dustin A. Deming, Ludmila L. Cavalcante, Sam J. Lubner, Daniel L. Mulkerin, Noelle K. Loconte, Jens C. Eickhoff, Jill M. Kolesar, Suzanne Fioravanti, Tim F. Greten, Kathryn Compton, Austin G. Doyle, George Wilding, Austin Duffy, Glenn Liu

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Background KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. Methods A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. Results 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg PO BID and cetuximab 250 mg/m2 weekly following a 400 mg/m2 load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. Conclusions The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.

Original languageEnglish
Pages (from-to)168-175
Number of pages8
JournalInvestigational New Drugs
Volume34
Issue number2
DOIs
StatePublished - Apr 1 2016

Bibliographical note

Funding Information:
This study was supported by grants from the National Cancer Institute: U01 CA062491to Glenn Liu and P30 CA014520 to University of Wisconsin–Madison Carbone Cancer Center. We gratefully acknowledge the support of AstraZeneca who provided the selumetinib for this clinical trial.

Publisher Copyright:
© 2015 Springer Science+Business Media New York.

Keywords

  • AZD6244
  • Cetuximab
  • Colon cancer
  • KRAS
  • Phase I
  • Selumetinib

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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