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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

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Summary

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.

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References

  1. Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174

    Article  CAS  PubMed  Google Scholar 

  2. Karapetis CS, Khambata-Ford S, Jonker DJ et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765

    Article  CAS  PubMed  Google Scholar 

  3. Benvenuti S, Sartore-Bianchi A, Nicolantonio DI F et al (2007) Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67:2643–2648

    Article  CAS  PubMed  Google Scholar 

  4. Souglakos J, Philips J, Wang R et al (2009) Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer 101:465–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yokota T, Ura T, Shibata N et al (2011) BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer 104:856–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nicolantonio DI F, Martini M, Molinari F et al (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26:5705–5712

    Article  Google Scholar 

  7. Yeh TC, Marsh V, Bernat BA et al (2007) Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res 13:1576–1583

    Article  CAS  PubMed  Google Scholar 

  8. Davies BR, Logie A, Mckay JS et al (2007) AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther 6:2209–2219

    Article  CAS  PubMed  Google Scholar 

  9. Adjei AA, Cohen RB, Franklin W et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 26:2139–2146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Banerji U, Camidge DR, Verheul HM et al (2010) The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 16:1613–1623

    Article  CAS  PubMed  Google Scholar 

  11. Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (Version 1.1). Eur J Cancer 45:228–247

    Article  CAS  PubMed  Google Scholar 

  12. Ikesue H, Vermeulen LC, Hoke R et al (2010) Stability of cetuximab and panitumumab in glass vials and polyvinyl chloride bags. Am J Health Syst Pharm 67:223–226

    Article  CAS  PubMed  Google Scholar 

  13. Ballif BA, Blenis J (2001) Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals. Cell Growth Differ 12:397–408

    CAS  PubMed  Google Scholar 

  14. Corcoran RB, Atreya CE, Falchook GS et al (2014) Phase 1-2 trial of the BRAF inhibitor dabrafenib (D) plus MEK inhibitor trametinib (T) in BRAF V600 mutant colorectal cancer (CRC): updated efficacy and biomarker analysis. J Clin Oncol 32:5s (suppl; abstr 3517)

  15. Bendell JC, Atreya CE, Theirry A et al Efficacy and tolerability in an open-label phase I/II study of MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in combination in patients (pts) with BRAF V600E mutated colorectal cancer (CRC). J Clin Oncol 32:5s (suppl; abstr 3515)

  16. Van Geel R, Elez E, Bendell JC, et al (2014) Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-Specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer. J Clin Oncol 32:5s (suppl; abstr 3514)

  17. Hong DS, Van Karlyle M, Fu S, et al (2014) Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAF-mutated advanced cancers and metastatic colorectal cancer. J Clin Oncol 32:5s (suppl; abstr 3516)

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Authors and Affiliations

  1. University of Wisconsin–Madison Carbone Cancer Center, 600 Highland Avenue, K6/544 CSC, Madison, WI, 53792, USA

    Dustin A. Deming, Ludmila L. Cavalcante, Sam J. Lubner, Daniel L. Mulkerin, Noelle K. LoConte, Jens C. Eickhoff, Jill M. Kolesar, George Wilding & Glenn Liu

  2. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Austin G. Doyle

  3. National Cancer Institute/Medical Oncology Branch, Bethesda, MD, USA

    Suzanne Fioravanti, Tim F. Greten, Kathryn Compton & Austin Duffy

Authors
  1. Dustin A. Deming
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  2. Ludmila L. Cavalcante
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  3. Sam J. Lubner
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  4. Daniel L. Mulkerin
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  5. Noelle K. LoConte
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  6. Jens C. Eickhoff
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  7. Jill M. Kolesar
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  8. Suzanne Fioravanti
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  9. Tim F. Greten
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  10. Kathryn Compton
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  11. Austin G. Doyle
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  12. George Wilding
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  13. Austin Duffy
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  14. Glenn Liu
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Corresponding author

Correspondence to Dustin A. Deming.

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Funding

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.

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The authors declare that they have no conflict of interest.

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Deming, D.A., Cavalcante, L.L., Lubner, S.J. et al. 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. Invest New Drugs 34, 168–175 (2016). https://doi.org/10.1007/s10637-015-0314-7

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  • DOI: https://doi.org/10.1007/s10637-015-0314-7

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