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
Open accessAbstract
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 p.o. BID and cetuximab 250 mg/m(2) weekly following a 400 mg/m(2) 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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Selumetinib or pimasertib plus cetuximab enhanced antiproliferative and proapoptotic effects in cells resistant to cetuximab in vitro and in vivo.
“Selumetinib or pimasertib plus cetuximab enhanced antiproliferative and proapoptotic effects in cells resistant to cetuximab in vitro and in vivo [102, 103].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [103]
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- Authors
- Deming, D. A., Cavalcante, L. L., Lubner, S. J., Mulkerin, D. L., LoConte, N. K., Eickhoff, J. C., Kolesar, J. M., Fioravanti, S., Greten, T. F., Compton, K., Doyle, A. G., Wilding, G., Duffy, A., & Liu, G.
- Affiliations
- University of Wisconsin Carbone Cancer Center (US)
- National Cancer Institute (US)
- National Institutes of Health (US)
- Corresponding author
- Deming, Dustin A.
- ORCID
- Venue
- Investigational New Drugs
- Published
- 2015-12-14
- Volume
- 34
- Issue
- 2
- Pages
- 168-175
- ISSN
- 0167-6997 (ISSN-L)
- 1573-0646
- PMC
- PMC4788533
- OpenAlex
- W2200675409
- Cited by
- 52
- References
- 17
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 7 · 2022: 2 · 2021: 6 · 2020: 8 · 2019: 6 · 2018: 5 · 2017: 5 · 2016: 4
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Investigational New Drugs (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (U01 CA062491, P30 CA014520)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- selumetinib, MEK inhibitors, cetuximab, KRAS-mutant colorectal cancer, anti-EGFR therapy resistance, RAS/MAPK pathway, combination therapy, maximum tolerated dose, dose-limiting toxicity, refractory solid tumors, pharmacokinetics, acneiform rash, hypomagnesemia
- MeSH terms
- Cetuximab, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Mutation, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Maximum Tolerated Dose, Mitogen-Activated Protein Kinase Kinases, Protein Kinase Inhibitors
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