Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer
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Lessons Learned: Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.d. Because the anticancer activity was limited, further development of this combination is not recommended until better biomarkers for response and resistance are defined. Background: Antitumor effects of MEK inhibitors are limited in KRAS-mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3-kinase–AKT pathway. Therefore, this phase I trial was initiated with the pan-HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild-type tumors. Methods: Afatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy. Results: Twenty-six patients were enrolled with colorectal cancer (n = 19), non-small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose-limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response. Conclusion: Afatinib and selumetinib can be combined in continuous and intermittent schedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited.
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Early-phase clinical trials evaluating afatinib with selumetinib, dacomitinib with PD-0325901, and cobimetinib with atezolizumab failed to prove efficacy.
“Early-phase clinical trials evaluating combinations such as afatinib (a pan-HER inhibitor) with selumetinib (a MEK inhibitor), dacomitinib (a panHER inhibitor) with PD-0325901 (a MEK1/2 inhibitor), and cobimetinib (a MEK inhibitor) with atezolizumab (an anti-PDL1), have failed to prove efficacy [78,79,80].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [78]
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SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo
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KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer
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van Geel, R. M. J. M., van Brummelen, E. M. J., Eskens, F. A. L. M., Huijberts, S. C. F. A., de Vos, F. Y. F. L., Lolkema, M. P. J. K., Devriese, L. A., Opdam, F. L., Marchetti, S., Steeghs, N., et al. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0776-z · Cited by 55 · see citing works
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- Authors
- Brummelen, E. M. J., Huijberts, S., Herpen, C., Desar, I., Opdam, F., Geel, R., Marchetti, S., Steeghs, N., Monkhorst, K., Thijssen, B., Rosing, H., Huitema, A., Beijnen, J., Bernards, R., & Schellens, J.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Radboud University Medical Center (NL)
- Maastricht University Medical Centre (NL)
- Utrecht University (NL)
- Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Corresponding author
- Huijberts, Sanne
- Opdam, Frans
- ORCID
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-12-29
- Volume
- 26
- Issue
- 4
- Pages
- 290-e545
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- PMC
- PMC8018304
- OpenAlex
- W3111380117
- Cited by
- 32
- References
- 11
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 9 · 2022: 5 · 2021: 6
- FWCI
- 1.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Oncologist (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- AstraZeneca
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- afatinib, selumetinib, KRAS mutation, colorectal cancer, non-small cell lung cancer, pancreatic cancer, MEK inhibitors, pan-HER inhibitor, combination therapy, intermittent dosing, dose-limiting toxicity, MAPK signaling, target engagement, maximum tolerated dose
- MeSH terms
- Afatinib, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Carcinoma, Non-Small-Cell Lung, Humans, Lung, Lung Neoplasms, Mutation, Pancreatic Neoplasms, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors
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