Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer
Open accessAbstract
Background: Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback activation of epidermal growth factor receptors (HER). Methods: In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336). Results: Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC. Conclusions: Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile.
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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 [79]
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Brummelen, E. M. J., Huijberts, S., Herpen, C., Desar, I., Opdam, F., Geel, R., Marchetti, S., Steeghs, N., Monkhorst, K., Thijssen, B., et al. (2021) · The Oncologist · doi:10.1002/onco.13631 · Cited by 32 · see citing works
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- Authors
- 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., Monkhorst, K., Thijssen, B., Rosing, H., Huitema, A. D. R., Beijnen, J. H., Bernards, R., & Schellens, J. H. M.
- Affiliations
- Erasmus MC Cancer Institute (NL)
- The Netherlands Cancer Institute (NL)
- University Medical Center Utrecht (NL)
- Utrecht University (NL)
- Corresponding author
- Huijberts, Sanne C. F. A.
- Opdam, Frans L.
- ORCID
- Venue
- British Journal of Cancer
- Published
- 2020-03-09
- Volume
- 122
- Issue
- 8
- Pages
- 1166-1174
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC7156736
- OpenAlex
- W3009113333
- Cited by
- 55
- References
- 21
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 7 · 2021: 11 · 2020: 4
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- British Journal of Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Pfizer
- Erasmus Medisch Centrum
- 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
- dacomitinib, PD0325901, KRAS mutation, pan-HER inhibitor, MEK inhibitors, colorectal cancer, non-small cell lung cancer, pancreatic cancer, MAPK signaling, combination therapy, dose-limiting toxicity, intermittent dosing, antitumour activity
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Carcinoma, Non-Small-Cell Lung, Diphenylamine, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Neoplasms, Pancreatic Neoplasms, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Mitogen-Activated Protein Kinase Kinases, Quinazolinones, ErbB Receptors
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