A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors
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Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.
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Horizontal combination, targeting parallel pathways, invariably leads to resistance or unacceptable toxicity.
“Targeting parallel pathways (‘horizontal combination’) also invariably leads to resistance or unacceptable toxicity94,95.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [95]
Combination strategies for horizontal inhibition of parallel pathways are marred by resistance and toxicity.
“In addition, we describe combination strategies for horizontal inhibition of parallel pathways, an approach also marred by resistance in addition to toxicity94,95.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [95]
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- Authors
- Grilley-Olson, J. E., Bedard, P. L., Fasolo, A., Cornfeld, M., Cartee, L., Razak, A. R. A., Stayner, L.-A., Wu, Y., Greenwood, R., Singh, R., Lee, C. B., Bendell, J., Burris, H. A., Del Conte, G., Sessa, C., & Infante, J. R.
- Affiliations
- University Health Network (CA)
- IRCCS Ospedale San Raffaele (IT)
- GlaxoSmithKline (United States) (US)
- University of North Carolina at Chapel Hill (US)
- Sarah Cannon (US)
- Venue
- Investigational New Drugs
- Published
- 2016-07-23
- Volume
- 34
- Issue
- 6
- Pages
- 740-749
- ISSN
- 0167-6997 (ISSN-L)
- 1573-0646
- PMC
- PMC7574157
- OpenAlex
- W2492626689
- Cited by
- 81
- References
- 27
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 2 · 2023: 13 · 2022: 10 · 2021: 4 · 2020: 11 · 2019: 15 · 2018: 7 · 2017: 7 · 2016: 1
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Investigational New Drugs (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- University of North Florida Digital Commons (University of North Florida) (submittedVersion)
- Funders
- GlaxoSmithKline
- National Institutes of Health (2k12ca120780-16)
- National Cancer Institute (K12-CA120780)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- trametinib, GSK2126458, PI3K/mTOR inhibitors, MEK inhibitors, combination therapy, advanced solid tumors, maximum tolerated dose, dose escalation, pharmacokinetic interactions, circulating tumor DNA, skin toxicity, gastrointestinal toxicity, antitumor immunity
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Benzenesulfonamides, Adult, Aged, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Staging, Neoplasms, Prognosis, Pyridazines, Pyridones, Pyrimidinones, Quinolines, Sulfonamides, Tissue Distribution, Biomarkers, Tumor, Survival Rate, Maximum Tolerated Dose, Protein Kinase Inhibitors, MAP Kinase Kinase 1, Young Adult, TOR Serine-Threonine Kinases
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