Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors
Open accessAbstract
Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral pimasertib in 21-day cycles in a modified 3 + 3 dose-escalation design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated. Results Of 33 patients evaluated, all experienced ≥1 treatment-emergent adverse event (TEAE) and 31 had treatment-related TEAEs, most frequently stomatitis and thrombocytopenia. TEAEs were reversible. No deaths were attributed to treatment. Nine patients had dose-limiting toxicities (stomatitis, thrombocytopenia, serum creatinine phosphokinase increase, visual impairment) and the MTD was determined as 45 mg/day pimasertib plus 25 mg/week temsirolimus. However, due to overlapping toxicities no further investigations were performed and the RP2D was not defined. PK profiles of both agents were not adversely affected. Seventeen patients (17/26 patients) had a best response of stable disease; five had stable disease lasting >12 weeks. Conclusions The RP2D was not defined and the pimasertib plus temsirolimus combination investigated did not warrant further study.
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High toxicities of targeting PI3K, AKT or mTOR in combination with MEK inhibitors have prevented their approval for use in human patients.
“However, high toxicities of targeting PI3K, AKT or mTOR, in combination with MEK inhibitors, have prevented their approval for use in human patients (81–83).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [82]
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- Authors
- Mita, M., Fu, S., Piha-Paul, S. A., Janku, F., Mita, A., Natale, R., Guo, W., Zhao, C., Kurzrock, R., & Naing, A.
- Affiliations
- Cedars-Sinai Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- EMD Serono, Inc. (United States) (US)
- University of California San Diego (US)
- Corresponding author
- Naing, Aung
- Venue
- Investigational New Drugs
- Published
- 2017-02-13
- Volume
- 35
- Issue
- 5
- Pages
- 616-626
- ISSN
- 0167-6997 (ISSN-L)
- 1573-0646
- PMC
- PMC5935457
- OpenAlex
- W2588419540
- Cited by
- 26
- References
- 38
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 4
- FWCI
- 1.68
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Investigational New Drugs (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Merck KGaA, Darmstadt, Germany
- EMD Serono Inc., Billerica, US
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- pimasertib, temsirolimus, mTOR inhibitors, MAPK signaling, dual pathway inhibition, advanced solid tumors, refractory cancer, combination therapy, dose-limiting toxicity, stomatitis, thrombocytopenia, pharmacokinetics, maximum tolerated dose
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Male, Middle Aged, Neoplasms, Niacinamide, Sirolimus, Maximum Tolerated Dose, Protein Kinase Inhibitors, MAP Kinase Kinase Kinase 1, MAP Kinase Kinase Kinase 2, Young Adult, TOR Serine-Threonine Kinases
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