Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors
Abstract
PURPOSE: Human epidermal growth factor (HER) -mediated signaling is critical in many cancers, including subsets of breast and lung cancer. HER family members signal via the phosphatidylinositide 3-kinase (PI3K) -AKT/protein kinase B-mammalian target of rapamycin (mTOR) cascade; mTOR activation is critical for the expression of multiple contributors to tumor growth and invasion. On the basis of preclinical data suggesting synergy of HER2 inhibition and mTOR inhibition in breast and lung cancer models, we conducted a phase I combination study of neratinib, a small-molecule irreversible pan-HER tyrosine kinase inhibitor, and temsirolimus, an mTOR inhibitor, in patients with advanced solid tumors. PATIENTS AND METHODS: This study enrolled patients to dosing combinations of neratinib and temsirolimus. The primary objective was to estimate the toxicity contour of the combination and establish recommended phase II doses. RESULTS: Sixty patients were treated on 12 of 16 possible dosing combinations. Diarrhea was the most common drug-related (93%) and dose-limiting toxicity (DLT), constituting four of 10 DLTs. Dose-limiting grade 3 metabolic abnormalities were also observed. Other frequent drug-related toxicities included nausea, stomatitis (both 53%), and anemia (48%). Two maximum-tolerated dose combinations were identified: 200 mg of neratinib/25 mg of temsirolimus and 160 mg of neratinib/50 mg of temsirolimus. Responses were noted in patients with HER2-amplified breast cancer resistant to trastuzumab, HER2-mutant non-small-cell lung cancer, and tumor types without identified mutations in the HER-PI3K-mTOR pathway. CONCLUSION: The combination of neratinib and temsirolimus was tolerable and demonstrated antitumor activity in multiple tumor types, warranting further evaluation.
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Neratinib in combination with the TORC1 inhibitor temsirolimus demonstrated clinical activity in HER2 mutant lung cancers.
“Along the same lines, neratinib in combination with the TORC1 inhibitor temsirolimus recently demonstrated clinical activity in HER2 mutant lung cancers (Gandhi et al., 2014).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Gandhi et al., 2014
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- Authors
- Gandhi, L., Bahleda, R., Tolaney, S. M., Kwak, E. L., Cleary, J. M., Pandya, S. S., Hollebecque, A., Abbas, R., Ananthakrishnan, R., Berkenblit, A., Krygowski, M., Liang, Y., Turnbull, K. W., Shapiro, G. I., & Soria, J.-C.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2014-01-10
- Volume
- 32
- Issue
- 2
- Pages
- 68-75
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2113762115
- Cited by
- 198
- References
- 36
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 15 · 2020: 15 · 2019: 8 · 2018: 21 · 2017: 27 · 2016: 29 · 2015: 32 · 2014: 22 · 2013: 5
- FWCI
- 13.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- neratinib, temsirolimus, HER2-positive breast cancer, HER2-mutant non-small cell lung cancer, HER2-amplified breast cancer, HER2 inhibition, mTOR inhibition, PI3K/AKT/mTOR pathway, combination therapy, dose-limiting toxicity, diarrhea, maximum tolerated dose, anticancer activity, advanced solid tumors
- MeSH terms
- Aged, Anemia, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Diarrhea, Dose-Response Relationship, Drug, Female, Gene Amplification, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Nausea, Neoplasms, Quinolines, Stomatitis, Signal Transduction, Treatment Outcome, Erb-b2 Receptor Tyrosine Kinases, Area Under Curve, Phosphatidylinositol 3-Kinases, Sirolimus, TOR Serine-Threonine Kinases
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