Cited by 198PI3K/AKT/mTOR signaling in cancerHER2/EGFR in Cancer ResearchLung Cancer Treatments and Mutations

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Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors

Gandhi, Leena, Bahleda, Rastislav, Tolaney, Sara M., Kwak, Eunice L., Cleary, James M., Pandya, Shuchi S., Hollebecque, Antoine, Abbas, Richat, Ananthakrishnan, Revathi, Berkenblit, Anna, Krygowski, Mizue, Liang, Yali, Turnbull, Kathleen W., Shapiro, Geoffrey I., Soria, Jean-Charles·2014·Journal of Clinical Oncology

DOI 10.1200/jco.2012.47.2787

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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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See all 198

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: Gandhi, Leena
Bahleda, Rastislav
Tolaney, Sara M.
Cleary, James M.
Hollebecque, Antoine
Ananthakrishnan, Revathi
Liang, Yali
Shapiro, Geoffrey I.
Soria, Jean-Charles
Venue: Journal of Clinical Oncology
Publisher: American Society of Clinical Oncology (ASCO)
Published: 2014-01-10
Volume: 32
Issue: 2
Pages: 68-75
ISSN: 0732-183X (ISSN-L)
1527-7755
DOI: 10.1200/jco.2012.47.2787
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
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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Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors

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