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.

• Authors: Leena Gandhi, Rastislav Bahleda, Sara M Tolaney, Eunice L Kwak, James M Cleary, Shuchi S Pandya, Antoine Hollebecque, Richat Abbas, Revathi Ananthakrishnan, Anna Berkenblit, Mizue Krygowski, Yali Liang, Kathleen W Turnbull, Geoffrey I Shapiro, Jean-Charles Soria
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 32 Issue 2 Pg. 68-75 (Jan 10 2014) ISSN: 1527-7755 [Electronic] United States
• PMID: 24323026 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Quinolines
• temsirolimus
• ERBB2 protein, human
• Receptor, ErbB-2
• TOR Serine-Threonine Kinases
• neratinib
• Sirolimus

Topics

• Aged
• Anemia (chemically induced)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Diarrhea (chemically induced)
• Dose-Response Relationship, Drug
• Female
• Gene Amplification
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Male
• Middle Aged
• Mutation
• Nausea (chemically induced)
• Neoplasms (drug therapy, genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Quinolines (administration & dosage, adverse effects, pharmacokinetics)
• Receptor, ErbB-2 (genetics, metabolism)
• Signal Transduction (drug effects)
• Sirolimus (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Stomatitis (chemically induced)
• TOR Serine-Threonine Kinases (metabolism)
• Treatment Outcome