Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor
Leena Gandhi1, Rastislav Bahleda, Sara M Tolaney
1Leena Gandhi, Sara M. Tolaney, James M. Cleary, and Geoffrey I. Shapiro, Dana-Farber Cancer Institute; Eunice L. Kwak, Massachusetts General Hospital; Shuchi S. Pandya, Beth Israel Deaconess Medical Center, Boston; Anna Berkenblit and Mizue Krygowski, Aveo Pharmaceuticals; Revathi Ananthakrishnan and Kathleen W. Turnbull, Inventiv Health, Cambridge, MA; Rastislav Bahleda, Antoine Hollebecque, and Jean-Charles Soria, Insitut Gussav Roussy, Villejuif, France; Richat Abbas and Yali Liang, Pfizer, Collegeville, PA.
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.
Insights
The combination of neratinib and temsirolimus showed tolerable toxicity and antitumor activity in advanced solid tumors. This suggests potential for further clinical evaluation in various cancer types.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Human epidermal growth factor (HER)-mediated signaling is crucial in cancers like breast and lung cancer.
- This signaling pathway involves phosphatidylinositide 3-kinase (PI3K)-AKT/protein kinase B-mammalian target of rapamycin (mTOR).
- mTOR activation is key for tumor growth and invasion, suggesting mTOR inhibition as a therapeutic strategy.
Purpose of the Study:
- To evaluate the safety and tolerability of combining neratinib (a pan-HER inhibitor) and temsirolimus (an mTOR inhibitor).
- To determine recommended Phase II doses for this combination therapy.
- To explore the potential synergistic effects of HER2 and mTOR inhibition in advanced solid tumors.
Main Methods:
- A Phase I clinical trial involving patients with advanced solid tumors.
- Dose escalation study of neratinib and temsirolimus combination therapy.
- Assessment of dose-limiting toxicities (DLTs) and maximum-tolerated doses (MTDs).
Main Results:
- Sixty patients were treated across 12 dosing combinations.
- Diarrhea was the most frequent dose-limiting toxicity (93%).
- Two maximum-tolerated doses were identified: neratinib 200mg/temsirolimus 25mg and neratinib 160mg/temsirolimus 50mg.
- Antitumor responses were observed in HER2-amplified breast cancer, HER2-mutant non-small-cell lung cancer, and other tumor types.
Conclusions:
- The combination of neratinib and temsirolimus is tolerable in patients with advanced solid tumors.
- This combination demonstrated promising antitumor activity across various cancer types.
- Further clinical investigation of neratinib and temsirolimus combination therapy is warranted.
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