A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma
Julie E Bauman, Hugo Arias-Pulido, Sang-Joon Lee, M Houman Fekrazad, Hiroyuki Ozawa, Elana Fertig, Jason Howard, Justin Bishop, Hao Wang, Garth T Olson, Michael J Spafford, Dennie V Jones, Christine H Chung, Julie E Bauman, Hugo Arias-Pulido, Sang-Joon Lee, M Houman Fekrazad, Hiroyuki Ozawa, Elana Fertig, Jason Howard, Justin Bishop, Hao Wang, Garth T Olson, Michael J Spafford, Dennie V Jones, Christine H Chung
Abstract
Objectives: The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy.
Materials and methods: Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0-2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines.
Results: Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ≥ 3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression.
Conclusions: The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted.
Conflict of interest statement
Conflict of interest statement
Dr. Jones formerly served as a scientific consultant and member of the speaker’s bureau for Genentech, Inc. No other competing interest is declared.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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Source: PubMed