A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma

Abstract

SUMMARY 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.

IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer

“…Dasatinib-related toxicities, including infection, pleural effusion, and edema, occurred at expected grades and frequencies. Notably, the edema was facial, a unique pattern that has been observed in patients with recurrent/metastatic HNSCC when exposed to mTOR inhibitors [28]. …”

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

“…In a Phase I study assessing a combination of temsirolimus, carboplatin, and paclitaxel in patients with SCCHN (NCT01016769), the confirmed objective partial response rate was 22% [68]. In a Phase II study in patients with recurrent or metastatic, platinum-refractory SCCHN, the combination of temsirolimus plus erlotinib was poorly tolerated [69], suggesting that investigation of more tolerable combinations of EGFR and PI3K/ AKT/mTOR pathway inhibitors in selected patients with SCCHN is warranted. Common toxicities associated with temsirolimus included fatigue, hyperglycemia, thrombocytopenia, diarrhea, peritonitis and pneumonia [68,69].…”

“…In a Phase II study in patients with recurrent or metastatic, platinum-refractory SCCHN, the combination of temsirolimus plus erlotinib was poorly tolerated [69], suggesting that investigation of more tolerable combinations of EGFR and PI3K/ AKT/mTOR pathway inhibitors in selected patients with SCCHN is warranted. Common toxicities associated with temsirolimus included fatigue, hyperglycemia, thrombocytopenia, diarrhea, peritonitis and pneumonia [68,69]. Temsirolimus is currently being tested in a Phase II study with or without cetuximab in patients with recurrent or metastatic head and neck cancer (NCT01256385) and in combination therapy with paclitaxel and carboplatin (NCT01016769).…”

State-of-the-Art and Emerging Treatment Options in the Management of Head and Neck Cancer: News from 2013

“…A phase II study of this regimen in R/M-HNSCC is ongoing at the Memorial Sloan Kettering Cancer Center, while, in another phase II trial (TEMHEAD) reported at the ECC 2012 by Grünwald et al [97], temsirolimus reached its primary end point with a PFS at 12 weeks of 40%. However, a phase II trial of combination erlotinib-temsirolimus failed to achieve a satisfactory PFS (1.9 months), reporting a poor safety profile [98]. …”