Inhibitors of the PI3K/Akt/mTOR Pathway

Tumor arrays analysis (Molinolo et al. 2007) showed activation of Akt-mammalian target of rapamycin (mTOR) pathway in 90% of SCCHN. A small subgroup of tumors have activated mTOR pathway without Akt activation, suggesting the existence of an Akt-independent stimulator of mTOR. Gupta et al. (2002) found a significant association between low p-Akt staining and local control in 38 patients treated with radiotherapy (p = 0.04).

Concerning PI3K inhibitors, one study explored BYL719 (NCT01602315) plus cetuximab. Preliminary results were presented at ASCO 2014 and showed that combined inhibition was well tolerated with encouraging antitumor activity (Razak et al. 2014). Patients were treated either by tablets (ARM A) or suspension (ARM B) of BYL719, 300 mg once daily The overall DCR was 60% (12/20 pts) and 47.1% (8/17), respectively.

A mTOR inhibitor, rapamycin, showed antiproliferative effects and induced apoptosis in SCCHN cell lines (Cassell et al. 2012). Other mTOR inhibitors displayed synergistic and additive effects in preclinical models when combined with EGFR inhibitors (Cassell et al. 2012), bevacizumab, cetuximab or radiotherapy (Bozec et al. 2011), or when used in combination with paclitaxel or carboplatin (Aissat et al. 2008).

In a phase II study, Bauman et al. evaluated the combination of oral erlotinib (150 mg daily), and temsirolimus (15 mg, intravenously, weekly), a mTOR inhibitor, in patients with platinum-refractory recurrent and/or metastatic SCCHN. The study was closed early after enrolling 12 patients due to high toxicity. Grade > 3 toxicities included fatigue (n = 5), diarrhea (n = 2), gastrointestinal infection/peritonitis (n = 2), dyspnea (n = 2), head and neck edema (n = 2), and neutropenia (n = 1). Among 8 evaluable patients, median PFS was 1.9 months. Median OS was 4.1 months (Bauman et al. 2012).