Phase II study of temsirolimus and erlotinib in patients (pts) with recurrent/metastatic (R/M), platinum-refractory head and neck squamous cell carcinoma (HNSCC).

Abstract

5549 Background: The Epidermal Growth Factor Receptor (EGFR) is a validated target in HNSCC. In R/M disease, primary or acquired resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. We hypothesized that concurrent mTOR blockade may improve efficacy of anti-EGFR therapy and conducted this phase II study. Methods: We evaluated the combination of erlotinib 150 mg po daily and temsirolimus 15 mg IV weekly in pts with platinum-refractory R/M HNSCC and ECOG PS 0-2. The exact, single-stage phase II design had 80% power (5% significance level) to detect improvement in progression-free survival (PFS) from 2.3 to 4.4 mos with 35 evaluable pts. Correlatives included determination of PIK3CA mutation (mut) status; p16, EGFR and PTEN expression; and immunomodulatory cytokine levels. Results: From Dec 2009 – Mar 2011, 12 pts enrolled. Six pts withdrew prior to first planned response assessment, due to toxicity (5) or death (1), prompting referral to the Data Safety and Monitoring Committee and early closure. Grade ≥ 3 toxicities included fatigue (5), diarrhea (2), GI infection/peritonitis (2), dyspnea (2), HN edema (2), and neutropenia (1). Among 8 progression-evaluable pt, median PFS was 1.9 mos. Median OS was 4.1 mos. 4/12 tumors were p16(+); 4/10 were EGFR(+); 11/11 showed no PTEN expression. PIK3CA mut was present in 1/11; the mut(+) pt withdrew after 3 wk for diarrhea/peritonitis with minor response. There were no associations between tumor p16, EGFR or PTEN status and oncologic outcomes. Five of 6 toxicity-related withdrawals occurred in p16(-) pts. Immunomodulatory cytokine levels in pre- and post-temsirolimus plasma did not significantly differ or associate with toxicity. Two pts with ≥ 4.4 mos PFS were p16(-) and PIK3CA mut(-). Conclusions: The combination of erlotinib and temsirolimus was poorly tolerated in this population, with toxicities predominant in p16(-) pts. Although the sample size was small, this R/M cohort demonstrated lack of PTEN expression and 9% PIK3CA mut, justifying further investigation of PI3K/Akt/mTOR pathway inhibitors in selected HNSCC pts.