Neoadjuvant PIK3CA Inhibition With Alpelisib in Head and Neck Squamous Cell Cancer: A Window-of-Opportunity Trial and Biomarker Study

Abstract

PIK3CA -activating mutations and amplifications are common in both human papillomavirus (HPV)–positive and HPV-negative head and neck squamous cell carcinomas (HNSCCs). PI3K pathway inhibition is postulated as a potential therapeutic strategy, and preclinical studies have demonstrated that the PI3Kα selective inhibitor alpelisib has broad tumoristatic activity across HNSCC genotypes. In this trial, patients with oral cavity HNSCC received either 400 mg or 200 mg of alpelisib once daily for up to 14 days preoperatively. The primary end point was the change in phosphorylated S6 (Ser235/236) expression in paired pre- and post-treatment tumor samples as assessed by immunohistochemistry. Secondary end points included changes in tumor size, pathologic response, phospho-AKT, Ki-67, and transcriptome differences between baseline and post-treatment tumor samples, as well as associations between baseline genomic variants and tumor response. Of the 15 patients enrolled, 14 completed the treatment. The first five patients received a dose of 400 mg once daily; however, three of five patients experienced grade 3 hypertension, fatigue, and oral mucositis; thus, the protocol was amended with a lower dose of 200 mg for the subsequent 10 patients. Pre- and post-treatment tumor samples were available for 13 patients. Of the 13 patients analyzed, eight patients had decreased levels of phosphorylated S6 serine 235/236, whereas three patients had no change and two patients had increased levels. Two clinical partial responses as per RECIST 1.1 were observed (13.3%); however, there were no pathological responses. Molecular profiling revealed seven patients had PIK3CA amplification, and no patients had PIK3CA point mutations. NanoString analysis demonstrated that alpelisib induced tumor transcriptome changes, including decreases in SPP1 transcript abundance. Preoperative alpelisib achieved a 13.3% response rate, reduced phospho-S6 Ser235/236 levels in eight of 13 patients, and induced tumor transcriptomic changes.