Efficacy of buparlisib according to PIK3CA mutation status in recurrent or metastatic head and neck squamous cell carcinoma: A multicenter phase II trial

BACKGROUND: The PI3K/AKT pathway activation is an independent marker of poor outcome in head and neck squamous-cell carcinoma (HNSCC), and involved in resistance to cetuximab. Molecular alterations in this pathway, particularly PIK3CA mutations, represent a key event of this dysregulation. Buparlisib is a pan-Class I PI3K inhibitor that inhibits tumor growth in HNSCC xenografts. METHODS: This phase II trial evaluated buparlisib (100 mg/d) in two parallel cohorts of refractory HNSCC patients (progression after platinum and cetuximab) with or without PIK3CA mutated in exons 9/20. The primary endpoint was the 2-month Disease Control Rate (DCR2m) as per centrally reviewed. Buparlisib would be considered ineffective if DCR2m ≤ 10% and promising if ≥ 30% (α: 5% unilateral, power: 90%): 7 successes for 35 evaluable patients per cohort were required. Secondary endpoints included ORR, PFS, OS, and safety. RESULTS: From January 2013 to July 2018, 58 HNSCC patients received ≥ 1 dose of buparlisib (PIK3CA wild-type, n = 36; PIK3CA-mutated, n = 22); 78% had received ≥ 2 prior lines of systemic therapy. The PIK3CA-mutated cohort was prematurely closed because of slow accrual. The DCR2m was 38.9% (95% CI [25.5- + ∞[) in PIK3CA wild-type and 36.4% (95% CI [19.5 - + ∞[) in PIK3CA-mutated patients. A total of 53.4% of patients experienced treatment-related grade ≥ 3 adverse events. The most frequent (>5%) were hyperglycemia, lymphopenia, asthenia, sodium decrease, depression, and dermatitis. Two toxic deaths were reported. CONCLUSION: Although the trial met the primary endpoint, buparlisib monotherapy was associated with unacceptable toxicity and showed limited efficacy in heavily pretreated HNSCC patients.