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

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. 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. 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. Although the trial met the primary endpoint, buparlisib monotherapy was associated with unacceptable toxicity and showed limited efficacy in heavily pretreated HNSCC patients.