Buparlisib (BKM120) in refractory head and neck squamous cell carcinoma harbouring or not a PI3KCA mutation: A phase II multicenter trial

Background The PI3K/AKT pathway activation is an independent marker of poor outcome in head and neck squamous-cell carcinoma (HNSCC). It is involved in resistance to cetuximab and PI3KCA mutations (5% of HNSCC) may be a key event of this dysregulation. Buparlisib is an oral, pan-Class I PI3K inhibitor that inhibits tumor growth in HNSCC xenografts. Methods This phase II evaluated the efficacy of oral buparlisib (100mg/d) in 2 parallel cohorts of refractory HNSCC (progression after platinum and cetuximab) with (PIK3CAmutated, exons 9/20) or without (PIK3CAnon-mutated) PI3KCA activating mutation. The primary endpoint was 2-month Disease Control Rate (DCR2m) as per centrally reviewed RECIST 1.1. Secondary endpoints included ORR, PFS, OS, and safety. Buparlisib would be considered ineffective if DCR2m ≤ 10% and promising if ≥ 30% (Simon’s optimal two-stage design; α: 5% unilateral, power: 90%): 7 successes/35 evaluable patients per cohort were required. Results 58 HNSCC heavily pre-treated (78% at least 2 prior lines) received at least one dose of buparlisib (PIK3CAnon-mutated, n = 36 and PIK3CAmutated, n = 22) The PIK3CAmutated cohort was prematurely closed because of slow accrual). The DCR2m was 38.9% (95% CI [25.5; + ∞[) for PIK3CAnon-mutated and 36.4% (95% CI [19.5; + ∞[) for PIK3CAmutated. No objective response was observed. Median PFS was 1.8 m (95% CI [1.6; 3.5]) and 1.7 m (95% CI [1.1; 4.1]) for PIK3CAnon-mutated and PIK3CAmutated respectively. Median OS was 5.8 m (95% CI [3.7; 9.2]) and 3.4 m (95% CI [2.6; 7.9]) for PIK3CAnon-mutated and PIK3CAmutated. Most common related AEs (>25%) included hyperglycemia, asthenia, anxiety, depression, lymphopenia, anemia, leucocyte increase, hematocrite decrease, Na decrease, nausea and diarrhea. Most frequent related AE ≥ Grade 3 (>5%) were hyperglycemia, lymphopenia, asthenia, Na decrease, depression, dermatitis. 14 pts (24.1%) discontinued buparlisib due to an AE. Conclusions Buparlisib had limited antitumor activity in heavily pre-treated HNSCC patients independent of PI3KCA mutational status. Clinical trial identification NCT01737450. Legal entity responsible for the study Centre Leon Berard. Funding INCA et Fondation ARC. Disclosure J. Fayette: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Honoraria (self): Merck Serono; Advisory / Consultancy: innate pharma; Advisory / Consultancy: Biogen. A. Daste: Honoraria (self), Advisory / Consultancy: BMS. C. Even: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self): Merck Serono. F. Peyrade: Honoraria (self): BMS; Honoraria (self): Merck Serono. C. Le Tourneau: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca.