3463 - 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 (PIK3CA^mutated, exons 9/20) or without (PIK3CA^non-mutated) PI3KCA activating mutation. The primary endpoint was 2-month Disease Control Rate (DCR_2m) as per centrally reviewed RECIST 1.1. Secondary endpoints included ORR, PFS, OS, and safety. Buparlisib would be considered ineffective if DCR_2m ≤ 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 (PIK3CA^non-mutated, n = 36 and PIK3CA^mutated, n = 22) The PIK3CA^mutated cohort was prematurely closed because of slow accrual). The DCR_2m was 38.9% (95% CI [25.5; + ∞[) for PIK3CA^non-mutated and 36.4% (95% CI [19.5; + ∞[) for PIK3CA^mutated. 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 PIK3CA^non-mutated and PIK3CA^mutated respectively. Median OS was 5.8 m (95% CI [3.7; 9.2]) and 3.4 m (95% CI [2.6; 7.9]) for PIK3CA^non-mutated and PIK3CA^mutated. 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.

Editorial acknowledgement

Legal entity responsible for the study

Centre Léon Bérard.

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.