PIK-ORL: A phase II, multicenter trial aiming to evaluate BKM120 in monotherapy in patients (pts) with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) after failure of platin and cetuximab or anti-EGFR-based therapy

Background

The PI3K/AKT pathway activation is an early event in HNSCC and an independent marker of poor outcome that seems to be involved in resistance to cetuximab. BKM120 is an oral, pan-Class I PI3K inhibitor that inhibits tumor growth in HNSCC xenografts.

Methods

This Phase II evaluates the clinical benefit of BKM120 (100mg/d, po) in 2 parallel cohorts of HNSCC pts with or without mutation in PI3KCA. Eligible pts progressed after platin and cetuximab or anti-EGFR therapy, and had documented PIK3CA status (exons 9 and 20). The primary endpoint was 2-month Disease Control Rate (DCR_2m) as per RECIST 1.1. Secondary endpoints were ORR, PFS, OS, and safety. Blood and tumor samples were obtained for pharmacodynamics (PD). Imaging data were centrally reviewed. Considering that BKM120 would be uninteresting if DCR_2m ≤ 10% and promising if ≥ 30% and using Simon's optimal two-stage design (α: 5% unilateral, power: 90%), 7 successes/35 evaluable pts were required for each cohort. Only results of the cohort without PI3KCA mutation are presented. .

Results

36 HNSCC pts without PI3KCA mutation (median age: 58.6 yrs) received at least one dose of BKM120. They were heavily pretreated (33% with at least 3 previous lines). Median treatment duration was 8 wks [min-max: 4 d-55.9 wks]. At the end of 2^nd Simon's Stage, the DCR_2m was 38.9% (14/36pts). No OR was observed. The most common related AE (>25%) included hyperglycemia, asthenia, anxiety, depression, lymphopenia, anemia, leucocyte increase, hematocrit decrease, nausea and diarrhea. 20 pts (55.6%) presented at least one related AE ≥ Grade 3 (>5%: hyperglycemia, lymphopenia, asthenia, Na or K decrease) and 10 pts (27.8%) prematurely discontinued BKM120 due to an AE. 11pts (30.6%) experienced a related SAE including 3 SUSARs (1 fatal hyperglycemic coma, 1 death of uncertain relationship, 1 severe dehydration). PFS, OS and PD data will be presented at the meeting. Cohort with PI3KCA mutation is ongoing (n = 17).

Conclusions

BKM120 deserves further investigation in relapsing HNSCC pts without PI3KCA mutation, nevertheless with close monitoring of metabolic tolerance.

Clinical trial identification

NCT01737450

Legal entity responsible for the study

Centre Leon Bérard

Funding

Institut National du Cancer and Fondation ARC

Disclosure

All authors have declared no conflicts of interest.