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Buparlisib and paclitaxel in patients with Articles

platinum-pretreated recurrent or metastatic squamous cell

carcinoma of the head and neck (BERIL-1): a randomised,

double-blind, placebo-controlled phase 2 trial

Denis Soulières, Sandrine Faivre, Ricard Mesía, Éva Remenár, Shau-Hsuan Li, Andrey Karpenko, Arunee Dechaphunkul, Sebastian Ochsenreither,
Laura Anna Kiss, Jin-Ching Lin, Raj Nagarkar, László Tamás, Sung-Bae Kim, Jozsef Erfán, Anna Alyasova, Stefan Kasper, Carlo Barone, Sabine Turri,
Arunava Chakravartty, Marie Chol, Paola Aimone, Samit Hirawat, Lisa Licitra

Summary
Background Phosphatidylinositol 3-kinase (PI3K) pathway activation in squamous cell carcinoma of the head and Lancet Oncol 2017; 18: 323–35
neck contributes to treatment resistance and disease progression. Buparlisib, a pan-PI3K inhibitor, has shown Published Online
preclinical antitumour activity and objective responses in patients with epithelial malignancies. We assessed whether January 25, 2017
the addition of buparlisib to paclitaxel improves clinical outcomes compared with paclitaxel and placebo in patients http://dx.doi.org/10.1016/
with recurrent or metastatic squamous cell carcinoma of the head and neck. S1470-2045(17)30064-5
See Comment page 273
Methods In this multicentre, randomised, double-blind, placebo-controlled phase 2 study (BERIL-1), we recruited Department of Medicine,
Centre Hospitalier de
patients aged 18 years and older with histologically or cytologically confirmed recurrent and metastatic squamous cell l’Université de Montréal,
carcinoma of the head and neck after disease progression on or after one previous platinum-based chemotherapy Montreal, QC, Canada
regimen in the metastatic setting. Eligible patients were enrolled from 58 centres across 18 countries and randomly (Prof D Soulières MD); Oncology
assigned (1:1) to receive second-line oral buparlisib (100 mg once daily) or placebo, plus intravenous paclitaxel Unit, Hôpitaux Universitaires
Paris Nord Val de Seine, Paris,
(80 mg/m² on days 1, 8, 15, and 22) in 28 day treatment cycles. Randomisation was done via a central patient screening France (Prof S Faivre MD);
and randomisation system with an interactive (voice and web) response system and stratification by number of Medical Oncology Department,
previous lines of therapy in the recurrent and metastatic setting and study site. Patients and investigators (including Institut Català d’Oncologia
local radiologists) were masked to treatment assignment from randomisation until the final overall survival analysis. L’Hospitalet, Barcelona, Spain
(Prof R Mesía MD); Head, Neck
The primary endpoint was progression-free survival by local investigator assessment per Response Evaluation Criteria and Jaw, Reconstructive Plastic
In Solid Tumors (version 1.1) in all randomly assigned patients. Efficacy analyses were done on the intention-to-treat Surgery and Laser Surgery
population, whereas safety was analysed in all patients who received at least one dose of study drug and had at least Department, Országos
one post-baseline safety assessment according to the treatment they received. This trial is registered with Onkológiai Intézet, Budapest,
Hungary (Prof É Remenár MD);
ClinicalTrials.gov, number NCT01852292, and is ongoing but no longer enrolling patients. Department of
Hematology-Oncology,
Findings Between Nov 5, 2013, and May 5, 2015, 158 patients were enrolled and randomly assigned to receive either Kaohsiung Chang Gung
buparlisib plus paclitaxel (n=79) or placebo plus paclitaxel (n=79). Median progression-free survival was 4·6 months Memorial Hospital and Chang
Gung University College of
(95% CI 3·5–5·3) in the buparlisib group and 3·5 months (2·2–3·7) in the placebo group (hazard ratio 0·65 [95% CI Medicine, Kaohsiung, Taiwan
0·45–0·95], nominal one-sided p=0·011). Grade 3–4 adverse events were reported in 62 (82%) of 76 patients in the (Prof S-H Li MD); Department of
buparlisib group and 56 (72%) of 78 patients in the placebo group. The most common grade 3–4 adverse events Oncology, Leningrad Regional
(occurring in ≥10% of patients in the buparlisib group vs the placebo group) were hyperglycaemia (17 [22%] of 76 vs Oncology Dispensary, Saint
Petersburg, Russian Federation
two [3%] of 78), anaemia (14 [18%] vs nine [12%]), neutropenia (13 [17%] vs four [5%]), and fatigue (six [8%] vs (Prof A Karpenko MD);
eight [10%]). Serious adverse events (regardless of relation to study treatment) were reported for 43 (57%) of 76 patients Department of Medicine,
in the buparlisib group and 37 (47%) of 78 in the placebo group. On-treatment deaths occurred in 15 (20%) of Prince of Songkla University,
Songkhla, Thailand
76 patients in the buparlisib group and 17 (22%) of 78 patients in the placebo group; most were caused by disease (A Dechaphunkul MD);
progression and none were judged to be related to study treatment. Department of Hematology,
Oncology and Tumor
Interpretation On the basis of the improved clinical efficacy with a manageable safety profile, the results of this Immunology, Charité
randomised phase 2 study suggest that buparlisib in combination with paclitaxel could be an effective second-line Comprehensive Cancer Center,
Berlin, Germany
treatment for patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and (Prof S Ochsenreither MD);
neck. Further phase 3 studies are warranted to confirm this phase 2 finding. Department of
Otorhinolaryngology, Szent
Imre University Teaching
Funding Novartis Pharmaceuticals Corporation. Hospital, Budapest, Hungary
(Prof L A Kiss MD); Department
Introduction type of cancer present with locally advanced disease, of Radiation Oncology,
Squamous cell carcinoma of the head and neck is the which might recur locally or as distant metastatic disease Taichung Veterans General
Hospital, Taichung,Taiwan
fifth most frequent cancer and the sixth most common after treatment. Platinum-based chemotherapy is the (Prof J-C Lin MD); Department
2
cause of cancer deaths globally. Most patients with this standard first-line treatment option, with paclitaxel as a of Surgical Oncology, Curie
1

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