Elsevier

The Lancet Oncology

Volume 18, Issue 3, March 2017, Pages 323-335
The Lancet Oncology

Articles
Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial

https://doi.org/10.1016/S1470-2045(17)30064-5Get rights and content

Summary

Background

Phosphatidylinositol 3-kinase (PI3K) pathway activation in squamous cell carcinoma of the head and neck contributes to treatment resistance and disease progression. Buparlisib, a pan-PI3K inhibitor, has shown preclinical antitumour activity and objective responses in patients with epithelial malignancies. We assessed whether the addition of buparlisib to paclitaxel improves clinical outcomes compared with paclitaxel and placebo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

Methods

In this multicentre, randomised, double-blind, placebo-controlled phase 2 study (BERIL-1), we recruited patients aged 18 years and older with histologically or cytologically confirmed recurrent and metastatic squamous cell carcinoma of the head and neck after disease progression on or after one previous platinum-based chemotherapy regimen in the metastatic setting. Eligible patients were enrolled from 58 centres across 18 countries and randomly assigned (1:1) to receive second-line oral buparlisib (100 mg once daily) or placebo, plus intravenous paclitaxel (80 mg/m2 on days 1, 8, 15, and 22) in 28 day treatment cycles. Randomisation was done via a central patient screening and randomisation system with an interactive (voice and web) response system and stratification by number of previous lines of therapy in the recurrent and metastatic setting and study site. Patients and investigators (including local radiologists) were masked to treatment assignment from randomisation until the final overall survival analysis. The primary endpoint was progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in all randomly assigned patients. Efficacy analyses were done on the intention-to-treat population, whereas safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01852292, and is ongoing but no longer enrolling patients.

Findings

Between Nov 5, 2013, and May 5, 2015, 158 patients were enrolled and randomly assigned to receive either buparlisib plus paclitaxel (n=79) or placebo plus paclitaxel (n=79). Median progression-free survival was 4·6 months (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 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 buparlisib group and 56 (72%) of 78 patients in the placebo group. The most common grade 3–4 adverse events (occurring in ≥10% of patients in the buparlisib group vs the placebo group) were hyperglycaemia (17 [22%] of 76 vs two [3%] of 78), anaemia (14 [18%] vs nine [12%]), neutropenia (13 [17%] vs four [5%]), and fatigue (six [8%] vs eight [10%]). Serious adverse events (regardless of relation to study treatment) were reported for 43 (57%) of 76 patients in the buparlisib group and 37 (47%) of 78 in the placebo group. On-treatment deaths occurred in 15 (20%) of 76 patients in the buparlisib group and 17 (22%) of 78 patients in the placebo group; most were caused by disease progression and none were judged to be related to study treatment.

Interpretation

On the basis of the improved clinical efficacy with a manageable safety profile, the results of this randomised phase 2 study suggest that buparlisib in combination with paclitaxel could be an effective second-line treatment for patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck. Further phase 3 studies are warranted to confirm this phase 2 finding.

Funding

Novartis Pharmaceuticals Corporation.

Introduction

Squamous cell carcinoma of the head and neck is the fifth most frequent cancer and the sixth most common cause of cancer deaths globally.1 Most patients with this type of cancer present with locally advanced disease, which might recur locally or as distant metastatic disease after treatment.2 Platinum-based chemotherapy is the standard first-line treatment option, with paclitaxel as a second-line option for platinum-pretreated metastatic disease.3 However, the unsatisfactory prognosis of patients pretreated with platinum has prompted investigation of novel treatments with targeted agents or immunotherapy.4

Research in context

Evidence before this study

We searched PubMed for reports of clinical trials published within the past 5 years using the terms “squamous cell carcinoma”, “head and neck”, and “metastatic”. We reviewed abstracts to identify trials of platinum-pretreated disease and specifically any studies that investigated phosphatidylinositol 3-kinase (PI3K) inhibitors in this setting. Although many agents and treatment combinations have been evaluated in this setting, no present second-line therapy options for squamous cell carcinoma of the head and neck are based on phase 3 trial results. Of note, few studies that specifically investigated PI3K inhibitors in squamous cell carcinoma of the head and neck were identified, despite laboratory data suggesting a role for PI3K inhibition in squamous cell carcinoma of the head and neck.

Added value of this study

Our results show that use of buparlisib, a novel, oral pan-PI3K inhibitor, in combination with paclitaxel produced clinically meaningful improvements in progression-free survival, overall survival, and the proportion of patients with an overall response compared with paclitaxel alone in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck. To our knowledge, these results provide the first clinical data to show a role for PI3K inhibition specifically in squamous cell carcinoma of the head and neck. Of note, this study achieved a nearly three-times increase in the proportion of patients with an overall response with buparlisib compared with placebo. Additionally, to our knowledge, this study recorded the longest median overall survival reported so far in the second-line setting, which compares favourably with the overall survival reported with existing first-line standard-of-care treatment (ie, cetuximab, platinum, or fluorouracil triplet).

Implications of all the available evidence

On the basis of the improved clinical efficacy with a manageable safety profile, our findings suggest that buparlisib in combination with paclitaxel could become an important second-line treatment option for patients with recurrent or metastatic squamous cell carcinoma of the head and neck eligible for taxane therapy. Further phase 3 studies are warranted to confirm this phase 2 finding.

The phosphatidylinositol 3-kinase (PI3K)–mTOR cell signalling pathway, which is often activated in patients with squamous cell carcinoma of the head and neck, whether they are chemotherapy-naive or chemotherapy-pretreated, has emerged as a potential mechanism of resistance to antineoplastic therapeutics.3 Although the precise mechanisms underlying the development of treatment resistance towards paclitaxel are largely unknown, activation of the PI3K–mTOR pathway has been shown to confer resistance to paclitaxel5 and an increase in protein kinase B (AKT) activity might be an early compensatory mechanism of resistance to chemotherapy.6 Therefore, PI3K pathway activation is believed to have an important role in either primary or secondary paclitaxel resistance.6 In preclinical models, concomitant inhibition of the PI3K pathway has been shown to enhance the efficacy of paclitaxel, compared with the administration of paclitaxel alone.5 Buparlisib (BKM120) is an oral pan-PI3K inhibitor selective for all isoforms (α, β, γ, δ) of class I PI3K.7 In xenograft models of squamous cell carcinoma of the head and neck, buparlisib treatment downregulated tumour PI3K–mTOR pathway signalling, reduced hypoxia, and remodelled tumour vasculature.8 The combination of buparlisib plus paclitaxel has shown promising signs of clinical activity in a phase 1B study in patients with advanced solid tumours, including patients who had disease progression on taxane-based chemotherapy regimens.9 Confirmed responses were recorded in several patients with tumours of squamous histology.10

On the basis of these initial findings, this phase 2 trial was designed to compare the efficacy and safety of buparlisib and placebo when combined with paclitaxel in patients with platinum-pretreated, recurrent or metastatic squamous cell carcinoma of the head and neck.

Section snippets

Study design and participants

BERIL-1 was an international, randomised, double-blind, placebo-controlled phase 2 trial done at 58 academic and tertiary referral centres across 18 countries (appendix p 1). Eligible patients were aged 18 years or older with histologically or cytologically confirmed recurrent or metastatic squamous cell carcinoma of the head and neck after disease progression on or after one previous platinum-based (carboplatin or cisplatin) chemotherapy regimen in the recurrent or second-line or more

Results

Between Nov 5, 2013, and May 5, 2015, 242 patients were enrolled in the study and assessed for eligibility for randomisation. Eligible patients were randomly assigned at 58 centres across 18 countries; 37 centres each had fewer than five patients enrolled and randomly assigned to treatment groups (appendix p 1). After 84 patients were excluded for various reasons (figure 1), a total of 158 patients were randomly assigned to receive either buparlisib and paclitaxel (n=79) or placebo and

Discussion

The results of this randomised phase 2 study show that the addition of buparlisib to paclitaxel therapy for patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck produces clinically meaningful improvement in progression-free survival, overall survival, and the proportion of patients with an overall response, with a manageable safety profile. To our knowledge, this study achieved the longest median overall survival (10·4 months) reported in this

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