Elsevier

The Lancet Oncology

Volume 18, Issue 5, May 2017, Pages 654-662
The Lancet Oncology

Articles
Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial

https://doi.org/10.1016/S1470-2045(17)30109-2Get rights and content

Summary

Background

Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer.

Methods

This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093.

Findings

Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29–8·24), versus 159 (33%) of 482 patients (95% CI 28·8–37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently reported grade 3 and 4 adverse events in the safety set were hyperglycaemia (seven [8%] of 92 patients), rash (four [4%]), and dyspnoea (three [3%]). Serious adverse events were reported in 20 (22%) patients; six (7%) were deemed treatment related, with dyspnoea (three [3%]) and pneumonia (two [2%]) reported most frequently. 12 (13%) of 92 patients had adverse events suspected to be related to treatment that led to discontinuation of everolimus and exemestane (the most common were rash, hyperglycaemia, and stomatitis, which each affected two [2%] patients).

Interpretation

Prophylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane and could be a new standard of oral care for patients receiving everolimus and exemestane therapy.

Funding

Novartis Pharmaceuticals Corporation.

Introduction

The phosphoinositide 3-kinase (PI3K)–serine/threonine-protein kinases (AKT)–mTOR pathway is the most frequently altered signal transduction pathway in breast cancer, making it an attractive therapeutic target.1 Combination therapy with the oral mTOR inhibitor everolimus and the aromatase inhibitor exemestane is approved for the treatment of advanced breast cancer in patients with hormone receptor-positive disease who have progressed on nonsteroidal aromatase inhibitors.2

The most common adverse event associated with everolimus is stomatitis, which is characterised by inflammation of the mucous membranes lining the mouth. Stomatitis is a class effect associated with mTOR inhibition that can adversely affect tolerability and treatment adherence.3, 4 The onset and pattern of mTOR inhibitor-associated stomatitis have been well characterised.4, 5, 6, 7 It presents as aphthous-like oral lesions, characterised by discrete shallow ulcerations.8, 9

Management of mTOR inhibitor-associated stomatitis by dose delays, reductions, or discontinuation of the mTOR inhibitor might compromise duration and intensity of therapy and might affect decisions to initiate treatment with mTOR inhibitors.3 Aphthous ulcers have been treated successfully by steroid-containing oral paste or rinse; anecdotal reports suggested that topical steroids could improve healing of everolimus-associated aphthous ulcers.3, 8, 10 Until now, clinical evidence has been scarce to guide mTOR inhibitor-associated stomatitis prophylactic strategies.

Research in context

Evidence before this study

We searched PubMed for original research articles in English published between Jan 8, 2006, and Oct 14, 2016, with the terms “breast cancer”, “mTOR inhibitor”, “stomatitis”, and “steroid mouthwash”. We did not identify any phase 2 or 3 trials that investigated the prophylactic use of steroid mouthwash for stomatitis in women who are postmenopausal and treated with everolimus and exemestane for hormone receptor-positive, HER2-negative metastatic breast cancer.

Added value of this study

To our knowledge, this is the first and largest stomatitis prevention study completed that combines therapeutic management with proactive patient engagement to reduce the incidence and severity of stomatitis in patients who are postmenopausal and receiving everolimus and exemestane as treatment for hormone receptor-positive, HER2-negative metastatic breast cancer. Our results show that a commercially available, inexpensive, and well tolerated dexamethasone mouthwash resulted in a more than ten-times reduction in the incidence of grade 2 or higher stomatitis by 8 weeks compared with BOLERO-2 historical controls. Patient-reported outcomes monitoring diet and oral pain further substantiated the efficacy of the dexamethasone mouthwash. The favourable dose intensity for everolimus and exemestane that was recorded in this trial might be a consequence of the reduced incidence of stomatitis, as well as the fact that dexamethasone mouthwash treatment was well tolerated with minimal toxicity.

Implications of all the available evidence

Steroid mouthwash as prophylaxis for everolimus-related stomatitis should be considered as a new standard of oral care for patients who are postmenopausal and receiving everolimus and exemestane for treatment of hormone receptor-positive, HER2-negative metastatic or advanced breast cancer. Several ongoing clinical trials are assessing specific preventive and therapeutic rinses for oral mucositis or stomatitis and might further support a use of steroid-based prophylaxis for everolimus-related stomatitis. This preventative approach might eventually be considered as an important treatment option in many diseases for which everolimus is in active use.

In a meta-analysis of phase 3 trials, 89% of all-grade stomatitis was prominent within 8 weeks of starting everolimus.5 In the phase 3 BOLERO-2 trial of everolimus and exemestane therapy for patients with hormone receptor-positive, HER2-negative metastatic breast cancer, at a median follow-up of 13 months2 (IQR 9·1–16·2; Rugo HS, unpublished data), all-grade stomatitis occurred in 321 (67%) of 482 patients, including grade 2 or worse in 159 (33%) and grade 3 severity in 39 (8%; appendix p 9).11

We did this phase 2 SWISH trial (dexamethasone mouthwash for everolimus-related stomatitis prevention in hormone receptor-positive metastatic breast cancer) to evaluate 0·5 mg/5 mL dexamethasone mouthwash for the prevention of stomatitis in postmenopausal women receiving everolimus and exemestane for hormone receptor-positive metastatic breast cancer. We used data from the BOLERO-2 trial as a historical control cohort for comparisons.

Section snippets

Study design and participants

SWISH was a US-based, phase 2, single-arm trial that assessed alcohol-free dexamethasone mouthwash for the prevention of stomatitis in patients treated with everolimus and exemestane for hormone receptor-positive, HER2-negative metastatic breast cancer. Eligible patients were enrolled at 23 investigational sites from academic and community settings in the USA (appendix p 6) on the basis of the following key inclusion criteria: women aged 18 years or older who were postmenopausal and had

Results

Between May 28, 2014, and Oct 8, 2015, 112 patients were screened and 92 eligible patients from 23 centres were enrolled in the SWISH trial (figure 1; appendix pp 6, 7). Of the 92 women enrolled, 86 were evaluable for efficacy; all 92 were evaluable for safety (figure 1). Six women were unevaluable for efficacy because administration of one or more doses of dexamethasone mouthwash was not confirmed. In the 86 evaluable patients, the median age was 61 years (IQR 56–67), 53 (62%) were white, 80

Discussion

The results of the SWISH trial show that a commercially available, inexpensive, and well tolerated dexamethasone mouthwash is effective in the prevention of or reduction in the incidence and severity of all-grade stomatitis, especially grade 2 or worse stomatitis at 8 weeks compared with historical controls from the BOLERO-2 trial. Patient-reported outcomes (ability to maintain a normal diet and oral pain scores) further substantiated the efficacy of dexamethasone mouthwash. Reduction of

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