November 2017 VOL 8, NO 11

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Clinical Research

Adverse Event Management During Treatment with Everolimus plus Exemestane for Postmenopausal Hormone Receptor–Positive (HR+), Human Epidermal Growth Factor Receptor 2–Negative (HER2–) Advanced Breast Cancer (ABC)

Jan Hronek; Lindsay Shelby
Sarah Cannon Research Institute, Nashville, TN 

Background: The combination of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, and the aromatase inhibitor, exemestane, is approved for use in postmenopausal women with HR+, HER2– ABC after failure on letrozole or anastrozole treatment. Efficacy of the combination was established in the phase 3 BOLERO-2 trial, which showed a significant gain in progression-free survival (PFS) using everolimus plus exemestane vs placebo plus exemestane (7.8 months vs 3.2 months, investigator assessed; hazard ratio, 0.45; 95% CI, 0.38-0.54).1 Recent advances in prophylactic management of everolimus-based toxicities may help minimize adverse event (AE) occurrence and severity, reducing the frequency of dose reductions and treatment interruptions, therefore maximizing the benefit of everolimus therapy to patients.

Objectives: Provide information on common AEs associated with everolimus treatment to assist with management and improve patient outcomes.

Methods: Articles from a PubMed search (terms: everoli­mus AND breast cancer AND adverse events) were evaluated for information on everolimus AEs and management. We summarize the key results and provide additional insights from the clinical experience of oncology nurses.

Results: Sixty-seven PubMed results were retrieved, including 20 clinical trial reports and 18 reviews. Common grade 3/4 AEs associated with everolimus and exemestane (>1.5% patients, real-world study, N = 2131) are stomatitis, asthenia, hyperglycemia, dyspnea, and noninfectious pneumonitis (NIP), with stomatitis and NIP (class effects of mTOR inhibition) being the most common AEs leading to treatment discontinuation.2 Stomatitis (inflammation of the mucous membrane of the mouth leading to oral lesions and shallow ulceration) tends to occur within 1 month of starting treatment. The phase 2 SWISH study revealed that prophylactic dexamethasone mouthwash (swish for 2 minutes and spit, 4 times daily for 8 weeks) led to a >10-fold reduction in the incidence of grade ≥2 stomatitis.3 Educating patients on food/drinks to avoid and good oral care from treatment initiation, and encouraging patients to notify their physician at the first sign of stomatitis symptoms, can also help prevent or manage the condition. Reviewing the signs/symptoms of stomatitis to differentiate it from mucositis is also important. NIP (inflammation of the lungs) tends to first occur within 3 months of treatment initiation. Patients presenting with worsening or new respiratory symptoms should be evaluated promptly for NIP. Other key symptoms include increased dyspnea (with/without exertion) and lower oxygen saturations. Educating patients to immediately notify their physician of possible symptoms is important. Most cases of NIP can be treated with everolimus dose interruptions, adjustments, and/or corticosteroids. Management of additional AEs will be discussed. Overall, AE incidence and dose interruption/modification tend to occur soon after everolimus plus exemestane initiation, leading to recommendations that patients are seen in clinic 2 weeks after initiating therapy and followed closely for the first few months.

Conclusions: The use of everolimus plus exemestane has led to significant gains in PFS for patients with HR+, HER2– ABC refractory to letrozole/anastrozole therapy. Patient education, prophylactic measures, early identification, and early intervention are reducing the incidence and severity of AEs associated with everolimus and are key to the continued success of everolimus-based therapies.

Sponsorship: This study was supported by Novartis Pharmaceuticals Corporation.


  1. Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30:870-884.
  2. Jerusalem G, Mariani G, Ciruelos EM, et al. Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer progressing on prior non-steroidal aromatase inhibitors: primary results of a phase IIIb, open-label, single-arm, expanded-access multicenter trial (BALLET). Ann Oncol. 2016;27:1719-1725.
  3. Rugo HS, Seneviratne L, Beck JT, et al. 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. Lancet Oncol. 2017;18:654-662.

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