Stomatitis is the most common adverse event (AE) associated with mTOR inhibitors, including EVE. In the pivotal BOLERO-2 trial, stomatitis was reported for 59% vs 12% (Gr3, 8% vs <1%) of pts with HR+, HER2– ABC who received EVE + EXE vs EXE alone. Of the limited real world evidence available, the BRAWO trial showed a stomatitis incidence of 39.8% (Gr3, 3.4%) in a similar pt population. Additional data are warranted to better understand the stomatitis incidence and time-course in order to minimize treatment discontinuations.


BALLET is a Phase 3b, European, multi-center, open-label, single-arm, expanded-access study that evaluated safety of EVE (10 mg/d) and EXE (25 mg/d) in 2131 postmenopausal women with HR+, HER2– ABC that progressed on prior NSAI treatment. Primary endpoint was safety; secondary endpoint was characterization of grade 3/4 AEs. In this exploratory analysis, we split the pts in two groups based on having experienced at least one all grade stomatitis event in the first 8 wks (cut-off chosen based on reports that 89.4% of stomatitis events occurred within 8 wks of EVE initiation [Rugo, ASCO 2014]) vs none.


This subgroup analysis included 919 pts with stomatitis (43.1% of the full population). Baseline pt characteristics were comparable to the overall study population, except for more comorbidity (cardiovascular and metabolic disorder) in stomatitis subset. Pts with stomatitis had a longer EVE treatment duration vs pts who didn't (5.8 mo [95%CI, 5.0-6.2] vs 4.7 mo [95%CI, 4.4-5.3]; hazard ratio, 1.121 [95%CI, 0.97-1.28] censored by pts who switched to commercial drug). The relative risk of initial onset of stomatitis at 6 wks was ∼40%; median time to onset was 28 days. Majority of stomatitis events were of grade 1/2 severity (80%); grade 3/4 stomatitis was reported for 20% of pts. Most frequent reasons for treatment discontinuation in pts with stomatitis were reimbursement (37.6%), disease progression (35.0%), and AEs (16.2%). Most frequent AEs which led to treatment discontinuation in these pts were stomatitis in 3.7% (Grade 3/4, 2%), pneumonitis in 2.9% (Grade 3/4, 1.3%) and asthenia in 1.8% (Grade 3/4, 1%). Median EVE relative dose intensity in pts with stomatitis was 0.92. In the stomatitis subset, dose interruptions and reductions were required for 66.7% and 37.6% of pts, respectively; most frequent reasons for dose adjustments were AEs (65.9%) which included stomatitis (46.8%), asthenia (6.3%), and pneumonitis (5.3%). Median time to first dose modification in pts with stomatitis was 30 days; median duration of dose interruptions was 16 days. On-treatment deaths (4.4%) were due to progressive disease (2.1%), AEs (1.7%), and other reasons (0.5%).


These results confirmed the stomatitis time-course observed previously and that the majority of these events are of low grade. Stomatitis was the most common cause of dose reductions and interruptions due to AEs and was manageable with dose adjustments; there was a positive association between stomatitis and longer treatment duration. Therefore, proactive management, diligent monitoring and appropriate dose modifications, are recommended to keep pts on treatment.

Citation Format: Ciruelos EM, Jerusalem G, Generali D, Lang I, Gavila JG, Michelotti A, Tjan-Heijnn VCG, Mariani G, Conte P, Beliera A, Camozzi M, Lorizzo K, Martin M. Stomatitis following everolimus (EVE) plus exemestane (EXE) in patients with hormone receptor-positive (HR+), HER2– advanced breast cancer (ABC) in the BALLET trial (CRAD001YIC04). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-10.