Humoral alloreactivity, manifested by the capillary deposition of complement C4d in about 50% of biopsied renal grafts, exerts a strong impact on graft survival when it operates within six months after transplantation.

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Background BRAWO is a German non-interventional study of 3000 patients (pts) with advanced/metastatic, hormone receptor positive and HER2 negative breast cancer treated with everolimus and exemestane (EVE+EXE). One of the objectives was the documentation of how stomatitis was managed and prevented in clinical routine. We report data of the 3rd preplanned interim analysis (IA) focusing on prophylaxis and management of stomatitis in daily clinical routine. Methods Here we report data of the first 1300 documented pts on efficacy and safety with focus on the adverse event stomatitis. Patient and treatment characteristics were associated with the occurrence of stomatitis. Furthermore chosen treatments for the management of stomatitis are described. Results At time of data cut-off 71% pts had discontinued the study, 29% were still under therapy. Patient and tumor characteristics were reported previously. The most commonly reported AEs of any grade were stomatitis (41.5%), fatigue (14.6%), nausea (12.2%), diarrhea (12.1%), dyspnea (11.3%). 75.2% of stomatitis events occurred during the first 5 weeks of treatment, regardless of the chosen starting dose 5 mg or 10 mg EVE per day. Median duration of a stomatitis episode was 28 days for 5 mg EVE start dose and 23 days for 10mg. However, there was a numerically lower stomatitis incidence and less severe intensity of stomatitis for a start dose of 5 mg vs 10 mg (Table 1). Table 1: Stomatitis incidence and severity by EVE start dose: Worst intensitiy of stomatitisTotal (n=1300)Start dose 5mg (n=316)Start dose 10mg (n=975)Other* (n=9)Number (%) of pts with at least one stomatitis event (any grade)513 (41.5)115 (36.4)421 (43.2)3 (33.3)Grade 1276 (21.2)73 (23.1)202 (20.7)1 (11.1)Grade 2198 (15.2)31 (9.8)165 (16.9)2 (22.2)Grade 330 (2.3)3 (0.9)27 (2.8)0Unknown35 (2.7)8 (2.5)27 (2.8)0*Other includes 2.5mg (n=3), 7.5mg (n=2), 15mg (n=1), 20mg(n=2), 30mg (n=1) 86.5% of pts received recommendations regarding stomatitis prophylaxis. The most frequent recommendations were: mild dental hygiene (e.g. soft toothbrush) (74.8%), avoidance of hot, sour or salty food (70.9%), rinsing with tea (61.7%), and cooling (e.g. sucking ice or frozen pineapple) (56,6%). At least one therapeutic measure was documented for 85.5% of stomatitis events. The most common therapeutic measures were non-drug mouthwash solution (58.3%), cooling (34.7%) or drug intervention (31.9%). Temporary EVE dose adjustments due to stomatitis were done in 11.6% of stomatitis events, temporary dose interruptions in 21.8%, respectively. Efficacy of EVE+EXE seemed to be independent of stomatitis occurrence within 8 weeks after therapy start: mPFS 6.9 months (95%CI, 6.4-8.0) without stomatitis, mPFS 7.4 months (95%CI, 6.3-8.6) with stomatitis. Discussion The percentage of patients with any grade stomatitis was lower in BRAWO (41.5%) than in the pivotal BOLERO-2 trial (59%), which might be explained by increased awareness and experience of treating physicians for prophylaxis and management of this type of adverse event under treatment with EVE+EXE. Most stomatitis events occurred during the first 5 weeks of treatment, which is consistent with data from BOLERO-2. Citation Format: Schütz F, Grischke E-M, Decker T, Uleer C, Schneeweiss A, Salat C, Wimberger P, Mundhenke C, Förster F, Kluth-Pepper B, Schubert J, Bloch W, Tesch H, Jackisch C, Lüftner D, Fasching PA. Stomatitis in patients treated with everolimus and exemestane - Results of the 3rd interim analysis of the non-interventional trial BRAWO. [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 P4-13-08.

Background BRAWO is a German non-interventional study of 3000 patients (pts) with advanced/metastatic, hormone-receptor-positive and HER2-negative breast cancer treated with everolimus and exemestane (EVE+EXE). The pivotal BOLERO-2 trial demonstrated that adding EVE to EXE improved PFS over EXE and was generally well tolerated in elderly patients with HR+ advanced breast cancer (>65 years as well as >70 years). Here we describe data of elderly patients treated with EVE+EXE in daily clinical routine. Methods We report data of the 3rd preplanned interim analysis (IA) of the first 1300 pts documented in BRAWO. Patient and disease characteristics in elderly patients (≥ 70 years, n=485) and patients <70 years (n=813) are described. Furthermore, safety and efficacy data for both subgroups are described. Results At time of data cut-off, 71% pts had discontinued the study, 29% were still ongoing. Patient and disease characteristics were comparable in both groups except for: median age (60y (range: 20-69y) vs. 75y (range 70-93y)), median time since 1st diagnosis (6.4y <70y vs. 8.8y ≥70 y), ECOG performance status 0 (56.6% <70y vs. 37.0% ≥70 y), and younger pts seemed to have less comorbidities (charlson comorbidity index (CCI)=0: 80.9% vs. 67.4%). The distribution of patients by therapy line was similar as well as tumor grading, hormone receptor status, Ki67-status and metastasis localization. More patients in the older group received fulvestrant (20.6% vs. 16.2%), in the younger group more patients received chemotherapy (20.3% vs. 14.2%) as last antineoplastic therapy. In general, more patients in the older subgroup did not receive any chemotherapy as pretreatment (53.6% vs 40.2%). More patients in the subgroup ≥70y received 5mg EVE as starting dose (30.3% vs. 20.8%) and had 5mg as end dose (37.9% vs. 26.9%). Median PFS was 7.1 months in the overall population, 7.0 months (6.5, 8.0; 95%CI) for pts <70y and 7.3 months (6.3, 8.6; 95%CI) for pts ≥70y. Kaplan Meier estimates for median treatment duration were longer for younger pts (167.0 days (155.0, 191.0; 95%CI vs. 128.0 days (112.0, 152.0; 95%CI)). Incidence and severity of stomatitis were comparable across subgroups (Table 1). Quality of life analysis revealed no significant differences between older and younger pts. Table 1: Incidence and severity of stomatitis Patient Characteristics< 70 years (n=813)≥ 70 years (n=485)Stomatitis  Number of patients with at least one Stomatitis Event (based on stomatitis questionnaires)339 (41.7%)200 (41.2%)Grade 1181 (22.3%)95 (19.6%)Grade 2119 (14.6%)79 (16.3%)Grade 319 (2.3%)11 (2.3%)unknown20 (2.5%)15 (3.1%)Number of Stomatitis Events431 (100.0%)252 (100%)Grade 1237 (55.0%)125 (49.6%)Grade 2136 (31.6%)87 (34.5%)Grade 319 (4.4%)13 (5.2%) Discussion The data described here show that EVE+EXE treatment is effective and safe for elderly patients in daily clinical routine. This is consistent with data from an exploratory analysis of the pivotal BOLERO-2 trial, where the same differences in baseline characteristics were observed for elderly pts compared to younger pts as in BRAWO. Efficacy was also comparable to elderly pts in BOLERO-2 (mPFS 6.8 months for EVE+EXE in pts ≥70 years). Citation Format: Tesch H, Grischke E-M, Fasching PA, Decker T, Uleer C, Schneeweiss A, Salat C, Wimberger P, Mundhenke C, Förster F, Kluth-Pepper B, Schubert J, Bloch W, Jackisch C, Schütz F, Lüftner D. Results of the 3rd interim analysis of the non-interventional trial BRAWO – Subanalysis of patients <70 years and ≥ 70 years. [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 P4-13-06.

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