Abstract P6-03-02: Budesonide and colesevelam reduce neratinib-induced diarrhea in a rat model

Abstract

Abstract Background: Neratinib (Puma Biotechnology Inc.) is an irreversible pan-HER tyrosine kinase inhibitor approved for use as extended adjuvant therapy in women with early-stage HER2+ breast cancer. Diarrhea is the main adverse event of neratinib; grade 3 events are common in the absence of antidiarrheal prophylaxis (40%) [Chan et al. Lancet Oncol 2016]. To investigate the underlying pathogenic mechanisms and to explore possible targets for its prevention, we developed a reproducible rat model of neratinib-induced diarrhea. Findings from the model indicated that neratinib-induced diarrhea is multifactorial, involving anatomical disruption and mucosal inflammation in the ileum and colon [Secombe et al. Asia Pac J Clin Oncol 2017]. We investigated the effects of budesonide, a locally-acting corticosteroid used for gastrointestinal conditions, and colesevelam, a bile acid sequestrant, on neratinib-associated diarrhea and intestinal changes in this model. Methods: Male albino Wistar rats were randomly allocated to vehicle control (5% DMSO/1% carboxymethyl cellulose), neratinib 50 mg/kg alone or combined with budesonide 1 mg/kg or colesevelam 300 mg/kg by oral gavage for 14 or 28 days. Diarrhea severity was graded daily [0, no diarrhea; 1, mild; 2, moderate; 3, severe]. A tissue injury score was assigned based on validated histological criteria (villus fusion and atrophy, disruption of brush border and enterocytes, crypt losses/architectural disruption, crypt cell disruption, infiltration of polymorphonuclear cells/lymphocytes, dilation of lymphatics/capillaries, edema). Inflammation was assessed using multiplex cytokine/chemokine ELISA.Fecal bile acids were measured in pooled fecal samples over an 8-hour period. Results: Findings at 28 days: VariableControl (n=16)Neratinib (n=16)Neratinib + budesonide (n=16)Neratinib + colesevelam (n=16)Incidence of diarrhea, %Grade 137.5000Grade 212.587.5100100Grade 3012.500Mean±SEM days with grade 2 diarrhea0.1±0.115.8±2.710.0±1.0*10.0±2.1*Median (range) tissue injury scoreDistal ileum0.5 (0–2.0)4.0 (3.0–5.0)††3.0 (2.0–4.0)3.0 (2.0–4.0)†Proximal colon2.0 (0–3.0)5.0 (4.0–6.0)††3.0 (2.0–5.0)*3.0 (2.0–5.0)Distal colon0.5 (0–2.0)2.5 (2.0–4.0)††1.0 (0–2.0)*1.5 (0–2.0)Median (range) cytokine levelsaIleumIFN-γ27 (15–48)49 (39–67)†43 (29–55)–IL-463 (15–111)223 (109–318)464 (309–559)**–IL-1021 (14–54)32 (10–84)60 (52–89)*–ColonIFN-γ22 (6–32)16 (12–22)16 (6–19)–IL-4147 (88–270)165 (15–327)345 (170–433)*–IL-1054 (18–128)55 (37–96)47 (43–60)–Mean±SEM total fecal bile acids, umol/mg3.5±0.43.9±0.2–5.5±0.4††*ang/ml (IFN-γ); pg/ml (IL-4, IL-10); *p<0.05, **p<0.005 vs neratinib; †p<0.05, ††p<0.005 vs control; IFN, interferon; IL, interleukin; SEM, standard error of the mean Conclusions: Budesonide and colesevelam reduced duration of neratinib-induced diarrhea and prevented severe diarrhea. Budesonide also reduced histopathological injury and inflammation via preservation of intestinal morphology and upregulation of anti-inflammatory cytokines in the ileum and colon. The phase II CONTROL study (Clinicaltrials.gov NCT02400476) is currently investigating the effects of adding budesonide or colestipol to loperamide prophylaxis in the prevention of neratinib-induced diarrhea and will help to determine the clinical relevance of our observations. Citation Format: Bowen JM, Secombe KR, Ball IA, Shirren J, Wignall AD, Finnie JW, Olek E, Martin D, Lalani AS, Keefe D. Budesonide and colesevelam reduce neratinib-induced diarrhea in a rat model [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-03-02.