Abstract P2-11-03: Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): Interim analysis from the multicenter, open-label, phase II control trial
Authors: Barcenas C , Olek E , Hunt D , Tripathy D , Ibrahim E , Wilkinson M , Hurvitz S , Iannotti N , Kellum A , Manalo Y , Wong S , Hansen V , Alvarez R , Chan A , Gore I , Kendall D , Wade J , Ruiz R , Fang P , Bryce R , Moran S 
Published: March 2017

Abstract
Background: Neratinib (Puma Biotechnology Inc) is an irreversible pan-HER inhibitor in late-phase development for the treatment of early-stage and metastatic HER2+ BC. Diarrhea, the main toxicity of neratinib, requires active management with loperamide prophylaxis given early in the course of treatment. CONTROL (PUMA-NER-6201) is an international, open-label, phase II study investigating the efficacy of loperamide prophylaxis in the prevention of neratinib-associated diarrhea. CONTROL has recently been expanded to include prophylaxis with loperamide + budesonide, which targets inflammation identified in a preclinical model of neratinib induced diarrhea.
Methods: Pts with HER2+ early-stage BC who had completed trastuzumab-based adjuvant therapy were eligible. All pts were to receive oral neratinib 240 mg/day for 1 year + structured loperamide prophylaxis on d1–56 (2 cycles). Adverse events were graded according to NCI-CTCAE, v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. A protocol defined interim analysis (data cut-off July 2016) was performed when ∼120 pts had completed ≥2 cycles of neratinib + loperamide prophylaxis. A preliminary analysis of the loperamide + budesonide cohort was also performed at this time. Clinicaltrials.gov: NCT02400476.
Results: For the interim analysis, 133 pts received neratinib + loperamide prophylaxis. A further 16 (of 40 planned) pts received neratinib + loperamide prophylaxis (2 cycles) + budesonide (1 cycle). Key results are shown in the table. Incidence of grade ≥3 diarrhea was 27.1% with loperamide prophylaxis and 12.5% with loperamide + budesonide prophylaxis vs 39.9% without protocol-mandated loperamide prophylaxis (ExteNET). Grade 2 diarrhea also decreased (20.3%, 18.8% vs 32.5%, respectively). Grade 3 diarrhea events were uncommon after cycle 1 in all CONTROL cohorts.
StudyCONTROLExteNET4Antidiarrheal prophylaxisLoperamideLoperamideLoperamideLoperamide + budesonideLoperamide prnProtocolOriginal1Modified2Cumulative (Original + Modified)Amd 32,3–N (ITT at data cut-off)28105133161408Diarrhea, %Any grade82.169.572.268.895.4Grade 225.019.020.318.832.5Grade ≥3521.428.627.112.539.8Grade 400000.1Median diarrhea episodes/ptGrade ≥22.01.01.01.03.0Grade ≥31.01.01.01.52.0Median time on study (neratinib), mo69.73.764.561.0611.61. Oral loperamide 4 mg with first neratinib dose, then 2 mg q4h d1–3, then 2 mg q6–8h d4–56.2. Oral loperamide 4 mg with first neratinib dose, then 4 mg tid d1–14, then 4 mg bid d15–56.3. Oral budesonide 9 mg qd d1–28.4. Analogous patient population [Chan et al. Lancet Oncol 2016].5. Primary endpoint (CONTROL).6. Cohorts are ongoing.
Conclusions: A structured loperamide prophylactic regimen for 2 cycles is associated with a lower incidence and severity of neratinib associated diarrhea, with notably less grade 2/3 diarrhea compared to ExteNET events. There appears to be some adaptation to the effects of neratinib, as higher-grade diarrhea occurs early and does not typically recur. Preliminary data suggest that adding budesonide may further improve outcomes; enrollment into the budesonide cohort continues.
Citation Format: Barcenas C, Olek E, Hunt D, Tripathy D, Ibrahim E, Wilkinson M, Hurvitz S, Iannotti N, Kellum A, Manalo Y, Wong S, Hansen V, Alvarez R, Chan A, Gore I, Kendall D, Wade J, Ruiz R, Fang P, Bryce R, Moran S. Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): Interim analysis from the multicenter, open-label, phase II control trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-03.