Abstract P5-14-03: Effect of prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2-positive early-stage breast cancer: Phase II CONTROL trial
Authors: Chan Arlene , Hurvitz Sara A , Marx Gavin , Ruiz-Borrego Manuel , Farrell Cynthia , Hunt Daniel , McCulloch Leanne , Chien A Jo , Tripathy Debu , Barcenas Carlos H ,   the CONTROL Investigators
Published: March 2020

Background: Neratinib (NERLYNX®), an irreversible pan-HER tyrosine kinase inhibitor, is used for the extended adjuvant treatment of patients with early-stage HER2-positive (HER2+) breast cancer following adjuvant trastuzumab-based therapy. Diarrhea is the main tolerability concern with neratinib and is common in the absence of proactive management. The CONTROL study (Clinicaltrials.gov: NCT02400476) is investigating the effectiveness of rationally structured antidiarrheal prophylaxis or neratinib dose escalation in the prevention of neratinib-associated diarrhea. CONTROL includes antidiarrheal prophylactic regimens with loperamide either alone or in combination with budesonide (locally acting corticosteroid) or colestipol (bile acid sequestrant), as well as two different neratinib dose-escalation schedules. Updated findings from CONTROL are reported. Methods: CONTROL is an international, multi-cohort, open-label, phase II study. Patients ≥18 years of age with stage I-IIIc HER2+ breast cancer were treated with oral neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts investigating: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide prophylaxis; 3) colestipol + loperamide prophylaxis; 4) colestipol + loperamide prn; 5) neratinib dose escalation + loperamide prn (two cohorts). Adverse events were graded according to NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Data cut-off: 17 June 2019. Results: A total of 514 patients have been enrolled. At the cut-off date, study treatment had been completed by 100% of patients in all cohorts except for the two neratinib dose-escalation cohorts (the colestipol + loperamide prn cohort had just 1 patient continuing treatment as of the cut-off date). All preventive strategies reduced the incidence of grade 3 diarrhea (Table) compared with that seen in ExteNET (historical control: 39.9%). Median cumulative duration of grade 3 diarrhea across the study cohorts ranged from 2-5 days for the entire 12-month treatment period. The proportion of patients discontinuing neratinib because of diarrhea was decreased in all cohorts compared with ExteNET (16.8%), except for Cohort 1. The majority of adverse events (including diarrhea) leading to treatment discontinuation occurred early while on treatment, primarily during the first or second cycle.

Table. Characteristics of treatment-emergent diarrheaLoperamide (n=137)Budesonide + loperamide (n=64)Colestipol + loperamide (n=136)Colestipol + loperamide prn (n=104)Neratinib dose escalation scheme 1 (n=60)Neratinib dose escalation scheme 2 (n=13)On neratinib treatment, %0001.0a85.084.6Diarrhea, %Grade 124.125.027.930.841.723.1Grade 224.832.834.632.738.346.2Grade 330.728.120.631.715.07.7Grade 4000000Median cumulative duration, days (range)Grade ≥25.0 (1-400)6.0 (1-117)4.0 (1-371)8.0 (1-375)5.0 (1-28)2.0 (1-6)Grade 33.0 (1-93)2.5 (1-6)3.5 (1-22)3.0 (1-55)2.0 (1-5)5.0 (5-5)Discontinuation (due to a diarrhea TEAE), %20.410.94.47.73.30Hospitalization (due to a diarrhea TEAE), %1.500000aAs of the data cut-off, the final patient in the colestipol + loperamide prn cohort had completed 1 year of neratinib treatment but had not yet had the final study visit.

Conclusions: The addition of budesonide or colestipol to loperamide prophylaxis given for 1-2 cycles reduces the incidence, severity and duration of neratinib-associated diarrhea. These strategies reduce the rate of neratinib discontinuation due to diarrhea, allowing patients to receive the benefits of 1 year of extended adjuvant neratinib therapy. Early findings with escalating the dose of neratinib over the first 2-4 weeks of treatment are promising. Updated data for the two neratinib dose-escalation cohorts will be presented at the meeting.

Citation Format: Arlene Chan, Sara A Hurvitz, Gavin Marx, Manuel Ruiz-Borrego, Cynthia Farrell, Daniel Hunt, Leanne McCulloch, A Jo Chien, Debu Tripathy, Carlos H Barcenas, the CONTROL Investigators. Effect of prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2-positive early-stage breast cancer: Phase II CONTROL trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-03.