Abstract PS13-20: Bringing diarrhea under CONTROL: Dose escalation reduces neratinib-associated diarrhea and improves tolerability in HER2-positive early-stage breast cancer

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 and for patients with HER2+ metastatic breast cancer in the 3rd-line setting. Diarrhea, particularly in the first 1-2 months, is the main tolerability concern with neratinib and is common in the absence of proactive management. In the ExteNET trial, where no mandatory prophylaxis was used, the rate of grade 3 diarrhea was 40%, 34% of patients experienced at least 1 dose hold, and 17% of patients discontinued due to diarrhea. The CONTROL trial previously showed that pre-emptive antidiarrheal prophylaxis (loperamide alone or in combination with budesonide or colestipol) or dose escalation (DE) reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Currently, antidiarrheal prophylaxis is initiated with the first dose of neratinib and used during the first 2 cycles of treatment (US PI). Updated findings from two DE cohorts in CONTROL are reported. Methods: CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients ≥18 years with stage I-IIIc HER2+ breast cancer were treated with neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts including 2 dose-escalation cohorts: DE1 (neratinib 120 mg/day on days 1-7, 160 mg/day on days 8-14, then 240 mg/day to day 365) + loperamide as needed (PRN); and DE2 (neratinib 160 mg/day on days 1-14, 200 mg/day on days 15-28, then 240 mg/day to day 365) + loperamide PRN. Adverse events were graded per NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Data cut-off: May 1, 2020. Results: Complete data for DE1 (60 patients) and interim data for the ongoing DE2 (60 patients) are presented. All patients in DE1 were off study and 40 (66.7%) of patients remained on treatment in the ongoing DE2. The median treatment duration for DE1 was 12.0 months (IQR 11.1-12.0) and for DE2 was 3.7 months (IQR 1.6-9.1). Overall, 48% and 57% of DE1 and DE2 patients, respectively, had prior pertuzumab; 0% and 3%, respectively, had prior T-DM1. The majority of patients in both DE1 and DE2 dose-escalated to 240 mg on planned schedule. The incidence of grade ≥3 diarrhea was 13.3% in DE1 and 20.0% in DE2. The median cumulative duration of grade ≥3 diarrhea over the entire 12-month treatment period was 3 days (range 1-6 days) for DE1 and 2 days (range 1-7 days) for DE2. In both DE1 and DE2, 7 patients (11.7%) had at least one dose hold while on study (none during escalation phase in DE1 and 4 during escalation phase in DE2). In both DE1 and DE2, 2 (3.3%) patients discontinued neratinib because of diarrhea (1 during escalation phase in each cohort). Updated data for the DE2 cohort will be presented. Conclusions: Adoption of neratinib DE reduced the incidence, severity, and duration of neratinib-associated diarrhea in CONTROL compared with ExteNET. DE1 was associated with low rates of dose holds and diarrhea-related discontinuations compared with all previously mandated prophylaxis strategies investigated in CONTROL and with ExteNET. Together these results show improved tolerability of neratinib with DE and suggest that DE combined with loperamide PRN may allow patients to stay on neratinib for the recommended period of time. Citation Format: Manuel Ruiz-Borrego, Arlene Chan, Gavin Marx, Adam Brufsky, A Jo Chien, Michael Thirlwell, Maureen Trudeau, Ron Bose, Jose A Garcia-Saenz, Daniel Egle, Daniel Hunt, Utpal Khambholja, Leanne McCulloch, Naisargee Shah, Debu Tripathy, Carlos H Barcenas, the CONTROL Investigators. Bringing diarrhea under CONTROL: Dose escalation reduces neratinib-associated diarrhea and improves tolerability in HER2-positive early-stage breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-20.