SAN ANTONIO – A structured prophylactic regimen of loperamide for 2 cycles is associated with a reduced incidence and severity of diarrhea induced by neratinib in patients with HER2-positive early-stage breast cancer, according to an interim analysis presented at the 2016 San Antonio Breast Cancer Symposium (SABCS).1

Neratinib, an irreversible pan-HER inhibitor in late-phase development for the treatment of early-stage and metastatic HER2-positive breast cancer, induces diarrhea in a significant proportion of patients, thus requiring active management with loperamide prophylaxis given early in the course of therapy.

“As most diarrhea events occur early in the course of neratinib treatment, a structured prophylactic regimen of loperamide given for 1 to 2 cycles has been introduced in all clinical trials of neratinib to better manage this toxicity,” said Carlos H. Barcenas, MD, The University of Texas MD Anderson Cancer Center, Houston.

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To investigate the efficacy of 1 to 2 cycles of loperamide prophylaxis in the prevention of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer, researchers designed the open-label, phase 2 CONTROL trial ( Identifier: NCT02400476). The study was expanded to include additional patient cohorts treated with other agents that may reduce neratinib-induced diarrhea.

For the study, researchers enrolled 175 patients with HER2-positive stage I-IIIC breast cancer who had completed trastuzumab-based adjuvant therapy, or had experienced adverse events leading to early termination.

Patients receiving neratinib 240 mg orally daily received oral loperamide prophylaxis for 2 cycles, either in an original schedule or a modified, simplified schedule, or loperamide in combination with oral budesonide for 1 cycle.

“The incidence of grade 3 or higher diarrhea, the primary study end point, was 28.1% (95% CI, 20.8-36.5) with loperamide prophylaxis and 15.0% (95% CI, 5.7-29.8) with loperamide prophylaxis plus budesonide vs 39.9% without protocol-mandated loperamide prophylaxis in the ExteNET trial,” explained Dr Barcenas.

Researchers also found that previous therapy with pertuzumab may increase the risk of grade 3 neratinib-induced diarrhea that is not able to be prevented with loperamide prophylaxis alone; however, rates of grade 3 diarrhea were similar between patients who had and had not previously received pertuzumab in the loperamide plus budesonide cohort.

“By controlling early diarrheal events, loperamide prophylaxis may help to improve long-term adherence and help to ensure that the efficacy benefits of neratinib are realized,” said Dr Barcenas. “Preliminary data suggest that adding budesonide to loperamide prophylaxis may further diminish the duration and number of episodes of diarrhea, as well as decrease the number of neratinib dose holds, dose reductions, and discontinuations.”


1. Barcenas C, Olek E, Hunt D, et al. 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. Poster presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX.