Abstract P4-21-10: Characterization of neratinib-induced diarrhea in patients with early-stage HER2+ breast cancer: Analyses from the phase III ExteNET trial
Authors: Mortimer J , Di Palma J , Jahanzeb M , Schmid K , Ye Y 
Published: March 2017

Background: ExteNET is an ongoing randomized placebo-controlled phase III trial designed to investigate the efficacy and safety of 12 months' treatment with neratinib in women with stage I–III HER2+ breast cancer after completion of adjuvant trastuzumab. At 2 years after randomization, a significant improvement in invasive disease-free survival was evident with neratinib vs placebo (stratified hazard ratio 0.67, 95% CI 0.50–0.91; P=0.0091) [Chan et al. Lancet Oncol 2016]. Neratinib was generally well tolerated with a low incidence of grade 3/4 events; diarrhea was the most common adverse event (grade 3, 39.8%, grade 4, 0.1%). We reviewed the safety data related to this study in order to better characterize the occurrence of neratinib-induced diarrhea (NID) and its impact on health-related quality of life (HRQoL).

Methods: Patients received neratinib 240 mg once daily or placebo for 12 months. Antidiarrheal prophylaxis was not dictated by the protocol, but investigators were advised to treat diarrhea early. Adverse events were monitored until 28 days after the last dose of study drug, and graded according to NCI-CTCAE, v3.0. Patient-reported HRQoL questionnaires (Functional Assessment of Cancer Therapy–Breast [FACT-B], v4; EuroQol 5-Dimensions [EQ-5D]) were completed at baseline and 1, 3, 6, 9 and 12 months. Descriptive analyses of FACT-B and EQ-5D scores by maximum grade of diarrhea were performed in patients with post-baseline HRQoL assessments. ClinicalTrials.gov: NCT00878709.

Results: Of 2840 women randomized, 2816 (1408 per group) received at least one dose of study drug and were evaluable for toxicity. Diarrhea was more common with neratinib than placebo (all-grade: 95.4% vs 35.4%; grade 3: 39.8% vs 1.6%; grade 4: 0.1% vs 0%). Median time to onset of any grade NID was 2 (IQR 2-4) days. Most grade 3 NID occurred early in the course of treatment with a reduction in frequency thereafter; 28.6% of patients had grade 3 events during month 1 decreasing to approx. 6% or less after month 3. For those experiencing grade 3/4 NID, the median number of events was 2 (IQR 1–3) with a median cumulative duration of 5 (IQR 2–9) days. NID resulted in dose reductions in 26.4%, dose holds in 33.9%, drug discontinuation in 16.8%, and hospitalizations in 1.4% of patients. In the neratinib group, FACT-B and EQ-5D scores decreased with increasing severity of diarrhea (Table); the changes in scores were not considered to be clinically meaningful.

   Mean score ± SDInstrumentMID rangenNo diarrheaGrade 1/2Grade 3/4FACT-B total7–81269112.7 ± 18.1110.6 ± 17.3107.6 ± 19.0EQ-5D index0.09–0.112730.86 ± 0.170.84 ± 0.180.82 ± 0.19EQ-5D VAS7–10127379.6 ± 14.178.6 ± 14.675.8 ± 15.6MID, minimally important difference; SD, standard deviation; VAS, visual analogue scale.

Conclusion: NID has a distinct clinical pattern, with a high incidence of grade 3 events in the first month and a dramatic decrease thereafter. In the absence of antidiarrheal prophylaxis, patients with severe diarrhea experience a median of 2 events lasting for a cumulative duration of 5 days. Loperamide prophylaxis given early in the course of treatment is currently being investigated in the prevention of NID with promising early results.

Citation Format: Mortimer J, Di Palma J, Jahanzeb M, Schmid K, Ye Y. Characterization of neratinib-induced diarrhea in patients with early-stage HER2+ breast cancer: Analyses from the phase III ExteNET 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 P4-21-10.