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Effective Management and Prevention of Neratinib-Induced Diarrhea

Federico Ustaris, MD; Cristina Saura, MD; Jack Di Palma, MD; Richard Bryce, MBChB, MRCGP, MFPM; Susan Moran, MD; Linda Neuman, MD; Rolando Ruiz, MD
Published: Friday, Dec 18, 2015

Jack Di Palma, MD

Jack Di Palma, MD

Abstract

Diarrhea is a common complication of many cancer treatments and a side effect well understood by most oncologists. It requires prompt and effective management to prevent sequelae, preserve dose intensity, and maintain patient quality of life. Neratinib (PB-272; Puma Biotechnology Inc, Los Angeles, CA, USA) is an irreversible panHER tyrosine kinase inhibitor in late-phase clinical development. Diarrhea, the most common toxicity associated with neratinib, is generally observed during the first cycle of treatment. Intensive loperamide prophylaxis (ie, 16 mg on day 1, tapering to 12 mg/day then 6-8 mg/day over the course of cycle 1) has been introduced in clinical trials of neratinib to better manage this toxicity. Safety data from these trials suggest that a prophylactic regimen reduces both the severity and duration of neratinib-associated diarrhea. Intensive loperamide prophylaxis should be used in all patients receiving neratinib for the first cycle of treatment.

Introduction

Neratinib (PB-272; Puma Biotechnology Inc, Los Angeles, CA, USA) is a potent small-molecule kinase inhibitor of human epidermal growth factor receptors HER1 (or EGFR1), HER2, and HER4.1,2 It binds irreversibly to the intracellular ATP-binding pocket of the HER2 receptor and reduces receptor autophosphorylation.2 In vitro studies show that neratinib blocks downstream signal transduction and cell cycle regulatory pathways in cancer cell lines, ultimately leading to decreased cell proliferation.2 In animal studies, neratinib inhibits the growth of EGFR– and HER2–dependent tumor xenograft models when given orally on a once-daily schedule.2

Neratinib is currently in late-stage clinical development, with regulatory submission planned in 2016. It has been investigated extensively in the treatment of metastatic HER2–positive breast cancer both as a single agent3-5 and in combination with chemotherapeutic and targeted agents.6-11 Overall response rates in phase II studies ranged from 29% to 40% with neratinib monotherapy in women with metastatic HER2–positive breast cancer who had previously been treated with chemotherapy and trastuzumab.3-5 Considerably higher response rates were observed when neratinib was combined with chemotherapeutic agents, for example, 63% with capecitabine8 and 72% to 75% with neratinib plus paclitaxel.6,10 Of note, neratinib showed clinical activity in women who had been previously treated with trastuzumab,4,8 suggesting that it may be able to circumvent trastuzumab resistance.

Neratinib is also being investigated in early-stage HER2– positive breast cancer. In a phase III trial of neratinib (ExteNET), a 12-month course of treatment improved invasive disease-free survival after 2 years of follow-up compared with placebo in women with early-stage HER2–positive breast cancer after trastuzumab-containing adjuvant therapy (hazard ratio 0.67, 95% CI 0.50–0.91; 1-sided P = .0046).12 Diarrhea was the most common adverse event with neratinib (grade 3, 40%; grade 4, <0.1%).12 As previous efforts to improve outcomes with extended adjuvant therapy with trastuzumab have been unsuccessful,13 neratinib is the first agent to significantly prolong disease-free survival in women with trastuzumab-treated early-stage breast cancer. Longer term follow-up and assessment of overall survival in the ExteNET trial is ongoing.

Neratinib is taken orally at a dosage of 240 mg once daily on a continuous schedule.4 At this dosage, neratinib is generally well tolerated with a low incidence of grade 3/4 adverse events.4 The most commonly reported adverse event and dose-limiting toxicity of neratinib is diarrhea,3,4 a known class effect of EGFR-directed tyrosine kinase inhibitors.14


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Online CME Activities
TitleExpiration DateCME Credits
Miami Breast Cancer Conference®: Attendee Tumor Board OnlineNov 30, 20181.5
Community Practice Connections™: 1st Annual Paris Breast Cancer Conference™Dec 31, 20181.5
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