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Review
. 2019 May;175(1):5-15.
doi: 10.1007/s10549-018-05102-x. Epub 2019 Jan 22.

The characterization, management, and future considerations for ErbB-family TKI-associated diarrhea

Hope S Rugo  1 , Jack A Di Palma  2 , Debu Tripathy  3 , Richard Bryce  4 , Susan Moran  5   6 , Elizabeth Olek  5 , Linda Bosserman  7
Affiliations
Review

The characterization, management, and future considerations for ErbB-family TKI-associated diarrhea

Hope S Rugo et al. Breast Cancer Res Treat. 2019 May.

Abstract

Purpose: Diarrhea is recognized as a common adverse event associated with tyrosine kinase inhibitors (TKIs), with those targeting the ErbB family of receptors being associated with the highest rate of diarrhea.

Methods: This paper reviews data on the incidence, timing, and duration of diarrhea associated with US Food and Drug Administration-approved ErbB family-targeted TKIs from the published literature, and sets forth recommendations for management.

Results: In the absence of anti-diarrheal prophylaxis the incidence of any-grade diarrhea varies and typically occurs early during the course of treatment. Although it is difficult to determine if the incidence and severity of diarrhea is related to inhibition of a particular kinase target because of the multi-targeted and overlapping activity of many agents, evidence suggests that second-generation TKIs with broader target profiles (i.e., afatinib, lapatinib, neratinib) result in a higher incidence of diarrhea compared with highly specific first- (erlotinib, gefitinib) or third- (osimertinib) generation agents. The mechanisms responsible for TKI-associated diarrhea are not fully understood and are likely multi-factorial, involving dysregulated ion transport, inflammation, and mucosal injury. Management strategies have been developed-and continue to be refined-to prevent and reduce the severity and duration of TKI-associated diarrhea. For agents associated with more significant symptoms, anti-diarrheal prophylaxis reduces the incidence and severity of diarrhea, and ongoing studies are evaluating specific strategies to further reduce incidence and duration of TKI-associated diarrhea.

Conclusions: Continued investigations into risk factors and pharmacogenomic markers for diarrhea may further improve management of this common toxicity.

Keywords: Cancer; Diarrhea; ErbB receptor; Tyrosine kinase inhibitor.

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Conflict of interest statement

Conflict of interest

The authors take complete responsibility for the integrity and accuracy of the data as a whole and have given final approval for the version to be published. Hope S. Rugo: Research funding to UCSF from Genentech/Roche, MacroGenics, and Pfizer; Travel support as an unpaid consultant to Puma Biotechnology, Inc. Jack A. Di Palma: Member, Independent Data Monitoring Committee, Puma Biotechnology. Debu Tripathy: Serves on Scientific Advisory Board for Puma Biotechnology, Inc. (unpaid.) Richard Bryce and Elizabeth Olek are employees of Puma Biotechnology, Inc. Susan Moran was previously employed by and is a shareholder of Puma Biotechnology, Inc. Linda Bosserman: Serves as an advisor and on the speaker bureau for Puma Biotechnology (paid).

Ethical approval

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

References

    1. US Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications. Updated July 3 (2018) https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Accessed 9 July 2018
    1. Jeong W, Doroshow JH, Kummar S. United States Food and Drug Administration approved oral kinase inhibitors for the treatment of malignancies. Curr Probl Cancer. 2013;37(3):110–144. doi: 10.1016/j.currproblcancer.2013.06.001. - DOI - PMC - PubMed
    1. Amitay-Laish I, Stemmer SM, Lacouture ME. Adverse cutaneous reactions secondary to tyrosine kinase inhibitors including imatinib mesylate, nilotinib, and dasatinib. Dermatol Ther. 2011;24(4):386–395. doi: 10.1111/j.1529-8019.2011.01431.x. - DOI - PubMed
    1. Bowen JM. Mechanisms of TKI-induced diarrhea in cancer patients. Curr Opin Support Palliat Care. 2013;7(2):162–167. doi: 10.1097/SPC.0b013e32835ec861. - DOI - PubMed
    1. Gilotrif [package insert] (2016) Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

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