Gastrointestinal Toxicities of Targeted Therapy

Introduction

Targeted therapies are a category of drugs that inhibit cancer by interfering with specific molecules involved in the growth, progression, and spread of malignant cells. Targeted therapies act on specific molecular targets, whereas most standard chemotherapies act on many rapidly dividing normal and cancer cells. Many different targeted therapies have been approved by the US Food and Drug Administration (FDA) to treat specific types of cancer. Targeted therapies are generally less toxic than standard chemotherapy drugs because just as they are sometimes more efficacious because they are designed to act on specific molecular targets, they have less effects on other cells. Some therapies, however, do have substantial side effects. The most common gastrointestinal side effects seen with targeted therapies are discussed in this chapter and include diarrhea, nausea, vomiting, hepatotoxicity, and gastrointestinal perforation.

Diarrhea

Targeted therapy-induced diarrhea: Targeted therapy-induced diarrhea is a challenge in daily clinical practice. The frequency, severity, and causes of symptoms differ based on the agent used and is common in patients receiving tyrosine kinase inhibitors (TKIs). Targeted therapies that are commonly associated with diarrhea include—endothelial growth factor receptor (EGFR)–targeted TKIs (e.g., erlotinib, gefitinib, afatinib, osimertinib), EGFR-targeted monoclonal antibodies (mAbs) (e.g., cetuximab, panitumumab), c-Kit TKIs (e.g., imatinib, sunitinib, regorafenib), multi-TKIs (e.g., sorafenib, sunitinib, axitinib), and mitogen-activated protein kinase (MEK) inhibitors (e.g., trametinib, selumetinib). The most commonly used method for assessing the severity of diarrhea is National Cancer Institute Common Toxicity Criteria (NCI CTC) ( Table 13.1 ).

c-KIT–Targeting Agents

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  Diarrhea and the c-KIT pathway: Diarrhea is one of the most common adverse effects observed during treatment with imatinib. Approximately 20% to 26% of patients experience diarrhea during therapy. Sunitinib and regorafenib cause diarrhea in 44%, and 34% to 40% of patients, respectively. The high expression of KIT in the intestinal cells of Cajal might be a potential mechanism for diarrhea by imatinib or sunitinib.

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  Mechanism of action: Stem cell growth factor receptor, c-KIT, or CD117, regulates cell proliferation and differentiation. Stem cell factor dimers interact with KIT, inducing receptor dimerization, leading to auto-inhibition and transphosphorylation of intercellular proteins and activation of intercellular signaling pathways. Normally this pathway plays an important role in mast cell survival and function, pigmentation, gametogenesis, differentiation of hematopoietic stem cells, and development of gastric pacemaker cells. c-KIT deregulation in cancer occurs mainly through c-KIT overexpression and genetic mutation. c-KIT mutations occur in gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), germ cell tumors, ^, melanoma, mastocytosis, and sinonasal NK/T cell lymphoma.

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  c-KIT TKIs: FDA-approved agents are imatinib, sunitinib, and regorafenib. Imatinib inhibits BCR-ABL kinase in CML, and also inhibits other receptor tyrosine kinases including c-KIT and PDGF, and is currently approved for c-KIT–positive GIST tumors. ^, Sunitinib is a second-generation multi-TKI used for GIST upon disease progression. Regorafenib is also a multikinase inhibitor approved for patients with GIST refractory to both imatinib and sunitinib.

VEGF–Targeting Agents

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  Diarrhea and the vascular endothelial growth factor (VEGF) pathway: VEGF–targeting TKIs that cause diarrhea include sorafenib, sunitinib (44%), pazopanib (52%, grade 3 diarrhea), axitinib (11%), vandetanib (52% any grade diarrhea, 5.6% high-grade diarrhea), regorafenib (34%–40%), lenvatinib, and cabozatinib (64%).

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  Mechanism of action: The VEGF family includes 5 glycoproteins: VEGFA, VEGFB, VEGFC, VEGFD, and placental growth factor (PGF), which interact with and activate receptors belonging to the tyrosine kinase family: VEGFR1, VEGFR2, and VEGFR3. Upon interaction with their ligands, VEGFRs activate downstream signaling pathways, leading to endothelial cell effects including proliferation, survival, migration, vasodilation, and increased permeability. VEGFRs are expressed on tumor cells and endothelial cells in NSCLC, gastric cancer, breast cancer, leukemia, prostate cancer, and hepatocellular carcinoma. VEGF signaling also has important effects that promote tumor angiogenesis and distant metastasis.

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  VEGF–targeted therapy: Inhibitors of the VEGF pathway include TKIs, mAbs against VEGF or VEGFRs, and soluble VEGF receptors. FDA-approved TKIs are sorafenib, sunitinib, pazopanib, axitinib, vandetanib, regorafenib, lenvatinib, cabozantinib, and ponatinib. Sorafenib is approved for the treatment of advanced renal cell carcinoma and is in late stage clinical trials for hepatocellular carcinoma, metastatic melanoma, and NSCLC. Bevacizumab is an mAb against VEGF, and is approved for colorectal cancer, breast cancer, cervical cancer, ovarian cancer, renal cell carcinoma, glioblastoma, and NSCLC.

CDK4/6 Inhibitors

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  Diarrhea and CDK4/6 inhibitors: Palbociclib and ribociclib often cause low-grade (grades 1 and 2) diarrhea, whereas abemaciclib commonly causes grade 3 diarrhea. Abemaciclib monotherapy for patients with hormone receptor (HR) positive, HER2 negative metastatic breast cancer typically causes diarrhea within 1 week of therapy initiation. Most cases of diarrhea resolve quickly, with a median duration of 7.5 days (grade 2) and 4.5 days (grade 3).

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  Mechanism of action: The cyclin D-cyclin–dependent kinase 4/6-Rb (CDK4/6) pathway controls the transition from the G1 (first growth phase) to the S phase (DNA replication phase). Mitogenic growth factor signaling activates the RAS/MAPK and PI3K pathways, leading to the upregulation of D-type cyclins (D1, D2 and D3) by increased transcription and decreased proteasomal degradation. D cyclin binds to CDK4 and CDK6 to form a complex required for DNA replication. Cyclin D1 overexpression occurs in breast cancer, head and neck squamous cell carcinoma (HNSCC), NSCLC, colorectal cancer, endometrial cancer, pancreatic cancer, melanoma, and neuroblastoma. ^,

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  CDK4/6 targeted–therapy : CDK4 and CDK6 have been targeted in HR positive, HER2 negative breast cancer. FDA-approved CDK4/6 inhibitors are palbociclib, ribociclib, and abemaciclib.