Targeted Therapies and Immunotherapy: General Principles (Oncology) – CE ALERT Don appropriate personal protective equipment (PPE) based on the patient’s signs and symptoms and indications for isolation precautions. Refer to Oncology Nursing Society (ONS) interim guidelines for PPE recommendations during an emergent shortage of PPE (e.g., pandemic).13 Hypersensitivity reactions, such as anaphylaxis, may occur with targeted therapy and immunotherapy; therefore, frequent assessments and monitoring are required. Only qualified physicians, physician assistants, advanced practice registered nurses (APRNs), or nurses with demonstrated competency administer antineoplastic therapies. Refer to the professional’s regulatory scope of practice and the organization’s practice. Take steps to eliminate interruptions and distractions during medication preparation. OVERVIEW Normal cell reproduction, growth, and apoptosis are controlled by complex signaling pathways at the extracellular and intracellular levels. Malfunctioning of these pathways occurs in malignancies, leading to increased proliferation, tissue invasion, metastases, and apoptosis inhibition.18 Development of targeted therapies overcame the lack of selectivity associated with conventional antineoplastic therapy by targeting specific protein pathways.5 Although these pathways can be present in normal tissue, they are overexpressed or mutated in cancerous tissue.1 Cancer immunotherapy represents precision medicine, which helps the immune system fight cancer and offers a type of targeted or personalized therapy.4,11 In comparison, traditional cytotoxic chemotherapy attacks both malignant and nonmalignant cells, causing disruption of the cell cycle and other cell functions. Targeted therapy may not be more or less effective than traditional antineoplastic therapies, but it offers a unique approach to the treatment of cancer and other diseases and has toxicities different from those of traditional antineoplastic therapy. Because targeted therapies are more predictable and have fewer side effects than chemotherapy, patients tolerate them better.4 Chemotherapy, biotherapy, and targeted therapy may be administered concurrently, offering improved survival for many patients with cancer.8 Targeted therapies can be divided into two broad categories: monoclonal antibodies (MoAbs) and small molecules. Many targeted therapies are named after the mechanism of action or the specific aimed kill target (Table 1). Copyright © 2020, Elsevier, Inc. All rights reserved. 1 of 16 Targeted Therapies and Immunotherapy: General Principles (Oncology) – CE Table 1 Examples of Targeted Therapy and Immunotherapy Classifications and Approved Indications Target(s) Agent(s) Indication(s) MoAbs EGFR Cetuximab • mCRC • SCCHN EGFR Panitumumab • mCRC VEGF Bevacizumab • mCRC • NSCLC • Glioblastoma • RCC • Cervical HER2 Trastuzumab • Breast • Gastric • GE junction CD20 on B cells Rituximab • Non-Hodgkin lymphoma • CLL CD52 Alemtuzumab • CLL Tyrosine kinase inhibitors BCR-ABL Bosutinib • CML Dasatinib • CML • ALL Ph+ Imatinib • ALL Ph+ • MDS • CML • GIST Nilotinib • CML EGFR pathway Lapatinib Breast HER2 (EGFR2) All EGFR Afatinib NSCLC EGFR1 Erlotinib • Metastatic NSCLC • Metastatic pancreatic VEGF Axitinib RCC MEK Trametinib Melanoma mTOR inhibitors mTOR pathway Temsirolimus • RCC Everolimus • RCC • SEGA • Advanced breast BRAF inhibitors Mutated BRAF Dabrafenib • Melanoma: unresectable or metastatic Vemurafenib • Melanoma Multikinase inhibitors Blocks receptor tyrosine Ceritinib Metastatic NSCLC kinases ALK, IGF-1R, InsR, and ROS1 Copyright © 2020, Elsevier, Inc. All rights reserved. 2 of 16 Targeted Therapies and Immunotherapy: General Principles (Oncology) – CE Blocks receptor tyrosine Crizotinib Metastatic NSCLC that is ALK positive kinases ALK, HGFR, c-MET VEGFR1,2,3; PDGF-R, FGFR Pazopanib • RCC • Sarcoma VEGFR2, PDGF, RAF Sorafenib • RCC • Hepatocellular Proteasome inhibitors Inhibits 20S proteasome Carfilzomib • Multiple myeloma • Mantle cell lymphoma Inhibits 26S proteasome Bortezomib • Multiple myeloma • Mantle cell lymphoma • Non-Hodgkin lymphoma Immunomodulators Thalidomide • Myeloma Lenalidomide • Myeloma, MDS Pomalidomid • Myeloma e Immunotherapy PD1 Pembrolizum Melanoma ab CTLA-4 Ipilimumab Melanoma ALL, acute lymphoblastic leukemia; ALK, tyrosine kinase receptor; BCR-ABL, mutated fusion gene; BRAF, Raf kinase family of growth signal transduction protein kinase; c-MET, transforming gene or proto-oncogene (also known as hepatocyte growth factor receptor [HGFR]); CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CTLA-4, cytotoxic T-lymphocytic–associated antigen 4; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GE, gastroesophageal; GIST, gastrointestinal stromal tumor; HER2, human epidermal growth factor receptors; HGFR, hepatocyte growth factor receptor; IGF-1R, insulin-like growth factor 1 receptor; InsR, insulin receptor gene; mCRC, metastatic colorectal cancer; MDS, myelodysplasia; MEK, mitogen activated protein kinase; MoAb, monoclonal antibody; mTOR, mammalian target of rapamycin; NSCLC, non–small cell lung cancer; PD1, programmed death-1; PDGF, platelet-derived growth factor; Ph+, Philadelphia chromosome; RAF, mutated gene protein kinase; RCC, renal cell cancer; ROS1, mutated gene; SCCHN, squamous cell carcinoma of head and neck; SEGA, subependymal giant cell astrocytoma; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor (From Wilkes, G.M. [2018]. Targeted therapy: Attacking cancer with molecular and immunological targeted agents. Asia-Pacific Journal of Oncology Nursing, 5[2], 137-155; Yarbro, C.H., Wujcik, D., Gobel, B.H. [Eds.]. [2018]. Cancer nursing: Principles and practice [8th ed.]. Burlington, MA: Jones & Bartlett Learning.) • MoAbs are large molecules that act similarly to immune system antibodies and are typically categorized as a type of immunotherapy. These drugs are given intravenously because they are proteins and would be destroyed by the gut.17 MoAbs are made by injecting animals (usually mice) with the target proteins, causing the animals to develop antibodies to that protein. These antibodies are then “humanized” by replacing most of the antibody with human antibody to make the resultant antibody less foreign to humans, thereby minimizing hypersensitivity reactions.5 • Small molecules are so named in reference to the drug’s ability to pass through cell membranes to interact with targets within a cell. Given orally, many of these agents act on multiple pathways in the cell.5 As a result, cell-signaling pathways that regulate basic cellular functions are blocked. Most of these agents are metabolized by the cytochrome P450 (CYP450) enzymes. Examples include tyrosine kinase inhibitors, proteasome Copyright © 2020, Elsevier, Inc. All rights reserved. 3 of 16 Targeted Therapies and Immunotherapy: General Principles (Oncology) – CE inhibitors, hedgehog pathway antagonists, angiogenesis inhibitors, and mammalian target of rapamycin (mTOR) inhibitors.17,18 MoAbs, such as cetuximab and trastuzumab, target epidermal growth factor receptors (EGFRs), including human epidermal growth factor receptor 1 (hEGFR1) and human epidermal growth factor receptor 2 (hEGFR2), as well as EGFRs found in the extracellular receptor kinase pathway. Rituximab specifically targets CD20-positive cells. Oftentimes, antibodies act directly on a receptor and are generally more specific than other targeted agents.12 The intracellular signaling kinase pathway includes SRc (proto-oncogene tyrosine-protein kinase), phosphatidylinositol 3-kinase (PI3k) or araA-sensitive gene (Ak+) or mTOR protein, and the mitogen-activated protein kinase pathway. These pathways are responsible for the communication between extracellular and intracellular signals. Two proteins, the breakpoint cluster region-tyrosine kinase protein, which is associated with chronic myeloid leukemia, and the mTOR protein, which is associated with renal cell, breast, ovarian, colon, and other cancers, are located intracellularly.17 Kinase inhibitors such as dasatinib, sorafenib, erlotinib, and gefitinib target tyrosine kinase found in the intracellular space as well. The third pathway, angiogenesis, involves the formation of new blood vessels (neovascularization) from existing vasculature and becomes abnormal in malignancy. Angiogenesis is stimulated by many factors, including hypoxia and growth factors such as vascular endothelial growth factor (VEGF). Overproduction of VEGF triggers abnormal angiogenesis. An example is the MoAb bevacizumab, which targets VEGF overexpression. Novel agents designed to overcome resistance to targeted therapies and immunotherapies have been developed. Antibody drug conjugates (ADCs) are agents that consist of a cytotoxic agent and an antibody that targets an antigen expressed on malignant cells. Trastuzumab emtansine is an example of an ADC approved for the treatment of metastatic breast cancer that has demonstrated resistance to trastuzumab. Chimeric antigen receptor (CAR)-T cells are an example of adoptive cell transfer effective in many B-cell malignancies.12 Vaccine therapy, another type of immunotherapy, is aimed at preventing cancer.11 Dose modifications, delays, or discontinuation of these therapies may be necessary when intolerable side effects develop, tumor progression occurs, or resistance develops.18 Dermatologic and gastrointestinal problems, specifically diarrhea, are common side effects of targeted therapy. Dermatologic