Targeted Cancer Therapies Claire Elizabeth Powers Smith, MD, Boston University School of Medicine, Boston, Massachusetts Vinayak Prasad, MD, MPH, University of California, San Francisco, California Targeted cancer therapies involve chemotherapeutic agents that attack, directly or indirectly, a specific genetic biomarker found in a given cancer. Targeted oncology includes monoclonal antibodies, small molecule inhibitors, antibody-drug con- jugates, and immunotherapy. For example, the monoclonal antibodies trastuzumab and pertuzumab target human epidermal growth factor receptor 2 (HER2) and are used when treating HER2-positive breast cancer. Although targeted oncology has improved survival by years for some incurable cancers such as metastatic breast and lung cancer, as few as 8% of patients with advanced cancer qualify for targeted oncology medications, and even fewer benefit. Other limitations include serious adverse events, illustrated by a 20% to 30% rate of heart attack, stroke, or peripheral vascular events among patients taking ponatinib, which is used in treating chronic myelogenous leukemia. Immune checkpoint inhibitor therapy–related adverse effects such as hypothyroidism are common, and more severe adverse events such as colitis and pneumonitis can be fatal and require immediate intervention. Drug interactions with widely prescribed medications such as antacids and warfarin are com- mon. Additionally, financial toxicities are a problem for patients with cancer who are using costly targeted therapies. Future directions for targeted oncology include tumor-agnostic drugs, which target a given mutation and could be used in treating cancers from multiple organ types. An overview of indications, mechanism of action, and toxicities of targeted cancer ther- apies is offered here. (Am Fam Physician. 2021;103(3):155-163. Copyright © 2021 American Academy of Family Physicians.) Targeted cancer therapy involves testing various In general, small molecule inhibitors are oral, whereas the types of cancer for genetic biomarkers that can predict remaining therapies are given intravenously. the response to chemotherapeutic agents that attack the biomarkers directly or indirectly.1,2 In the past decade, the MONOCLONAL ANTIBODIES U.S. Food and Drug Administration (FDA) has approved Monoclonal antibodies are identical immunoglobulins that approximately 40 new targeted therapies for 12 different bind a specific antigen. Targeted oncology monoclonal anti- cancers3-6 (Table 1). Despite this innovation, the per- bodies are most commonly used to target an antigen on a centage of patients with cancer who are eligible for such therapies is small. In 2018, an estimated 8.3% of 610,000 patients with advanced or metastatic cancer were eligible WHAT’S NEW ON THIS TOPIC for targeted therapy.7 The number of patients who ben- efit from these drugs is even smaller and ranges widely, Targeted Cancer Therapies depending on the tumor and drug. Targeted oncology has In the past decade, the U.S. Food and Drug Administration mainly shown benefit in the metastatic (incurable) setting, has approved approximately 40 new targeted therapies for with rare success for patients treated with surgery in the 12 different cancers. local or regional setting. Patients with metastatic epidermal growth factor receptor– mutated lung cancer who are treated with osimertinib Types of Targeted Therapy (Tagrisso) live a median of 39 months, more than double the Targeted therapies can be divided into four general cate- survival of similar patients who were treated with the first epidermal growth factor receptor inhibitor, erlotinib (Tarceva), gories: monoclonal antibodies, small molecule inhibitors, between 2007 and 2011. antibody-drug conjugates, and immunotherapy (Figure 1). In 2020, the average patient out-of-pocket cost for a course of oral cancer therapy was $5,663. According to one large CME This clinical content conforms to AAFP criteria for analysis, 20% of patients with cancer take less medication CME. See CME Quiz on page 141. than prescribed, 19% only partially fill oral cancer therapy Author disclosure: No relevant financial affiliations. prescriptions, and 24% avoid filling a prescription at all. 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TABLE 1 FDA-Approved Targeted Therapies for Cancer, 2010 to 2019 Drugs Target Drug type FDA-approved indication Toxicities, adverse effects, precautions Unique monitoring cancer cell, leading to downregulation Acute myelogenous leukemia of oncogene signaling, or to flag tumor Enasidenib (Idhifa), ivosidenib (Tibsovo) IDH1/2 Small molecule Newly diagnosed and relapsed/refractory Edema, hepatotoxicity, prolonged QTc Alkaline phosphatase, ALT, AST, CBC, cells for destruction by the immune inhibitors IDH1/2+ acute myelogenous leukemia chemistry, CK, ECG, total bilirubin 8 system. The anti–human epider- Gilteritinib (Xospata), midostaurin (Rydapt) FLT3 Small molecule Newly diagnosed and relapsed/refractory Hepatotoxicity, prolonged QTc, rash, Alkaline phosphatase, ALT, AST, CBC, mal growth factor receptor 2 (HER2) inhibitors FLT3+ acute myelogenous leukemia vomiting chemistry, ECG, total bilirubin monoclonal antibodies trastuzumab Anaplastic thyroid cancer (Herceptin) and pertuzumab (Perjeta) Dabrafenib (Tafinlar) plus trametinib (Mekinist) BRAF and MEK Small molecule Locally advanced or metastatic with V600E Colitis, cutaneous squamous cell cancers, Alkaline phosphatase, ALT, AST, blood have drastically improved outcomes inhibitors mutation fever, heart failure, hepatotoxicity, hypergly- glucose, ECG, electrolytes, renal function, for HER2-positive breast cancer, which cemia, rash, thrombosis skin examination, total bilirubin accounts for 15% to 25% of patients Bladder cancer 9 with breast cancer. All patients with Erdafitinib (Balversa) FGFR2/3 Small molecule Metastatic or locally advanced FGFR2/3 Central serous retinopathy, hand-foot syn- Eye examination, phosphate breast cancer should undergo testing inhibitor alterations drome, hyperphosphatemia, oncholysis for HER2 overexpression.10 Trastu- Breast cancer zumab binds to HER2 on tumor cells, Ado-trastuzumab emtansine (Kadcyla) HER2 Antibody-drug Early stage HER2+ with residual disease after Cardiotoxicity, hepatotoxicity, interstitial lung Alkaline phosphatase, ALT, AST, CBC, leading to internalization and down- conjugate neoadjuvant treatment; metastatic HER2+ disease, neuropathy ECG, total bilirubin regulation of HER2, which is a pro- growth stimulator. Trastuzumab is not Alpelisib (Piqray) PIK3CA Small molecule PIK3CA-mutated metastatic Dermatologic (Stevens-Johnson syndrome), A1C, blood glucose inhibitor hyperglycemia, severe diarrhea as effective in treating advanced gas- troesophageal cancer with HER2 over- Atezolizumab (Tecentriq) PD-L1 Immunotherapy PD-L1–positive metastatic triple nega- Colitis, endocrinopathies, hepatitis, myocar- Alkaline phosphatase, ALT, AST, blood expression, offering only a 12% overall tive breast cancer, in combination with ditis, pneumonitis, rash glucose, renal function, total bilirubin, chemotherapy TSH response rate.11 Cetuximab (Erbitux) is another monoclonal antibody used Fam-trastuzumab deruxtecan (Enhertu) HER2 Antibody-drug Metastatic HER2+ Cardiotoxicity, hematologic, interstitial lung CBC, echocardiography as targeted therapy; it binds to the epi- conjugate disease (9%) dermal growth factor receptor (EGFR), Olaparib (Lynparza), talazoparib (Talzenna) Poly- (adenosine Small molecule Breast cancer gene–mutated metastatic Hematologic, increased mean corpuscular CBC, renal function leading to downregulation of this diphosphate- inhibitors volume, pneumonitis, rare acute myeloge- potent growth modulator. Cetuximab ribose) polymerase nous leukemia and a similar anti-EGFR monoclonal Pertuzumab (Perjeta) HER2 Monoclonal Metastatic, neoadjuvant, and adjuvant Cardiotoxicity, diarrhea Echocardiography antibody, panitumumab (Vectibix), are antibody HER2+ effective in treating metastatic colorec- Chronic lymphocytic leukemia tal cancer without mutations in the Ibrutinib (Imbruvica) BTK Small molecule Chronic lymphocytic leukemia with 17p Atrial fibrillation, diarrhea, edema, Alkaline phosphatase, ALT, AST, CBC, RAS gene because RAS mutations make inhibitor deletion hemorrhage renal function, total bilirubin tumor cells resistant to the effects of Venetoclax (Venclexta) BCL2 Small molecule Chronic lymphocytic leukemia with 17p Severe pancytopenia, tumor lysis syndrome CBC, electrolytes, renal function; may 12 the EGFR blockade. Detailed testing inhibitor deletion require hospitalization for tumor lysis