
Am Fam Physician. 2021;103(3):155-163
Author disclosure: No relevant financial affiliations.
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 conjugates, 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 common. 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 therapies is offered here.
Targeted cancer therapy involves testing various types of cancer for genetic biomarkers that can predict the response to chemotherapeutic agents that attack the biomarkers directly or indirectly.1,2 In the past decade, the U.S. Food and Drug Administration (FDA) has approved approximately 40 new targeted therapies for 12 different cancers3–6 (Table 1). Despite this innovation, the percentage 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 for targeted therapy.7 The number of patients who benefit from these drugs is even smaller and ranges widely, depending on the tumor and drug. Targeted oncology has mainly shown benefit in the metastatic (incurable) setting, with rare success for patients treated with surgery in the local or regional setting.
WHAT'S NEW ON THIS TOPIC
Targeted Cancer Therapies
In the past decade, the U.S. Food and Drug Administration has approved approximately 40 new targeted therapies for 12 different cancers.
Patients with metastatic epidermal growth factor receptor–mutated lung cancer who are treated with osimertinib (Tagrisso) live a median of 39 months, more than double the survival of similar patients who were treated with the first epidermal growth factor receptor inhibitor, erlotinib (Tarceva), between 2007 and 2011.
In 2020, the average patient out-of-pocket cost for a course of oral cancer therapy was $5,663. According to one large analysis, 20% of patients with cancer take less medication than prescribed, 19% only partially fill oral cancer therapy prescriptions, and 24% avoid filling a prescription at all.

Drugs | Target | Drug type | FDA-approved indication | Toxicities, adverse effects, precautions | Unique monitoring |
---|---|---|---|---|---|
Acute myelogenous leukemia | |||||
Enasidenib (Idhifa), ivosidenib (Tibsovo) | IDH1/2 | Small molecule inhibitors | Newly diagnosed and relapsed/refractory IDH1/2+ acute myelogenous leukemia | Edema, hepatotoxicity, prolonged QTc | Alkaline phosphatase, ALT, AST, CBC, chemistry, CK, ECG, total bilirubin |
Gilteritinib (Xospata), midostaurin (Rydapt) | FLT3 | Small molecule inhibitors | Newly diagnosed and relapsed/refractory FLT3+ acute myelogenous leukemia | Hepatotoxicity, prolonged QTc, rash, vomiting | Alkaline phosphatase, ALT, AST, CBC, chemistry, ECG, total bilirubin |
Anaplastic thyroid cancer | |||||
Dabrafenib (Tafinlar) plus trametinib (Mekinist) | BRAF and MEK | Small molecule inhibitors | Locally advanced or metastatic with V600E mutation | Colitis, cutaneous squamous cell cancers, fever, heart failure, hepatotoxicity, hyperglycemia, rash, thrombosis | Alkaline phosphatase, ALT, AST, blood glucose, ECG, electrolytes, renal function, skin examination, total bilirubin |
Bladder cancer | |||||
Erdafitinib (Balversa) | FGFR2/3 | Small molecule inhibitor | Metastatic or locally advanced FGFR2/3 alterations | Central serous retinopathy, hand-foot syndrome, hyperphosphatemia, oncholysis | Eye examination, phosphate |
Breast cancer | |||||
Ado-trastuzumab emtansine (Kadcyla) | HER2 | Antibody-drug conjugate | Early stage HER2+ with residual disease after neoadjuvant treatment; metastatic HER2+ | Cardiotoxicity, hepatotoxicity, interstitial lung disease, neuropathy | Alkaline phosphatase, ALT, AST, CBC, ECG, total bilirubin |
Alpelisib (Piqray) | PIK3CA | Small molecule inhibitor | PIK3CA-mutated metastatic | Dermatologic (Stevens-Johnson syndrome), hyperglycemia, severe diarrhea | A1C, blood glucose |
Atezolizumab (Tecentriq) | PD-L1 | Immunotherapy | PD-L1–positive metastatic triple negative breast cancer, in combination with chemotherapy | Colitis, endocrinopathies, hepatitis, myocarditis, pneumonitis, rash | Alkaline phosphatase, ALT, AST, blood glucose, renal function, total bilirubin, TSH |
Fam-trastuzumab deruxtecan (Enhertu) | HER2 | Antibody-drug conjugate | Metastatic HER2+ | Cardiotoxicity, hematologic, interstitial lung disease (9%) | CBC, echocardiography |
Olaparib (Lynparza), talazoparib (Talzenna) | Poly- (adenosine diphosphate-ribose) polymerase | Small molecule inhibitors | Breast cancer gene–mutated metastatic | Hematologic, increased mean corpuscular volume, pneumonitis, rare acute myelogenous leukemia | CBC, renal function |
Pertuzumab (Perjeta) | HER2 | Monoclonal antibody | Metastatic, neoadjuvant, and adjuvant HER2+ | Cardiotoxicity, diarrhea | Echocardiography |
Chronic lymphocytic leukemia | |||||
Ibrutinib (Imbruvica) | BTK | Small molecule inhibitor | Chronic lymphocytic leukemia with 17p deletion | Atrial fibrillation, diarrhea, edema, hemorrhage | Alkaline phosphatase, ALT, AST, CBC, renal function, total bilirubin |
Venetoclax (Venclexta) | BCL2 | Small molecule inhibitor | Chronic lymphocytic leukemia with 17p deletion | Severe pancytopenia, tumor lysis syndrome | CBC, electrolytes, renal function; may require hospitalization for tumor lysis syndrome monitoring |
Chronic myelogenous leukemia | |||||
Bosutinib (Bosulif), dasatinib (Sprycel), nilotinib (Tasigna), ponatinib (Iclusig) | BCR-ABL | Small molecule inhibitors | Initial treatment: dasatinib, nilotinib, bosutinib; second-line treatment or T315I mutation: ponatinib | Arterial thrombotic events (ponatinib), diarrhea (bosutinib), edema, effusions (dasatinib), heart failure (all), hematologic, pancreatitis, prolonged QTc (nilotinib) | Alkaline phosphatase, ALT, AST, blood pressure, CBC, chemistry, ECG, glucose, lipid profile, total bilirubin; provide low-dose aspirin with ponatinib |
Colorectal cancer | |||||
Cetuximab (Erbitux) | EGFR | Monoclonal antibody | Metastatic without mutation in RAS | Acneiform rash, hypomagnesemia | Electrolytes |
Gastroesophageal cancer | |||||
Trastuzumab (Herceptin) | HER2 | Monoclonal antibody | Metastatic with HER2 overexpression | Cardiotoxicity | Echocardiography |
Gastrointestinal stromal tumor | |||||
Imatinib (Gleevec) | c-KIT | Small molecule inhibitor | Adjuvant following complete resection of c-KIT positive gastrointestinal stromal tumor | Edema, heart failure, hematologic | Alkaline phosphatase, ALT, AST, CBC, electrolytes, renal function, total bilirubin |
Lung cancer (adenocarcinoma) | |||||
Afatinib (Gilotrif), dacomitinib (Vizimpro), erlotinib (Tarceva), gefitinib (Iressa), osimertinib (Tagrisso) | EGFR | Small molecule inhibitors | Metastatic, EGFR exon 19 deletion or exon 21 (L858R) substitution | Diarrhea, hepatotoxicity, prolonged QTc, rash, trichiasis | Alkaline phosphatase, ALT, AST, ECG, electrolytes, renal function, total bilirubin |
Alectinib (Alecensa), brigatinib (Alunbrig), ceritinib (Zykadia), crizotinib (Xalkori), lorlatinib (Lorbrena) | Anaplastic lymphoma kinase | Small molecule inhibitors | Metastatic, anaplastic lymphoma kinase fusion | Bradycardia, hepatotoxicity, nausea, ocular toxicity, QT prolongation, vomiting | Alkaline phosphatase, ALT, AST, CBC, renal function, total bilirubin |
Crizotinib, entrectinib (Rozlytrek) | ROS1 | Small molecule inhibitors | Metastatic, ROS1 positive | Entrectinib: cardiotoxicity, cognitive impairment, fractures, hepatotoxicity, ocular toxicity | Alkaline phosphatase, ALT, AST, ECG, echocardiography, electrolytes, total bilirubin |
Dabrafenib | BRAF | Small molecule inhibitor | Metastatic, BRAF V600E mutation | Cutaneous squamous cell cancer, colitis, fever, heart failure, hepatotoxicity, hyperglycemia, rash, thrombosis | Alkaline phosphatase, ALT, AST, blood glucose, echocardiography, skin examination, total bilirubin |
Melanoma | |||||
Binimetinib (Mektovi), cobimetinib (Cotellic), dabrafenib, encorafenib (Braftovi), trametinib, vemurafenib (Zelboraf) | BRAF + MEK | Small molecule inhibitors | Metastatic, V600E, V600K mutation (all) Adjuvant (dabrafenib + trametinib) | BRAF inhibitors: alopecia, arthralgia, diarrhea, fatigue, nausea, rash MEK inhibitors: diarrhea, rash, retinopathy | Alkaline phosphatase, ALT, AST, blood glucose, echocardiography, skin examination, total bilirubin |
Mismatch repair deficient solid tumors | |||||
Ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) | PD-1 or CTLA-4 | Immunotherapies | Metastatic mismatch repair deficient solid tumor | Adrenal insufficiency, colitis, myocarditis (rare but morbid), pneumonitis, rash, thyroiditis | Alkaline phosphatase, ALT, AST, blood glucose, renal function, total bilirubin, TSH |
Neurotrophin receptor kinase fusion solid tumors | |||||
Entrectinib, larotrectinib (Vitrakvi) | Neurotrophin receptor kinase | Small molecule inhibitors | Metastatic solid tumors with neurotrophin receptor kinase fusion protein | Cardiotoxicity, cognitive impairment, fractures, hepatotoxicity, ocular toxicity | Alkaline phosphatase, ALT, AST, ECG, echocardiography, total bilirubin |
Ovarian | |||||
Niraparib (Zejula), olaparib, rucaparib (Rubraca) | Poly- (adenosine diphosphate-ribose) polymerase | Small molecule inhibitors | Advanced or metastatic ovarian cancer with breast cancer gene mutation | Myelodysplastic syndrome, pancytopenia | CBC |
Types of Targeted Therapy
Targeted therapies can be divided into four general categories: monoclonal antibodies, small molecule inhibitors, antibody-drug conjugates, and immunotherapy (Figure 1). In general, small molecule inhibitors are oral, whereas the remaining therapies are given intravenously.

MONOCLONAL ANTIBODIES
Monoclonal antibodies are identical immunoglobulins that bind a specific antigen. Targeted oncology monoclonal antibodies are most commonly used to target an antigen on a cancer cell, leading to downregulation of oncogene signaling, or to flag tumor cells for destruction by the immune system.8 The anti–human epidermal growth factor receptor 2 (HER2) monoclonal antibodies trastuzumab (Herceptin) and pertuzumab (Perjeta) have drastically improved outcomes for HER2-positive breast cancer, which accounts for 15% to 25% of patients with breast cancer.9 All patients with breast cancer should undergo testing for HER2 overexpression.10 Trastuzumab binds to HER2 on tumor cells, leading to internalization and down-regulation of HER2, which is a progrowth stimulator. Trastuzumab is not as effective in treating advanced gastroesophageal cancer with HER2 overexpression, offering only a 12% overall response rate.11 Cetuximab (Erbitux) is another monoclonal antibody used as targeted therapy; it binds to the epidermal growth factor receptor (EGFR), leading to downregulation of this potent growth modulator. Cetuximab and a similar anti-EGFR monoclonal antibody, panitumumab (Vectibix), are effective in treating metastatic colorectal cancer without mutations in the RAS gene because RAS mutations make tumor cells resistant to the effects of the EGFR blockade.12 Detailed testing for RAS mutations is necessary before choosing a chemotherapy regimen for metastatic colorectal cancer.
SMALL MOLECULE INHIBITORS
Small molecule inhibitors impede a vast number of targets to slow or kill tumor cells. The majority target protein kinases that are highly active progrowth signaling initiators present in all cells and are exploited by many cancers. Examples of protein kinases targeted by small molecule inhibitors include the EGFR, anaplastic lymphoma kinase, and HER2. These protein kinases are also expressed across healthy tissues, so small molecule inhibitors also have systemic effects.
Many small molecule inhibitors, such as sunitinib (Sutent), are not considered targeted therapy. This drug targets multiple, wild-type intracellular kinases and does not require testing for mutations in the tyrosine kinases that it targets (e.g., vascular endothelial growth factors).13 Alternatively, osimertinib (Tagrisso) is used only in advanced non–small cell lung cancer that contains an activating mutation in the EGFR.14
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