brand logo

Am Fam Physician. 2021;103(3):155-163

This clinical content conforms to AAFP criteria for CME.

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 cancers36 (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.

DrugsTargetDrug typeFDA-approved indicationToxicities, adverse effects, precautionsUnique monitoring
Acute myelogenous leukemia
Enasidenib (Idhifa), ivosidenib (Tibsovo)IDH1/2Small molecule inhibitorsNewly diagnosed and relapsed/refractory IDH1/2+ acute myelogenous leukemiaEdema, hepatotoxicity, prolonged QTcAlkaline phosphatase, ALT, AST, CBC, chemistry, CK, ECG, total bilirubin
Gilteritinib (Xospata), midostaurin (Rydapt)FLT3Small molecule inhibitorsNewly diagnosed and relapsed/refractory FLT3+ acute myelogenous leukemiaHepatotoxicity, prolonged QTc, rash, vomitingAlkaline phosphatase, ALT, AST, CBC, chemistry, ECG, total bilirubin
Anaplastic thyroid cancer
Dabrafenib (Tafinlar) plus trametinib (Mekinist)BRAF and MEKSmall molecule inhibitorsLocally advanced or metastatic with V600E mutationColitis, cutaneous squamous cell cancers, fever, heart failure, hepatotoxicity, hyperglycemia, rash, thrombosisAlkaline phosphatase, ALT, AST, blood glucose, ECG, electrolytes, renal function, skin examination, total bilirubin
Bladder cancer
Erdafitinib (Balversa)FGFR2/3Small molecule inhibitorMetastatic or locally advanced FGFR2/3 alterationsCentral serous retinopathy, hand-foot syndrome, hyperphosphatemia, oncholysisEye examination, phosphate
Breast cancer
Ado-trastuzumab emtansine (Kadcyla)HER2Antibody-drug conjugateEarly stage HER2+ with residual disease after neoadjuvant treatment; metastatic HER2+Cardiotoxicity, hepatotoxicity, interstitial lung disease, neuropathyAlkaline phosphatase, ALT, AST, CBC, ECG, total bilirubin
Alpelisib (Piqray)PIK3CASmall molecule inhibitorPIK3CA-mutated metastaticDermatologic (Stevens-Johnson syndrome), hyperglycemia, severe diarrheaA1C, blood glucose
Atezolizumab (Tecentriq)PD-L1ImmunotherapyPD-L1–positive metastatic triple negative breast cancer, in combination with chemotherapyColitis, endocrinopathies, hepatitis, myocarditis, pneumonitis, rashAlkaline phosphatase, ALT, AST, blood glucose, renal function, total bilirubin, TSH
Fam-trastuzumab deruxtecan (Enhertu)HER2Antibody-drug conjugateMetastatic HER2+Cardiotoxicity, hematologic, interstitial lung disease (9%)CBC, echocardiography
Olaparib (Lynparza), talazoparib (Talzenna)Poly- (adenosine diphosphate-ribose) polymeraseSmall molecule inhibitorsBreast cancer gene–mutated metastaticHematologic, increased mean corpuscular volume, pneumonitis, rare acute myelogenous leukemiaCBC, renal function
Pertuzumab (Perjeta)HER2Monoclonal antibodyMetastatic, neoadjuvant, and adjuvant HER2+Cardiotoxicity, diarrheaEchocardiography
Chronic lymphocytic leukemia
Ibrutinib (Imbruvica)BTKSmall molecule inhibitorChronic lymphocytic leukemia with 17p deletionAtrial fibrillation, diarrhea, edema, hemorrhageAlkaline phosphatase, ALT, AST, CBC, renal function, total bilirubin
Venetoclax (Venclexta)BCL2Small molecule inhibitorChronic lymphocytic leukemia with 17p deletionSevere pancytopenia, tumor lysis syndromeCBC, electrolytes, renal function; may require hospitalization for tumor lysis syndrome monitoring
Chronic myelogenous leukemia
Bosutinib (Bosulif), dasatinib (Sprycel), nilotinib (Tasigna), ponatinib (Iclusig)BCR-ABLSmall molecule inhibitorsInitial treatment: dasatinib, nilotinib, bosutinib; second-line treatment or T315I mutation: ponatinibArterial 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)EGFRMonoclonal antibodyMetastatic without mutation in RASAcneiform rash, hypomagnesemiaElectrolytes
Gastroesophageal cancer
Trastuzumab (Herceptin)HER2Monoclonal antibodyMetastatic with HER2 overexpressionCardiotoxicityEchocardiography
Gastrointestinal stromal tumor
Imatinib (Gleevec)c-KITSmall molecule inhibitorAdjuvant following complete resection of c-KIT positive gastrointestinal stromal tumorEdema, heart failure, hematologicAlkaline phosphatase, ALT, AST, CBC, electrolytes, renal function, total bilirubin
Lung cancer (adenocarcinoma)
Afatinib (Gilotrif), dacomitinib (Vizimpro), erlotinib (Tarceva), gefitinib (Iressa), osimertinib (Tagrisso)EGFRSmall molecule inhibitorsMetastatic, EGFR exon 19 deletion or exon 21 (L858R) substitutionDiarrhea, hepatotoxicity, prolonged QTc, rash, trichiasisAlkaline phosphatase, ALT, AST, ECG, electrolytes, renal function, total bilirubin
Alectinib (Alecensa), brigatinib (Alunbrig), ceritinib (Zykadia), crizotinib (Xalkori), lorlatinib (Lorbrena)Anaplastic lymphoma kinaseSmall molecule inhibitorsMetastatic, anaplastic lymphoma kinase fusionBradycardia, hepatotoxicity, nausea, ocular toxicity, QT prolongation, vomitingAlkaline phosphatase, ALT, AST, CBC, renal function, total bilirubin
Crizotinib, entrectinib (Rozlytrek)ROS1Small molecule inhibitorsMetastatic, ROS1 positiveEntrectinib: cardiotoxicity, cognitive impairment, fractures, hepatotoxicity, ocular toxicityAlkaline phosphatase, ALT, AST, ECG, echocardiography, electrolytes, total bilirubin
DabrafenibBRAFSmall molecule inhibitorMetastatic, BRAF V600E mutationCutaneous squamous cell cancer, colitis, fever, heart failure, hepatotoxicity, hyperglycemia, rash, thrombosisAlkaline phosphatase, ALT, AST, blood glucose, echocardiography, skin examination, total bilirubin
Melanoma
Binimetinib (Mektovi), cobimetinib (Cotellic), dabrafenib, encorafenib (Braftovi), trametinib, vemurafenib (Zelboraf)BRAF + MEKSmall molecule inhibitorsMetastatic, 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-4ImmunotherapiesMetastatic mismatch repair deficient solid tumorAdrenal insufficiency, colitis, myocarditis (rare but morbid), pneumonitis, rash, thyroiditisAlkaline phosphatase, ALT, AST, blood glucose, renal function, total bilirubin, TSH
Neurotrophin receptor kinase fusion solid tumors
Entrectinib, larotrectinib (Vitrakvi)Neurotrophin receptor kinaseSmall molecule inhibitorsMetastatic solid tumors with neurotrophin receptor kinase fusion proteinCardiotoxicity, cognitive impairment, fractures, hepatotoxicity, ocular toxicityAlkaline phosphatase, ALT, AST, ECG, echocardiography, total bilirubin
Ovarian
Niraparib (Zejula), olaparib, rucaparib (Rubraca)Poly- (adenosine diphosphate-ribose) polymeraseSmall molecule inhibitorsAdvanced or metastatic ovarian cancer with breast cancer gene mutationMyelodysplastic syndrome, pancytopeniaCBC

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

Already a member/subscriber?  Log In

Subscribe

From $145
  • Immediate, unlimited access to all AFP content
  • More than 130 CME credits/year
  • AAFP app access
  • Print delivery available
Subscribe

Issue Access

$59.95
  • Immediate, unlimited access to this issue's content
  • CME credits
  • AAFP app access
  • Print delivery available

Article Only

$25.95
  • Immediate, unlimited access to just this article
  • CME credits
  • AAFP app access
  • Print delivery available
Purchase Access:  Learn More

Continue Reading

More in AFP

More in Pubmed

Copyright © 2021 by the American Academy of Family Physicians.

This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP.  See permissions for copyright questions and/or permission requests.