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 cancers^3–6 (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.

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