Targeted Therapy: A Precision Medicine Guide

How Targeted Therapy Differs from Chemotherapy

Traditional chemotherapy works by killing any rapidly dividing cell in the body. While effective against cancer, this approach also damages healthy cells in the bone marrow, digestive tract, and hair follicles, causing familiar side effects like nausea, hair loss, and immune suppression. Targeted therapy takes a fundamentally different approach by identifying and attacking specific molecular abnormalities that drive cancer growth.

Cancer cells grow because of specific genetic mutations or protein abnormalities that send constant “grow and divide” signals. Targeted drugs are designed to block these specific signals. Because targeted drugs are selective for cancer-driving abnormalities, they generally cause different (and often less severe) side effects than chemotherapy, though they are not without risks.

The effectiveness of targeted therapy depends on whether a patient's tumor harbors the specific molecular target. This is why molecular testing is essential before starting treatment — a drug targeting EGFR mutations will not help a patient whose tumor lacks EGFR mutations.

Molecular Testing and Companion Diagnostics

Before starting targeted therapy, your oncologist will order molecular testing (also called biomarker testing or genomic profiling) on your tumor tissue or blood. This testing identifies the specific genetic mutations or protein abnormalities driving your cancer.

Types of Molecular Tests

• Next-Generation Sequencing (NGS): Analyzes hundreds of genes simultaneously from a tumor sample. Comprehensive genomic profiling panels (such as FoundationOne CDx or Tempus xT) can identify mutations, fusions, amplifications, and other alterations across all major targetable genes in a single test
• Fluorescence In Situ Hybridization (FISH): Detects specific gene rearrangements and amplifications using fluorescent probes. Commonly used to confirm ALK and ROS1 fusions in lung cancer and HER2 amplification in breast cancer
• Immunohistochemistry (IHC): Measures protein expression on tumor cells using antibody staining. Used for HER2, PD-L1, estrogen/progesterone receptors, and ALK protein expression
• Liquid Biopsy: Analyzes circulating tumor DNA (ctDNA) in a blood sample. Useful when tumor tissue is insufficient or unavailable, and for monitoring treatment response and detecting resistance mutations over time

Companion Diagnostics

A companion diagnostic is an FDA-approved test specifically paired with a targeted drug. The test must confirm the presence of the drug's target before the drug can be prescribed. For example, the Vysis ALK Break Apart FISH Probe Kit is a companion diagnostic for crizotinib in ALK-positive lung cancer. Using the right companion diagnostic ensures patients receive drugs matched to their tumor biology.

Major Molecular Targets and Drug Classes

EGFR (Epidermal Growth Factor Receptor)

EGFR mutations are found in 10–15% of non-small cell lung cancers overall and up to 50% in never-smokers of Asian descent. EGFR tyrosine kinase inhibitors (TKIs) block the overactive EGFR signaling. Osimertinib (Tagrisso), a third-generation EGFR TKI, is the current first-line standard due to its superior efficacy, central nervous system penetration, and activity against the T790M resistance mutation. Earlier-generation drugs include erlotinib, gefitinib, and afatinib.

ALK (Anaplastic Lymphoma Kinase)

ALK gene fusions occur in approximately 5% of non-small cell lung cancers, typically in younger patients and non-smokers. Alectinib (Alecensa) is the preferred first-line ALK inhibitor, offering strong efficacy and brain penetration. Lorlatinib is used for ALK-positive disease that has progressed on earlier ALK inhibitors.

HER2 (Human Epidermal Growth Factor Receptor 2)

HER2 overexpression or amplification drives approximately 15–20% of breast cancers and a smaller percentage of gastric and other cancers. Trastuzumab (Herceptin) was the landmark HER2-targeted drug. The antibody-drug conjugate trastuzumab deruxtecan (Enhertu) has shown remarkable activity in HER2-positive and HER2-low breast cancer, lung cancer, and gastric cancer.

BRAF

BRAF V600E mutations are found in approximately 50% of melanomas and smaller percentages of lung, colorectal, and thyroid cancers. BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) are combined with MEK inhibitors (trametinib, cobimetinib, binimetinib) for improved efficacy, as single-agent BRAF inhibition leads to rapid resistance through MEK pathway reactivation.

KRAS G12C

KRAS mutations are the most common oncogenic driver in solid tumors, but were long considered “undruggable.” The development of sotorasib (Lumakras) and adagrasib (Krazati) specifically targeting the G12C mutation was a breakthrough. KRAS G12C occurs in approximately 13% of non-small cell lung cancers and 3–4% of colorectal cancers.

NTRK Fusions

NTRK gene fusions are rare but occur across many cancer types. Larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) have tissue-agnostic approvals for any NTRK fusion-positive solid tumor, producing high response rates regardless of where the cancer originated.

RET Fusions and Mutations

RET alterations are found in lung cancer, thyroid cancer, and other tumor types. Selpercatinib (Retevmo) and pralsetinib (Gavreto) are selective RET inhibitors with high response rates and manageable side effects.

MET Alterations

MET exon 14 skipping mutations and MET amplification drive a subset of lung cancers. Capmatinib (Tabrecta) and tepotinib (Tepmetko) are approved for MET exon 14 skipping mutations in non-small cell lung cancer.

Major Drug Classes in Detail

Tyrosine Kinase Inhibitors (TKIs)

TKIs are small-molecule drugs that block the activity of specific tyrosine kinases — enzymes that act as “on switches” for cell growth. Most TKIs are taken as daily oral pills. They are the largest category of targeted therapies, with drugs targeting EGFR, ALK, BRAF, MEK, RET, NTRK, MET, and many other kinases. Common side effects include skin rash, diarrhea, fatigue, and liver enzyme elevations.

Monoclonal Antibodies

Monoclonal antibodies are laboratory-made proteins designed to bind specific targets on cancer cells. They work through several mechanisms: blocking growth signals (trastuzumab blocks HER2), flagging cancer cells for immune destruction (rituximab marks CD20 on lymphoma cells), or blocking blood vessel growth (bevacizumab blocks VEGF). Most are given as intravenous infusions.

Antibody-Drug Conjugates (ADCs)

ADCs combine a monoclonal antibody with a potent chemotherapy payload connected by a chemical linker. The antibody directs the drug to cancer cells expressing the target protein, where the payload is released inside the cell to kill it. Trastuzumab deruxtecan (Enhertu) has been transformative in HER2-positive and HER2-low breast cancer. Other important ADCs include enfortumab vedotin (Padcev) for bladder cancer and sacituzumab govitecan (Trodelvy) for triple-negative breast cancer.

PARP Inhibitors

PARP inhibitors block the poly (ADP-ribose) polymerase enzyme, which cancer cells with BRCA1/2 mutations need for DNA repair. By blocking PARP in tumors that already have defective DNA repair, these drugs cause lethal DNA damage through a concept called synthetic lethality. Olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca) are approved for ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer with BRCA mutations or homologous recombination deficiency.

CDK4/6 Inhibitors

CDK4/6 inhibitors block cyclin-dependent kinases 4 and 6, which cancer cells need to progress through the cell cycle. Palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) are standard treatment for hormone receptor-positive, HER2-negative metastatic breast cancer in combination with hormone therapy. Ribociclib has demonstrated overall survival benefits and is increasingly used in earlier-stage disease.

Drug Resistance and Overcoming It

One of the central challenges of targeted therapy is drug resistance. Most patients who initially respond to a targeted drug will eventually develop resistance, typically within 9–18 months. Resistance occurs through several mechanisms:

• On-target resistance: New mutations in the target gene prevent the drug from binding (e.g., EGFR T790M mutation developing during first-generation EGFR TKI treatment)
• Bypass pathway activation: The cancer activates alternative signaling pathways to circumvent the blocked target (e.g., MET amplification bypassing EGFR inhibition)
• Histologic transformation: The cancer changes cell type (e.g., EGFR-mutant adenocarcinoma transforming to small cell lung cancer)
• Downstream mutations: Mutations in proteins downstream of the target reactivate the growth signal despite target blockade

Strategies to combat resistance include sequential therapy with next-generation drugs (osimertinib after first-generation EGFR TKIs), combination therapy targeting multiple pathways simultaneously, and repeat molecular testing at progression to identify the resistance mechanism and guide the next treatment.

Last reviewed: March 2026. This information is for educational purposes only and is not a substitute for professional medical advice. Always consult your oncologist about your specific treatment plan.