Targeted Therapy: Precision Medicine in Oncology

How molecular targeted agents work and why genomic testing matters before starting treatment

Key Points

• Targeted therapies attack specific molecular alterations that drive cancer growth — genomic testing identifies who benefits.
• Next-generation sequencing (NGS) should be performed on all eligible patients with advanced solid tumors before starting treatment.
• Liquid biopsy (circulating tumor DNA) is increasingly used when tissue is insufficient or inaccessible.
• Most targeted therapies are oral medications — drug interactions (especially CYP3A4) and adherence are critical safety concerns.
• Resistance to targeted therapy is nearly universal over time; rebiopsy at progression can identify the mechanism and guide next-line therapy.
• FDA tumor-agnostic approvals (NTRK fusions, MSI-H, TMB-H, RET fusions, BRAF V600E) allow treatment regardless of primary tumor site.

What Is Targeted Therapy?

Traditional cytotoxic chemotherapy attacks all rapidly dividing cells — cancer cells and normal cells alike. Targeted therapy is fundamentally different: it is designed to interfere with specific molecular targets — proteins, enzymes, or signaling pathways — that are aberrantly activated in cancer cells but not (or much less so) in normal cells. This selectivity is the basis for the improved side effect profiles of many targeted agents compared to chemotherapy. Targeted therapy requires that the cancer cells actually express the molecular target — which is why biomarker testing is essential…

Key Oncogenic Drivers and Their Drugs

The landscape of molecularly targeted therapy has exploded over the past two decades. Key driver alterations and their approved therapies include: EGFR mutations (NSCLC): Exon 19 deletions and exon 21 L858R substitutions are the classic sensitizing mutations, present in ~15% of US NSCLC patients (higher in never-smokers and Asian populations). First/second-generation EGFR TKIs (erlotinib, gefitinib, afatinib) have been superseded by third-generation osimertinib (Tagrisso) as the preferred first-line agent — it covers classical mutations and the resistance mutation T790M, with superior CNS…

The Importance of Molecular Testing (NGS)

The era of one-size-fits-all oncology is over. For patients with advanced solid tumors, comprehensive molecular profiling using next-generation sequencing (NGS) is essential before selecting treatment. NGS panels analyze hundreds of cancer-relevant genes simultaneously from a tumor sample, identifying point mutations, insertions/deletions, copy number alterations, and structural rearrangements (fusions). Comprehensive genomic profiling platforms (FoundationOne CDx, Tempus xT, Caris Molecular Intelligence, MSK-IMPACT) also report PD-L1, TMB, and MSI status. Tissue biopsy remains the gold…

Common Side Effects by Drug Class

While targeted therapies are generally better tolerated than cytotoxic chemotherapy, each class has a characteristic side effect profile: EGFR inhibitors: Acneiform (papulopustular) rash in 70–80% of patients — paradoxically, rash severity correlates with efficacy. Paronychia (nail fold inflammation), diarrhea, dry skin/mucous membranes, mucositis, and rare but serious interstitial lung disease (ILD). HER2 agents: Trastuzumab and pertuzumab carry a risk of cardiotoxicity (left ventricular dysfunction) — baseline and periodic LVEF monitoring with echocardiography or MUGA scan is required.…

Drug Resistance

Acquired resistance to targeted therapy is almost universal with prolonged exposure — the average duration of response to first-generation TKIs in EGFR-mutant NSCLC was 10–13 months before progression. Understanding resistance mechanisms is essential for guiding subsequent therapy. Primary (intrinsic) resistance means the tumor never responds. Examples include EGFR exon 20 insertions (poorly responsive to 1st/2nd-gen TKIs), KRAS mutations coexisting with other drivers (generally predict poor immunotherapy response), and high baseline tumor heterogeneity. Acquired resistance develops after…

Oral Oncolytics: Adherence and Safety

Most targeted therapies are oral medications — a major convenience compared to IV chemotherapy, but one that brings unique safety and adherence challenges. Drug interactions: Many targeted therapies are metabolized by CYP3A4 and/or are P-glycoprotein (P-gp) substrates. Strong CYP3A4 inhibitors (azole antifungals, ritonavir, clarithromycin, grapefruit juice) can dramatically increase drug levels, causing toxicity. Strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine, St. John's Wort) can reduce levels, causing treatment failure. Every patient starting a targeted therapy should have a…