Targeted Therapy
Targeted therapy uses agents directed at specific molecular alterations driving cancer growth, including tyrosine kinase inhibitors, monoclonal antibodies, and PARP inhibitors, enabling personalised oncology.
Key Facts
Targeted therapy differs from chemotherapy by acting on specific molecular targets rather than all dividing cells Imatinib (Gleevec) was the first major targeted agent; inhibits BCR-ABL tyrosine kinase in CML (transformed survival from 30% to >90% at 5 years) Trastuzumab (Herceptin): anti-HER2 monoclonal antibody for HER2+ breast cancer (reduces recurrence by 50%); risk of cardiotoxicity (monitor LVEF) BRAF inhibitors (vemurafenib, dabrafenib) + MEK inhibitors (trametinib): for BRAF V600E mutant melanoma (60-70% response rate) EGFR TKIs (osimertinib, erlotinib, gefitinib): first-line for EGFR-mutant NSCLC; osimertinib preferred (FLAURA trial) ALK inhibitors (crizotinib, alectinib): for ALK-rearranged NSCLC; alectinib preferred (ALEX trial) PARP inhibitors (olaparib, niraparib, rucaparib): exploit synthetic lethality in BRCA-mutant and HRD-positive cancers (ovarian, breast, prostate, pancreatic) CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib): combined with endocrine therapy for HR+/HER2- breast cancer (PALOMA, MONARCH trials)
Overview
Key Facts
Targeted therapy represents a paradigm shift in oncology, enabling treatment directed at specific molecular abnormalities driving individual cancers. This approach underlies precision/personalised medicine.
Epidemiology
- Targeted agents now form part of standard treatment for the majority of common cancers
- Molecular profiling is increasingly performed at diagnosis to guide therapy selection
- Next-generation sequencing panels identify actionable mutations in 30-50% of advanced cancers
Aetiology
- Not applicable (treatment modality)
Pathophysiology
- Tyrosine kinase inhibitors (TKIs): small molecules that inhibit intracellular kinase domains (competitive or non-competitive ATP binding site inhibition)
- Monoclonal antibodies: bind extracellular targets (receptors, ligands); mechanisms include direct signalling blockade, ADCC (antibody-dependent cellular cytotoxicity), complement activation
- PARP inhibitors: block poly(ADP-ribose) polymerase, preventing single-strand break repair; in BRCA-deficient cells (impaired HRR), this leads to synthetic lethality
- CDK inhibitors: block cyclin-dependent kinases 4/6, preventing cell cycle progression from G1 to S phase
- Resistance mechanisms: secondary mutations (T790M in EGFR), bypass pathway activation, target amplification
Clinical Presentation
Key Indications
- CML: imatinib, dasatinib, nilotinib (BCR-ABL TKIs)
- HER2+ breast cancer: trastuzumab, pertuzumab, T-DXd (trastuzumab deruxtecan)
- EGFR-mutant NSCLC: osimertinib
- ALK-rearranged NSCLC: alectinib, lorlatinib
- BRAF-mutant melanoma: dabrafenib + trametinib
- BRCA-mutant cancers: olaparib (ovarian, breast, prostate, pancreatic)
- HR+/HER2- breast cancer: CDK4/6 inhibitors + endocrine therapy
- RCC: sunitinib, pazopanib, cabozantinib (VEGFR TKIs)
- GIST: imatinib (KIT/PDGFRA mutations)
Common Side Effects by Drug Class
- TKIs: diarrhoea, rash (acneiform with EGFR inhibitors), fatigue, hypertension (VEGFR inhibitors)
- Anti-HER2: cardiotoxicity (reduced LVEF), infusion reactions
- PARP inhibitors: myelosuppression (anaemia, thrombocytopenia), nausea, fatigue
- CDK4/6 inhibitors: neutropenia, diarrhoea (abemaciclib), QT prolongation (ribociclib)
- BRAF/MEK inhibitors: pyrexia, rash, photosensitivity, cutaneous SCC (BRAF alone)
Red Flags
- Cardiac symptoms with trastuzumab (dyspnoea, oedema): check LVEF
- Severe diarrhoea with TKIs (dehydration risk)
- Interstitial lung disease with EGFR TKIs (rare but fatal)
- Hepatotoxicity with any targeted agent (monitor LFTs)
- Secondary cutaneous malignancy with BRAF inhibitors (SCC/keratoacanthoma)
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Drug toxicity vs disease progression | Symptom timing, imaging | Repeat scans, drug level |
| Cardiotoxicity vs cardiac disease | Dyspnoea, oedema on targeted therapy | Echocardiogram, BNP |
| Drug-induced pneumonitis | Cough, dyspnoea on TKIs | HRCT, drug history |
| Secondary malignancy | New lesion in treated patient | Biopsy |
Diagnosis / Investigation
Bedside
- Observations, clinical assessment
- ECG (QT interval for ribociclib, sunitinib)
Bloods
- FBC (myelosuppression with PARP inhibitors, CDK inhibitors)
- LFTs (hepatotoxicity)
- TFTs (sunitinib causes hypothyroidism)
- BNP/NT-proBNP if cardiac symptoms
Imaging
- Echocardiogram: baseline and regular monitoring with trastuzumab (every 3 months)
- CT response assessment: typically every 2-3 months
Special Tests
- Molecular profiling (NGS panel): identify targetable mutations before treatment
- FISH/IHC: HER2 status in breast/gastric cancer
- PCR: BCR-ABL transcript monitoring in CML
- Liquid biopsy (ctDNA): monitor resistance mutations (e.g. EGFR T790M)
Management
Non-pharmacological
- Pre-treatment molecular profiling to confirm target
- Patient education about expected side effects
- Cardiac monitoring plan for cardiotoxic agents
- Fertility counselling where appropriate
Pharmacological
- Drug-specific management of side effects:
- EGFR rash: prophylactic doxycycline 100mg OD, topical steroids
- Trastuzumab cardiotoxicity: hold if LVEF drops >10 percentage points; consider ACE inhibitor/beta-blocker
- VEGFR TKI hypertension: amlodipine 5-10mg or ramipril 2.5-10mg
- PARP inhibitor anaemia: dose reduction, transfusion support
- Diarrhoea: loperamide 4mg stat then 2mg after each loose stool (max 16mg/day)
Surgical/Interventional
- Excision of BRAF inhibitor-related cutaneous SCCs
- Interventional procedures for toxicity management (stenting, drainage)
Referral Criteria
- All targeted therapy prescribed by oncologists within MDT
- Molecular tumour board for complex cases
- Cardio-oncology referral for cardiac toxicity
- Clinical trial consideration for patients with actionable mutations
Prognosis
- CML with imatinib: 5-year survival >90% (previously 30%); transformed to chronic manageable disease
- HER2+ breast cancer: trastuzumab reduces mortality by 30-35%
- EGFR-mutant NSCLC: median OS with osimertinib approximately 38 months (FLAURA trial)
- BRAF-mutant melanoma: median OS with combined BRAF/MEK inhibition approximately 25-33 months
- BRCA-mutant ovarian cancer with olaparib: 70% reduction in risk of progression (SOLO-1)
- Resistance inevitably develops in most metastatic settings; duration of response varies
Other Relevant Information
Key Targeted Therapy Agents and Indications
| Agent | Target | Cancer | Landmark Trial |
|---|---|---|---|
| Imatinib | BCR-ABL | CML, GIST | IRIS |
| Trastuzumab | HER2 | Breast, gastric | HERA |
| Osimertinib | EGFR | NSCLC | FLAURA |
| Alectinib | ALK | NSCLC | ALEX |
| Dabrafenib + trametinib | BRAF + MEK | Melanoma | COMBI-d |
| Olaparib | PARP | Ovarian, breast, prostate | SOLO-1 |
| Palbociclib | CDK4/6 | HR+ breast | PALOMA-2 |
| Bevacizumab | VEGF | CRC, ovarian, RCC | AVAiL |
Resistance Mechanisms
| Mechanism | Example |
|---|---|
| Secondary mutation | EGFR T790M (resistance to first-gen TKIs) |
| Bypass pathway | MET amplification in EGFR-mutant NSCLC |
| Target amplification | BCR-ABL amplification in CML |
| Histological transformation | NSCLC to SCLC under EGFR TKI pressure |