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 |