Key Facts

Targeted therapies represent a paradigm shift from cytotoxic chemotherapy to precision oncology. They exploit specific molecular alterations in cancer cells, often identified through companion diagnostic testing.

Epidemiology

Targeted therapies are now used in over 50% of new cancer drug approvals. In the UK, NICE technology appraisals determine NHS availability. The Cancer Drugs Fund provides interim access to promising therapies awaiting full evaluation.

Aetiology

Major categories:

• Monoclonal antibodies (-mab): Trastuzumab, rituximab, bevacizumab, pembrolizumab
• Small molecule inhibitors (-ib): Imatinib, erlotinib, vemurafenib
• Immune checkpoint inhibitors: Anti-PD-1 (pembrolizumab, nivolumab), anti-PD-L1 (atezolizumab), anti-CTLA-4 (ipilimumab)
• CDK4/6 inhibitors: Palbociclib, ribociclib (HR+/HER2- breast cancer)
• PARP inhibitors: Olaparib (BRCA-mutated ovarian/breast cancer)

Pathophysiology

Cancer cells acquire hallmark capabilities through specific molecular alterations (oncogene addiction). Targeted therapies exploit this dependency:

• Tyrosine kinase pathway dysregulation
• Growth factor receptor overexpression
• Immune evasion mechanisms
• DNA repair deficiency

Indications (Selected)

• CML: Imatinib (BCR-ABL positive)
• HER2+ breast cancer: Trastuzumab ± pertuzumab
• NSCLC with EGFR mutation: Erlotinib, gefitinib, osimertinib
• Metastatic melanoma: BRAF/MEK inhibitors (BRAF V600E+), checkpoint inhibitors
• Renal cell carcinoma: Sunitinib, pazopanib, nivolumab+ipilimumab

Immune-Related Adverse Events (irAEs)

• Dermatological: Rash, pruritus, vitiligo (30-40%)
• GI: Diarrhoea, colitis (10-20%)
• Endocrine: Thyroiditis, hypophysitis, adrenal insufficiency, type 1 diabetes
• Hepatic: Hepatitis (5-10%)
• Pulmonary: Pneumonitis (1-5%) — potentially fatal
• Other: Myocarditis, nephritis, neurotoxicity

Red Flags

• New respiratory symptoms on checkpoint inhibitors → exclude pneumonitis
• Diarrhoea with checkpoint inhibitors → consider colitis (can perforate)
• Acute heart failure on trastuzumab → urgent echocardiography

Bedside

• Observations: During infusions — monitor for infusion reactions
• ECG: QT prolongation with some TKIs (e.g., vandetanib)

Bloods

• Baseline: FBC, U&Es, LFTs, TFTs, glucose, cortisol (for checkpoint inhibitors)
• Monitoring: TFTs every 4-6 weeks on checkpoint inhibitors
• Tumour markers: Where applicable (e.g., PSA, CA-125)

Imaging

• CT staging: RECIST criteria for response assessment
• Echocardiogram: Baseline and every 3 months with trastuzumab (LVEF monitoring)
• HRCT: If pneumonitis suspected

Special Tests

• Companion diagnostics: HER2 IHC/FISH, EGFR mutation testing, BRAF V600E, PD-L1 expression, BRCA testing, MSI/MMR status
• Liquid biopsy: Circulating tumour DNA for mutation detection
• NGS (next-generation sequencing): Comprehensive genomic profiling

Non-pharmacological

• Patient education on irAE recognition
• Steroid alert card for patients on checkpoint inhibitors
• Specialist nurse support

Pharmacological

Immune-related adverse events management:

• Grade 1: Continue treatment, monitor closely
• Grade 2: Hold immunotherapy, consider prednisolone 0.5-1mg/kg/day
• Grade 3: Hold immunotherapy, prednisolone 1-2mg/kg/day
• Grade 4: Permanently discontinue, IV methylprednisolone 1-2mg/kg/day, consider infliximab if steroid-refractory

Specific management:

• Trastuzumab cardiotoxicity: Hold if LVEF drops >10% or below 50%; usually reversible (unlike anthracyclines)
• EGFR inhibitor rash: Topical clindamycin, oral doxycycline 100mg OD prophylactically
• Hypertension with VEGF inhibitors: Amlodipine or ACE inhibitor

Referral Criteria

• All targeted therapy prescribing by specialist oncology teams
• MDT discussion for treatment selection and biomarker interpretation
• Urgent referral for suspected grade 3-4 irAEs

• CML with imatinib: 5-year survival >90% (previously <30% with chemotherapy alone)
• HER2+ breast cancer: Trastuzumab reduces recurrence by 50% in adjuvant setting
• Metastatic melanoma: Checkpoint inhibitors achieve 5-year survival of 35-40% (previously <10%)
• NSCLC with EGFR mutation: Median survival improved from 12 to 30+ months with TKIs
• Cardiotoxicity with trastuzumab: Usually reversible; permanent discontinuation needed in 5-10%

Key Targeted Therapies Summary

Landmark Trials