Targeted cancer therapies (tyrosine kinase inhibitors and monoclonal antibodies)
Targeted cancer therapies are small-molecule tyrosine kinase inhibitors and monoclonal antibodies (including antibody-drug conjugates) that block a specific driver such as BCR-ABL, EGFR, ALK, BRAF, HER2, VEGF, or CD20, and are given only after the target is confirmed on tumor testing. Their toxicities follow the target: acneiform rash and hypomagnesemia with EGFR blockade, hypertension, bleeding, perforation, and poor wound healing with VEGF blockade, reversible cardiomyopathy with trastuzumab, atrial fibrillation with ibrutinib, QT prolongation and hypothyroidism with many TKIs, and hepatitis B reactivation with rituximab, each with a defined screening and hold rule.
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What this article covers
- Overview
Definition: targeted therapies inhibit a particular molecular mutation or aberration identified by genomic profiling of tumor tissue or blood.
- Epidemiology
Transformative in CML: BCR-ABL TKIs have pushed 5-year overall survival above 90% and reduced the need for transplantation.
- Risk factors
Combination with an anthracycline: the strongest amplifier of trastuzumab cardiomyopathy.
- Pathophysiology
BCR-ABL TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib): block the constitutively active BCR-ABL kinase of the Philadelphia chromosome; imatinib is also adjuvant therapy for high-risk gastrointestinal stromal tumor.
- Clinical features
Cardiac: trastuzumab LV systolic dysfunction and heart failure; coronary insufficiency with nilotinib and ponatinib; pulmonary hypertension with dasatinib; atrial fibrillation with ibrutinib; QT…
- Differential diagnosis
Immune checkpoint inhibitor toxicity: autoimmune colitis, pneumonitis, hepatitis, hypophysitis, and adrenalitis that respond to glucocorticoids, rather than on-target kinase effects.
- Diagnosis
Establish the indication by confirming the target: histologic diagnosis and stage plus a positive predictive biomarker on an approved test are required before any targeted agent.
- Management
First, confirm the target and start the matched agent at its standard dose, continued until progression or unacceptable toxicity unless a fixed course is stated: Osimertinib 80 mg PO once daily for…
- Complications
Heart failure: from trastuzumab, sunitinib, and other multitargeted TKIs.
- Prognosis
Response depends on the target: anti-EGFR antibodies fail in RAS-mutant colorectal cancer, and BRAF inhibitors fail in BRAF wild-type tumors.
- Prevention
Cardiac surveillance: baseline echocardiography before trastuzumab, repeat at 3, 6, 9, and 12 months in high-risk patients (age over 60, two or more risk factors, LVEF 50% to 55%, prior myocardial…
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