6.1 Targeted Therapies, Tyrosine Kinase Inhibitors & ADCs

4.1 Targeted Therapies, Tyrosine Kinase Inhibitors & ADCs

The evolution of systemic cancer therapy from non-specific cytotoxic chemotherapy to precision targeted oncology has transformed the management of solid tumors and hematologic malignancies. Targeted therapies exploit specific genetic alterations, overexpressed cell-surface antigens, or dysregulated intracellular signaling cascades driving oncogenesis. For the Advanced Oncology Certified Nurse Practitioner (AOCNP®), mastering the mechanisms of action, pharmacogenomic biomarker requirements, distinct class toxicity profiles, and evidence-based management algorithms for small molecule inhibitors, monoclonal antibodies, antibody-drug conjugates, and synthetic lethality agents is essential for clinical practice and board certification.

---

1. Small Molecule Tyrosine Kinase Inhibitors (TKIs) vs. Monoclonal Antibodies

Targeted anti-cancer agents are broadly categorized into small molecule inhibitors (typically designated by the suffix -inib) and monoclonal antibodies (designated by the suffix -mab). These drug classes differ fundamentally in molecular weight, mechanism of target engagement, route of administration, and intracellular access.

---

2. Key Tyrosine Kinase Inhibitors & Biomarker-Driven Therapy

Tyrosine kinase inhibitors bind to specific intracellular kinase catalytic sites, blocking downstream signal transduction pathways necessary for tumor cell proliferation, survival, and angiogenesis. Selection of TKI therapy mandates baseline pharmacogenomic testing using next-generation sequencing (NGS), polymerase chain reaction (PCR), or fluorescence in situ hybridization (FISH).

Major TKI Classes & Clinical Applications

• Epidermal Growth Factor Receptor (EGFR) Inhibitors: First-generation (erlotinib, gefitinib), second-generation (afatinib), and third-generation (osimertinib) TKIs target EGFR mutation-positive non-small cell lung cancer (NSCLC). Osimertinib selectively inhibits classical EGFR sensitizing mutations (exon 19 deletion, L858R) as well as the exon 20 T790M resistance mutation, and serves as the preferred first-line therapy due to superior central nervous system (CNS) penetration.
• Anaplastic Lymphoma Kinase (ALK) Inhibitors: Alectinib, brigatinib, and lorlatinib target ALK gene rearrangements (e.g., EML4-ALK fusion) in NSCLC. Lorlatinib demonstrates robust activity against acquired ALK resistance mutations (such as G1202R) and CNS metastases.
• BRAF / MEK Inhibitor Combinations: Dual inhibition of BRAF (dabrafenib, encorafenib) and MEK (trametinib, binimetinib) targets the MAPK/ERK pathway in BRAF V600E/K-mutant melanoma, NSCLC, and colorectal cancer. Combined BRAF/MEK inhibition significantly reduces the paradoxically induced cutaneous squamous cell carcinomas seen with single-agent BRAF monotherapy.
• BCR-ABL Kinase Inhibitors: Imatinib, dasatinib, nilotinib, and ponatinib target the BCR-ABL fusion protein resulting from the t(9;22) Philadelphia chromosome in chronic myeloid leukemia (CML). Ponatinib is uniquely effective against the recalcitrant T315I gatekeeper mutation.
• Vascular Endothelial Growth Factor Receptor (VEGFR) Multikinase Inhibitors: Cabozantinib, lenvatinib, sunitinib, and pazopanib inhibit VEGFR-1/2/3, platelet-derived growth factor receptors (PDGFR), and RET/MET, disrupting tumor angiogenesis in renal cell carcinoma (RCC), hepatocellular carcinoma, and thyroid cancer.

---

3. Antibody-Drug Conjugates (ADCs) & Synthetic Lethality

Architecture & Mechanism of ADCs

Antibody-Drug Conjugates (ADCs) represent an innovative targeted therapeutic modality designed to deliver highly potent cytotoxic payloads directly to tumor cells while minimizing off-target systemic toxicity. An ADC consists of three structural components:

1. Targeting Monoclonal Antibody: Binds selectively to a tumor-associated cell-surface antigen (e.g., HER2, TROP-2, Nectin-4, CD30, CD22).
2. Chemical Linker: A stable peptide or non-cleavable linker that prevents premature payload release in circulation but releases the payload upon intracellular internalization.
3. Cytotoxic Payload: Highly potent cell-killing agents—such as microtubule inhibitors (monomethyl auristatin E [MMAE]) or topoisomerase I inhibitors (deruxtecan [DXd], SN-38)—that are far too toxic for administration as free systemic chemotherapy.

Upon binding the target antigen, the ADC-antigen complex is internalized via receptor-mediated endocytosis into lysosomes, where lysosomal enzymes cleave the linker, releasing the payload. Payloads with high membrane permeability exert a bystander killing effect, diffusing into adjacent antigen-negative tumor cells within the tumor microenvironment.

Poly(ADP-Ribose) Polymerase (PARP) Inhibitors & Synthetic Lethality

PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib) exploit the concept of synthetic lethality in tumor cells possessing homologous recombination deficiency (HRD), particularly those harboring deleterious germline or somatic BRCA1 or BRCA2 mutations. PARP enzymes repair single-strand DNA breaks via base excision repair. Inhibiting PARP leads to the accumulation of unrepaired single-strand breaks, which collapse into double-strand DNA breaks during replication. Normal cells repair double-strand breaks via homologous recombination; however, BRCA-deficient cells lack functional homologous recombination and are forced to rely on error-prone non-homologous end joining (NHEJ), resulting in catastrophic genomic instability and cell death.

---

4. Evidence-Based Toxicity Management Algorithms

Advanced Practice Registered Nurses must recognize and manage distinct targeted therapy toxicity profiles to preserve quality of life and prevent fatal complications.

A. EGFR Inhibitor Cutaneous Toxicity Management

Inhibition of EGFR in epidermal keratinocytes leads to impaired follicular maturation, inflammation, and an acneiform papulopustular rash affecting scalp, face, chest, and upper back in > 80% of patients.

• Prophylaxis (Grade 0–1): Initiate preemptive treatment on Day 1 of EGFR TKI/mAb therapy: hydrocortisone 1% cream applied to face/chest BID, alcohol-free moisturizer, broad-spectrum SPF ≥ 30 sunscreen, and oral doxycycline 100 mg BID (or minocycline 100 mg daily) for 6 to 8 weeks.
• Grade 2 Rash (Moderate papulopustules, mild pruritus): Continue TKI; continue oral doxycycline/minocycline; add topical alclometasone 0.05% or triamcinolone 0.1% cream.
• Grade 3 Rash (Severe, confluent, ulcerating, superinfected): Hold EGFR TKI; administer oral doxycycline plus short-course oral prednisone (0.5 mg/kg/day for 7 days); obtain bacterial cultures; resume TKI at one reduced dose level upon improvement to ≤ Grade 1.

B. VEGF / VEGFR Cardiovascular Toxicities

VEGF pathway inhibition impairs endothelial cell maintenance, decreases nitric oxide production, and causes renal microvascular injury.

• Hypertension: Baseline BP screening mandatory. Initiate anti-hypertensive therapy (ACE inhibitors/ARBs or dihydropyridine calcium channel blockers like amlodipine) for BP ≥ 130/80 mmHg or increase of ≥ 20 mmHg diastolic. Avoid non-dihydropyridine CCBs (diltiazem, verapamil) due to CYP3A4 inhibition.
• Proteinuria & Bleeding: Dipstick urinalysis prior to each cycle; hold VEGF inhibitor for 24-hour urine protein ≥ 2 grams; permanently discontinue for nephrotic syndrome. Discontinue therapy 28 days prior to elective surgery to prevent surgical wound dehiscence.

C. ADC-Associated Interstitial Lung Disease (ILD) / Pneumonitis

ILD/pneumonitis is a potentially fatal class effect of topoisomerase-I payload ADCs (particularly Trastuzumab deruxtecan).

• Grade 1 (Asymptomatic, radiographic change only): Permanently interrupt T-DXd. Initiate systemic corticosteroids (prednisone 0.5–1 mg/kg/day) until resolution. Monitor CT scans closely. If fully resolved within 28 days, T-DXd may be resumed with cautious monitoring; otherwise, permanently discontinue.
• Grade 2 (Symptomatic: new/worsening cough, dyspnea, fever, hypoxia): Permanently discontinue ADC. Immediately initiate systemic corticosteroids (prednisone 1 mg/kg/day or equivalent). Taper steroids slowly over at least 4 weeks. Consult Pulmonology and perform high-resolution chest CT.
• Grade 3–4 (Severe respiratory compromise, supplemental O2 required): Permanently discontinue ADC. Hospitalize patient immediately; administer IV methylprednisolone 1–2 mg/kg/day. Consider empirical broad-spectrum coverage and ICU admission.