Generic Name

Trodelvy

Mechanism

• Targeted delivery: The antibody binds the Trop‑2 antigen, overexpressed in most basal‑like breast cancers and urothelial carcinomas, enabling selective tumor localization.
• Linker cleavage: The SMCC‑based linker is cleaved intracellularly by lysosomal enzymes, releasing the cytotoxic payload SN‑38.
• Anti‑proliferative effect: SN‑38 irreversibly inhibits DNA topoisomerase‑I, inducing double‑strand DNA breaks and consequent apoptosis.
• Bystander killing: Released SN‑38 diffuses into neighboring tumor cells, amplifying antitumor activity beyond Trop‑2‑positive cells.

Pharmacokinetics

• Administration: Intravenous infusion, 90 min over day 1 and day 8 of each 21‑day cycle.
• Half‑life: Approx. 20 h for the conjugate, 24 h for free SN‑38.
• Volume of distribution: ~4 L.
• Clearance: Linear, ~1.3 L day⁻¹.
• Metabolism: SN‑38 is metabolized primarily by UGT1A1 and CYP3A4; conjugate catabolized by proteolysis.
• Excretion: Renal (~25 %) and biliary (~45 %).
• Drug interactions: Concomitant CYP3A4/UGT1A1 inhibitors (e.g., ketoconazole) elevate SN‑38 exposure; inducers (rifampin) lower levels.

Indications

• Metastatic triple‑negative breast cancer (TNBC): Patients with at least one prior chemotherapy regimen for metastatic disease.
• Metastatic urothelial carcinoma (UC): Patients who have progressed on or after platinum‑based therapy or are not candidates for such therapy.

Contraindications

• Absolute contraindication: Known hypersensitivity to any component of the product.
• Caution:
• Severe active infection (≥ grade 3)
• Elevated bilirubin > 1.5 × ULN
• Pregnancy and lactation (data limited)
• Use of potent CYP3A4 or UGT1A1 inhibitors unless dose moderated.
• Warnings:
• Infusion reactions: Anaphylaxis, rash, pruritus
• Hematologic toxicity: Neutropenia, thrombocytopenia
• Mucocutaneous: Diarrhea, oral mucositis, alopecia
• Liver: Hepatotoxicity, elevated transaminases
• Nervous system: Peripheral neuropathy (rare).

Dosing

• Premedication: Diphenhydramine 25 mg IV + acetaminophen 500 mg orally or IV is recommended prior to the first infusion to mitigate hypersensitivity.
• Rescue: Infusion can be slowed to 120 min if mild reactions occur; severe reactions require discontinuation.

Adverse Effects

Common (≥ 10 %)
• Neutropenia
• Diarrhea (often severe, ≥ grade 1)
• Nausea & vomiting
• Decreased appetite
• Hand‑foot syndrome
• Alopecia
• Hypersensitivity (rash, urticaria)

Serious (≥ 1 %)
• Febrile neutropenia
• Severe/grade 4 neutropenia or thrombocytopenia
• Drug‑induced hypersensitivity/anaphylaxis
• Life‑threatening diarrhea (e.g., ileus, paralytic ileus)
• Hepatotoxicity (↑ AST/ALT > 5× ULN)
• Pericardial effusion (rare)

*Note*: Grade 3–4 toxicities frequently necessitate dose reduction, delay, or discontinuation.

Monitoring

• CBC with differential: Baseline, day 1, day 3, day 8, and pre‑cycle.
• CMP (liver, renal, electrolytes): Baseline, day 1 and every 3rd cycle.
• Infection surveillance: Check for fevers, chills; obtain cultures if febrile.
• Diarrhea assessment: Daily symptom diary; use standardized grading scales (CTCAE).
• Infusion monitoring: Watch for rash, pruritus, difficulty breathing; have epinephrine ready.
• Drug‑interaction screening: Review all concomitant meds for CYP3A4/UGT1A1 modulation.

Clinical Pearls

• Premedication is critical: A diphenhydramine/acetaminophen block minimizes first‑dose infusion reactions and improves tolerability.
• Use of prophylactic G‑CSF is not routine but may be considered for patients with prior febrile neutropenia or pre‑cycle ANC < 1.0 × 10⁹ cells/L.
• Diarrhea management: Early loperamide (2 mg every 2 h for the first dose) and oral rehydration salts prevent progression to grade ≥ 3; consider octreotide for refractory cases.
• Drug‑interaction alert: Avoid high‑dose rifampin, carbamazepine, or valproic acid unless essential; dose adjust if strong CYP3A4 inhibitors (ketoconazole, itraconazole) are prescribed.
• Trop‑2 expression: Although FDA approval is FDA‑label based, research suggests higher Trop‑2 expression correlates with improved response; consider tissue testing where feasible.
• Infusion schedule: The abbreviated 21‑day cycle (day 1 & 8) permits convenient outpatient administration and aligns with standard chemotherapy visits.
• Patient education: Emphasize signs of neutropenic fever, severe diarrhea, and rash; provide an emergency contact and prompt reporting guidelines.

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• Key Takeaway: Trodelvy harnesses targeted antibody‑drug conjugate technology to deliver SN‑38 directly to Trop‑2‑positive tumors, demonstrating significant efficacy in both metastatic TNBC and UC. Optimal outcomes hinge on vigilant monitoring, proactive infusion reaction prophylaxis, and early intervention for hematologic and GI toxicities.