Trodelvy - Drug Monograph

Introduction

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class antibody-drug conjugate (ADC) approved for the treatment of certain advanced solid tumors. It combines a humanized monoclonal antibody targeting Trop-2 (a cell surface antigen highly expressed in many epithelial cancers) with SN-38, the active metabolite of irinotecan. Trodelvy represents a significant advancement in targeted cancer therapy, offering a novel approach to delivering cytotoxic payloads directly to tumor cells.

Mechanism of Action

Trodelvy exerts its antitumor effects through a multi-step mechanism: 1. Target Binding: The antibody component binds to Trop-2 (trophoblast cell-surface antigen 2), which is overexpressed in many epithelial cancers 2. Internalization: The antibody-drug conjugate is internalized into the tumor cell via endocytosis 3. Payload Release: The linker is hydrolyzed by intracellular esterases, releasing SN-38 (7-ethyl-10-hydroxycamptothecin) 4. Cytotoxic Action: SN-38 inhibits topoisomerase I, preventing DNA re-ligation during replication, leading to double-strand DNA breaks and apoptosis 5. Bystander Effect: The hydrophilic linker allows some SN-38 to diffuse into neighboring cells, potentially killing Trop-2-negative tumor cells

Indications

FDA-approved indications:

• Metastatic triple-negative breast cancer (mTNBC) in adults who have received at least two prior therapies for metastatic disease
• Locally advanced or metastatic urothelial cancer in adults who previously received platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor
• HR-positive, HER2-negative breast cancer in adults who have received endocrine-based therapy and at least two additional systemic therapies for metastatic disease

Dosage and Administration

• Premedicate with antipyretic, H1 blocker, H2 blocker, and corticosteroid to minimize infusion reactions
• Administer as an IV infusion over 3 hours
• Continue treatment until disease progression or unacceptable toxicity

• Hematologic toxicity: Withhold or reduce dose based on severity
• Non-hematologic toxicity: Manage with dose delays, reductions, or discontinuation
• Hepatic impairment: Reduce dose for moderate to severe impairment (Child-Pugh B or C)
• Renal impairment: No dosage adjustment needed for mild to moderate impairment; use caution in severe impairment

Pharmacokinetics

• Steady-state volume of distribution: ~15 L
• Protein binding: SN-38 is highly bound to human plasma proteins (>95%)
• Limited penetration across blood-brain barrier

• SN-38 undergoes glucuronidation primarily via UGT1A1
• CYP450 enzymes play minimal role in metabolism

• Half-life: Terminal half-life of sacituzumab govitecan is ~16 hours
• SN-38 half-life: ~19 hours
• Excretion: Primarily hepatic (biliary/fecal); minimal renal excretion

Contraindications

• History of severe hypersensitivity reaction to sacituzumab govitecan-hziy or its components
• Severe neutropenia (absolute neutrophil count <500 cells/mm³) that persists despite dose delays
• Severe diarrhea that persists despite optimal supportive care

Warnings and Precautions

• Severe neutropenia: Monitor blood counts periodically during treatment
• Severe diarrhea: Monitor and manage with antidiarrheals and fluid replacement

• Hypersensitivity reactions: Including anaphylaxis; premedicate and monitor during infusion
• Nausea/vomiting: Use antiemetic prophylaxis
• Embryo-fetal toxicity: Can cause fetal harm; advise effective contraception
• UGT1A1 polymorphism: Patients with UGT1A1*28 allele are at increased risk of neutropenia
• Lactation: Advise not to breastfeed during treatment and for 1 month after last dose

Drug Interactions

• UGT1A1 inhibitors: May increase SN-38 exposure and toxicity risk
• Strong CYP3A4 inducers: May decrease SN-38 concentrations
• Other myelosuppressive agents: May exacerbate neutropenia
• Live vaccines: Avoid concurrent administration

Adverse Effects

• Neutropenia (61%), anemia (52%), diarrhea (62%), nausea (64%), fatigue (50%), vomiting (35%)
• Alopecia (44%), constipation (32%), rash (30%), decreased appetite (26%)

• Sepsis (2%)
• Severe neutropenia (37%)
• Severe diarrhea (9%)
• Anaphylaxis (<1%)
• Pneumonitis (<1%)

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel (including liver and renal function)
• Assessment of performance status

• Monitor for infusion reactions during and for 30 minutes post-infusion
• Weekly assessment of bowel function and diarrhea management
• Regular assessment for signs of infection
• Monitoring for nausea/vomiting and nutritional status

• ECG in patients with cardiac risk factors
• Pregnancy testing in women of reproductive potential

Patient Education

• Report fever, chills, or other signs of infection immediately
• Maintain adequate hydration, especially during episodes of diarrhea
• Use antidiarrheal medication as prescribed at first sign of loose stools
• Practice effective contraception during and for 6 months after treatment
• Notify healthcare provider of all medications, including over-the-counter products
• Expect hair loss during treatment
• Plan for fatigue management and energy conservation
• Keep all scheduled laboratory appointments for safety monitoring

References

1. Bardia A, et al. Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2019;380(8):741-751. 2. FDA prescribing information: TRODELVY® (sacituzumab govitecan-hziy). 2023. 3. Tagawa ST, et al. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol. 2021;39(22):2474-2485. 4. Rugo HS, et al. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022;40(29):3365-3376. 5. National Comprehensive Cancer Network (NCCN) Guidelines. Breast Cancer Version 4.2023. 6. Starodub AN, et al. First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors. Clin Cancer Res. 2015;21(17):3870-3878.