What is Sacituzumab govitecan (antibody-drug conjugate)?

Sacituzumab Govitecan: Mechanism and Clinical Application

Sacituzumab govitecan is an antibody-drug conjugate that targets Trop-2 (trophoblast cell-surface antigen 2) with a humanized monoclonal antibody connected to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan. 1

Molecular Structure and Mechanism

Drug Composition:

• Antibody component: Anti-Trop-2 monoclonal antibody (sacituzumab; hRS7) that binds to Trop-2, a membrane glycoprotein overexpressed on many epithelial tumors 2, 3
• Cytotoxic payload: SN-38, the active metabolite of irinotecan, which is an ultra-potent topoisomerase I inhibitor 1, 2
• Linker technology: Hydrolyzable CL2A linker that maintains stability during transport with pH-sensitive payload release specifically in the tumor microenvironment 2
• Drug-to-antibody ratio: Approximately 8:1, which is higher than many other antibody-drug conjugates 2, 3

Mechanism of Action:

• The antibody binds to Trop-2-expressing tumor cells and undergoes rapid internalization 2
• Once inside the acidic tumor environment, the pH-sensitive linker releases SN-38 2
• SN-38 induces DNA breakage and inhibits nucleic acid synthesis by forming a drug-induced topoisomerase 1:DNA complex that interferes with cell proliferation, causing apoptosis 2
• Bystander effect: Free SN-38 can exit the tumor cell and enter the tumor microenvironment to kill adjacent tumor cells regardless of whether they express Trop-2, amplifying the therapeutic effect 2, 3

FDA-Approved Indications

Triple-Negative Breast Cancer:

• Approved for metastatic triple-negative breast cancer in patients who have received two or more previous systemic therapies, with at least one therapy in the metastatic setting 1
• ASCO strongly recommends sacituzumab govitecan for patients with metastatic triple-negative breast cancer who have received at least two prior therapies for metastatic disease (high evidence quality, strong recommendation) 1

Hormone Receptor-Positive/HER2-Negative Breast Cancer:

• Approved for unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer in pretreated patients 2, 4

Urothelial Cancer:

• Received accelerated FDA approval for metastatic urothelial cancer 4, 3

Clinical Efficacy Data

ASCENT Trial Results (Metastatic Triple-Negative Breast Cancer):

• Enrolled 529 patients with metastatic triple-negative breast cancer who had received at least two prior lines of therapy 1
• Progression-free survival: 5.6 months with sacituzumab govitecan versus 1.7 months with standard chemotherapy (hazard ratio 0.41, P < 0.0001) 1
• Overall survival: 12.1 months versus 6.7 months with standard chemotherapy (hazard ratio 0.48, P < 0.0001) 1
• Objective response rate: 35% versus 5% with standard chemotherapy 5

Broader Tumor Activity:

• Demonstrated efficacy across multiple solid tumor types including endometrial cancer (22.2% ORR), small-cell lung cancer (17.7% ORR), and castrate-resistant prostate cancer (9.1% ORR) 6

Dosing and Administration

Standard Dosing Regimen:

• 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity 2, 7
• This dose was determined by therapeutic index improvement based on efficacy and safety in dose-finding studies 2
• No dose adjustments required for mild-to-moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, tumor type, UGT1A1 genotype, or Trop-2 expression 7

Toxicity Profile and Management

Most Common Severe Toxicities (Grade ≥3):

• Neutropenia: 51% (versus 33% with standard chemotherapy) 1
• Diarrhea: 10% (versus <1% with standard chemotherapy) 1
• Leukopenia: 10% (versus 5% with standard chemotherapy) 1
• Anemia: 8% (versus 5% with standard chemotherapy) 1
• Febrile neutropenia: 6% (versus 2% with standard chemotherapy) 1

Important Safety Considerations:

• Treatment discontinuation rate due to adverse events was low at 5% 1
• Neutropenia (all grades) was numerically more frequent in UGT1A1*28 homozygotes (60.9%) compared to heterozygotes (38.3%) or wild type (33.3%), though dose adjustment is not required 6
• Most adverse events are manageable with supportive care 3

Clinical Context and Positioning

Treatment Algorithm Placement:

• For metastatic triple-negative breast cancer, sacituzumab govitecan is positioned after at least two prior therapies for metastatic disease 1, 8
• The PFS and OS advantage in heavily pretreated patients with a reasonable toxicity profile makes sacituzumab govitecan appropriate in the third- or later-line setting 1
• In patients with both PD-L1-positive disease and BRCA1/2 mutations, the selection between immunotherapy or PARP inhibitor for first-line treatment versus sacituzumab govitecan for later lines remains an area of clinical judgment 1