Sacituzumab Govitecan (Trodelvy): Clinical Overview
Approved Indications
Sacituzumab govitecan is FDA-approved for metastatic triple-negative breast cancer (mTNBC) after at least two prior therapies for metastatic disease, with at least one therapy given in the metastatic setting. 1, 2, 3
- The drug also has FDA approval for unresectable locally advanced or metastatic HR+/HER2- breast cancer after endocrine-based therapy and ≥2 additional systemic therapies in the advanced setting 4
- For metastatic urothelial carcinoma, sacituzumab govitecan is being investigated but did not demonstrate survival advantage over chemotherapy in the TROPICS-04 trial for patients pretreated with platinum and checkpoint inhibitors 1
Dosing Schedule
Administer 10 mg/kg intravenously on Days 1 and 8 of each 21-day cycle, continuing until disease progression or unacceptable toxicity. 5, 2
- This dosing regimen was established through dose-finding studies that optimized the therapeutic index based on efficacy and safety 6
- Treatment responses occur early, with median onset at 1.9 months 7
Mechanism of Action
Sacituzumab govitecan is a Trop-2-directed antibody-drug conjugate linked to SN-38 (the active metabolite of irinotecan, a topoisomerase I inhibitor) via a hydrolyzable CL2A linker 1, 6
- The drug has an ~8:1 drug-to-antibody ratio and delivers SN-38 through rapid internalization into Trop-2-expressing tumor cells 6
- Free SN-38 exhibits a bystander effect, killing adjacent tumor cells regardless of Trop-2 expression 6
- Trop-2 is highly expressed in most triple-negative breast cancers (88% of archival specimens show moderate to strong positivity) 7
Efficacy Data
Triple-Negative Breast Cancer
The ASCENT trial demonstrated substantial survival benefits: median PFS of 5.6 months versus 1.7 months with chemotherapy (HR 0.41, P<0.0001) and median OS of 12.1 months versus 6.7 months (HR 0.48, P<0.0001). 1, 2
- Objective response rate was 35% versus 5% with standard chemotherapy 1
- These benefits were observed in 468 patients without brain metastases 2
- The clinical benefit rate (complete response + partial response + stable disease ≥6 months) was 46% in earlier phase I/II studies 7
HR+/HER2- Breast Cancer
The TROPiCS-02 trial showed statistically significant improvements in both PFS and OS compared with physician's choice chemotherapy in heavily pretreated HR+/HER2- metastatic breast cancer 4
Side Effects and Toxicity Profile
Most Common Grade ≥3 Adverse Events
Neutropenia is the most frequent severe toxicity, occurring in 51% of patients (versus 33% with standard chemotherapy). 1, 2
- Diarrhea: 10% (versus <1% with chemotherapy) 1, 2
- Leukopenia: 10% (versus 5%) 2
- Anemia: 8% (versus 5%) 2
- Febrile neutropenia: 6% (versus 2%) 2
- Fatigue: Common but specific grade ≥3 rates vary 4
Critical Safety Warnings
The drug carries a black box warning for patients homozygous for UGT1A1*28 genotype, who have increased risk of severe neutropenia and diarrhea. 1
- Treatment discontinuation due to adverse events was only 5%, indicating manageable toxicity despite high-grade events 1, 2
- Other common adverse reactions include nausea, alopecia (45-47%), peripheral neuropathy (34%), decreased appetite (31%), and skin rash (16%) 1, 8
Monitoring Requirements
Hematologic Monitoring
Monitor complete blood counts before each dose to assess for neutropenia, leukopenia, and anemia 2, 4
- Implement dose modifications for grade ≥3 neutropenia or febrile neutropenia 4
- Growth factor support may be necessary for neutropenia management 2
Gastrointestinal Monitoring
Closely monitor for diarrhea, which can be severe (grade ≥3 in 10% of patients) 1, 2
- Initiate aggressive antidiarrheal management at first sign of loose stools 4
- Consider UGT1A1*28 genotype testing before treatment initiation to identify high-risk patients 1
Other Monitoring
- Assess for peripheral neuropathy at each visit 1
- Monitor for skin reactions and alopecia 1
- Evaluate for signs of fatigue and decreased appetite 1, 4
Treatment Sequencing and Alternative Therapies
For mTNBC After First-Line Therapy
Sacituzumab govitecan is the preferred option after at least two prior therapies, particularly if patients have received anthracyclines, taxanes, carboplatin, and capecitabine in earlier settings. 1, 9
Alternative Options for mTNBC
- For germline BRCA1/2 mutations: PARP inhibitors (olaparib or talazoparib) are appropriate alternatives after prior chemotherapy, with median PFS of 7.0 months versus 4.2 months with chemotherapy (HR 0.58, P<0.001) 2, 9
- After sacituzumab progression: Standard chemotherapy options include eribulin, capecitabine, gemcitabine, or vinorelbine 1
- Eribulin specifically: May have enhanced efficacy in triple-negative subsets (OS 14.4 versus 9.4 months, HR 0.70) 1
First-Line mTNBC Treatment Context
- For PD-L1-positive disease: Immune checkpoint inhibitor plus chemotherapy is standard first-line (pembrolizumab plus chemotherapy improves median PFS from 5.6 to 9.7 months, HR 0.65) 9
- For PD-L1-negative disease: Single-agent chemotherapy with taxanes is preferred if not previously used 9
Clinical Positioning
ASCO issued a strong recommendation with high-quality evidence supporting sacituzumab govitecan in the third-line or later setting for mTNBC. 1, 2
- The PFS and OS advantages in heavily pretreated patients with reasonable toxicity profile make sacituzumab govitecan appropriate in third-line or later settings 1
- ESMO considers it the preferred treatment option after anthracyclines and taxanes, particularly when no theragnostic markers (like germline BRCA mutations) are available 1
- The drug received accelerated FDA approval in April 2020 for mTNBC, though it is not currently EMA-approved for this indication 1, 3