Navigating Triple-Negative Breast Cancer Treatment With Sacituzumab Govitecan

Triple-negative breast cancer (TNBC) is an aggressive subtype that accounts for approximately 15% of all instances of breast cancer in the United States and has limited therapeutic options. However, the introduction of immunotherapies and targeted agents such as antibody drug conjugates (ADC) has significantly improved patient outcomes and quality of life, increasing the 10-year disease-free survival rate in approximately 90% of patients.¹

3D illustration of TNBC cell | Image Credit: © LASZLO - stock.adobe.com

Sacituzumab govitecan-hziy (SG, Trodelvy; Gilead Sciences) is a Trop-2-targeting ADC that has yielded significant improvements in progression-free survival (PFS) and overall survival (OS) in patients with TNBC. Its unique design allows the agent to be precisely delivered to BC cells without endangering surrounding healthy tissues. However, similar to many other agents, SG is associated with various adverse events (AEs), leading to a need for AE management through dose modification.²

Clinical pharmacists play a critical role in optimizing SG therapy by monitoring for adverse events, guiding dose adjustments, and providing supportive care strategies to enhance patient adherence and outcomes. Their expertise in toxicity management, patient education, and interdisciplinary collaboration ensures that patients receive the maximum benefit from treatment while minimizing complications.

What is TNBC?

Due to the early discovery of HER2 positivity (HER2+) and estrogen receptor positivity (ER+), this subtype of BC has been largely misinterpreted. Therapy options for TNBC are limited to cytotoxic chemotherapy, which remains the standard of care for early-stage TNBC. This is due to the lack of targets for numerous hormonal and HER2-targeted therapies.¹

“[TNBC] really has been a diagnosis of exclusion,” Rebecca Dent, MD, deputy chief executive officer of the National Cancer Center Singapore, Singapore, explained at the 2024 San Antonio Breast Cancer Symposium in San Antonio. “So, it was really in the ’60s that we finally realized we have [ER+] breast cancer. And then it took into the ’90s to come up with some criteria as to how to define [ER+] breast cancer with the sole purpose, really, to develop therapies that target this ER+ subtype. Then we have [HER2+] breast cancers, but again, IEC [information, education, and communication] defined. So, triple-negative was really defined by what it wasn't, rather than what it was.”¹

ADCs offer a revolutionary approach to the treatment of TNBC. By combining the cytotoxic potential of chemotherapy with the accuracy of monoclonal antibodies, ADCs enable the direct delivery of medicines to neoplasms with the least amount of harm to healthy organs. Given the prevalence of heterogeneity and treatment resistance in malignancies like TNBC, this "Trojan horse" mechanism is very helpful.³

Sacituzumab Govitecan-hziy

SG is an ADC comprised of SN-38, an irinotecan derivative, conjugated to a Trop-2-targeting antibody, and has been approved by the FDA for multiple indications. In 2021, it was first approved as a monotherapy for patients with unresectable locally advanced or metastatic TNBC who have received 2 or more prior systemic therapies. This decision was based on positive data from the phase 3 ASCENT trial (NCT02574455), which showed SG therapy yielded greater PFS benefits when compared with single-agent chemotherapy.^3,4

The trial evaluated 529 patients who were randomly assigned 1:1 to receive either 10 mg/kg SG as an intravenous infusion on days 1 and 8 of a 21-day cycle (n = 267) or physician’s choice of single-agent chemotherapy (n = 262). The primary efficacy end point was PFS with a key secondary end point of OS.⁵

The final results showed that patients who received SG had a median PFS of 4.8 months (95% CI: 4.1, 5.8), whereas chemotherapy patients had a median PFS of 1.7 months (95% CI: 1.5, 2.5) (HR 0.43; 95% CI: 0.35, 0.54; P < .0001). The reported median OS was 11.8 months (95% CI: 5.9, 7.6) and 6.9 months (95% CI: 10.5, 13.8) for the SG and chemotherapy groups, respectively (HR 0.51; 95% CI: 0.41, 0.62; P < .0001). These improved clinical benefits supported the efficacy of SG and supported its final approval.⁵

In 2023, SG received an additional approval for HR+/HER2- BC after demonstrating improvements in overall survival and PFS in the TROPiCS-02 study (NCT03901339).^3,6

Illustration of an antibodu drug conjugate | Image Credit: © AddMeshCube - stock.adobe.com

The FDA recommends 10 mg per kg of SG for metastatic TNBC due to its enhanced efficacy with controllable toxicity. A 180 mg injection of SG is made, reconstituted in 20 mL of sterile saline, diluted to 1.1 to 3.4 mg/mL, and administered intravenously twice over the course of 21 days. Doses are divided into 2 infusions for patients weighing more than 178 kg, and weight fluctuations above 10% are adjusted.³

The initial dosage is given over the course of 3 hours, and the patient is closely watched both during and for 30 minutes following the therapy. The medication can then be administered over a period of 1 to 2 hours, with a comparable observation time. If there are no grade 1 hypersensitivity events, infusion rates can be gradually raised. Although the initial infusion rates vary, they can start at 50 mg per hour and rise to a maximum of 1000 mg per hour in subsequent doses.³

Managing Adverse Effects

Managing AEs is crucial for not only ensuring the success of treatment through the use of medication management techniques but also improving the everyday quality of life for patients. The most common AEs associated with SG therapy identified in clinical trials are nausea (67%), diarrhea (62%), fatigue (55%), anemia (50%), vomiting (49%), and neutropenia (64%), of which 42% are greater than or equal to grade 3. Hypersensitivity reactions have also been reported in 37% of individuals, with grade 3 and 4 AEs in 2% of populations.³

Data from a pooled safety analysis of 1063 patients who received SG in the ASCENT, TROPiCS-02, TROPHY-U-01 (NCT03547973), and IMMU-132-01 (NCT01631552) studies found that neutropenia occurred in 75% of cases, with grade 3 to 4 neutropenia in 49% and febrile neutropenia in 6%, typically emerging after a median of 16 days. Neutropenic colitis was reported in 1.4% of patients. Neutropenia was the primary reason for dose interruptions, with 1% of patients discontinuing treatment due to related adverse events.^3,7,8

Dose modifications are the most effective way to manage, mitigate, or reduce the risk of AEs associated with SG therapy. When approaching greater than or equal to grade 3 AEs, the SG dose is reduced by 25% after the first occurrence and by 50% after the second, and treatment should be discontinued after 3 severe events.³

Therapy is stopped for 2 to 3 weeks in cases of grade 3 to 4 neutropenia to allow for hematologic recovery before starting again. Withholding dosages for grade 3 to 4 nausea, vomiting, or diarrhea until symptoms recover to less than or equal to grade 1 is another way to manage SG. After excluding infections, loperamide ([Diamode; Medique Products]; 4 mg first, then 2 mg per episode, up to 16 mg daily) should be started for diarrhea. It should be stopped 12 hours after the problem has been resolved, with supportive care provided as needed. Premedication with a 2- or 3-drug regimen is advised to prevent therapy-associated nausea and vomiting because SG is emetogenic.³

The evolution of targeted therapies like sacituzumab govitecan-hziy has reshaped the treatment landscape for TNBC, offering new hope where options were once limited. However, the success of these therapies depends not only on their efficacy but also on careful management of adverse effects to ensure patients can tolerate and benefit from treatment. As research continues to refine ADC technology and optimize treatment strategies, the role of clinical pharmacists and oncology specialists remains essential in bridging the gap between innovation and patient-centered care. By advancing both therapeutic development and supportive care practices, the future of TNBC treatment moves closer to a balance of efficacy, safety, and improved quality of life.

REFERENCES

1. Exploring the role of tumor biology in redefining triple-negative breast cancer treatment. Pharmacy Times. December 14, 2024. Accessed February 26, 2025. https://www.pharmacytimes.com/view/exploring-the-role-of-tumor-biology-in-redefining-triple-negative-breast-cancer-treatment

2. FDA approves sacituzumab govitecan-hziy for HR+/HER2- metastatic breast cancer. Pharmacy Times. February 3, 2023. Accessed February 26, 2025. https://www.pharmacytimes.com/view/fda-approves-sacituzumab-govitecan-hziy-for-hr-her2--metastatic-breast-cancer

3. Khan S, Jandrajupalli S, Bushara N, et al. Targeting refractory triple-negative breast cancer with sacituzumab govitecan: A new era in precision medicine. Cells. December 22, 2024. doi: 10.3390/cells13242126

4. Trial of sacituzumab govitecan in participants with refractory/​relapsed metastatic triple-negative breast cancer (TNBC) (ASCENT). Updated June 15, 2022. Accessed February 26, 2025. https://clinicaltrials.gov/study/NCT02574455

5. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. April 7, 2021. Accessed February 26, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-sacituzumab-govitecan-triple-negative-breast-cancer

6. Study of sacituzumab govitecan-hziy versus treatment of physician's choice in participants with HR+/​HER2- metastatic breast cancer (TROPiCS-02). Updated October 21, 2024. Accessed February 26, 2025. https://clinicaltrials.gov/study/NCT03901339

Study of sacituzumab govitecan in participants with urothelial cancer that cannot be removed or has spread (TROPHY U-01). Updated February 3, 2025. Accessed February 26, 2025. https://clinicaltrials.gov/study/NCT03547973

7. Study of sacituzumab govitecan-hziy (IMMU-132) in adults with epithelial cancer. Updated August 12, 2021. Accessed February 26, 2025. https://clinicaltrials.gov/study/NCT01631552