The U.S. Food and Drug Administration (FDA) has approved sacituzumab govitecan-hziy (Trodelvy®; Gilead Sciences) for the treatment of adult patients with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.
The breast cancer subtype HR+/HER2- is the most common subtype with an age-adjusted rate of 87.4 new cases per 100,000 women, based on 2015–2019 cases. 
Almost one in three cases of early-stage breast cancer eventually become metastatic, and among patients with HR+/HER2- metastatic disease, the five-year relative survival rate is approximately 32%. 
Patients with HR+/HER2- metastatic breast cancer become resistant to endocrine-based therapy, their primary treatment option is limited to single-agent chemotherapy. In this setting, it is common to receive multiple lines of chemotherapy regimens over the course of treatment. however, the prognosis remains poor.
Sacituzumab govitecan is a first-in-class antibody-drug conjugate or ADC targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers.
The drug’s target, Trop-2, is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and bladder cancers. Sacituzumab govitecan was intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload through a proprietary hydrolyzable linker. This unique combination delivers potent activity to both Trop-2 expressing cells and the microenvironment. 
The FDA approved the drug in 2020 in second-line and later metastatic triple-negative breast cancer (TNBC) under accelerated approval based on tumor response rate and duration of response.
Sacituzumab govitecanwas fully approved for the treatment of adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease, in 2021.
The new FDA approval is based on statistically significant and clinically meaningful progression-free survival and overall survival data from the Phase 3 TROPiCS-02 study. This study is a global, multicenter, open-label, Phase 3 study, randomized 1:1 to evaluate Trodelvy versus physicians’ choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine) in 543 patients with HR+/HER2- metastatic breast cancer who were previously treated with endocrine therapy, CDK4/6 inhibitor and two to four lines of chemotherapy for metastatic disease.
Based on the outcome of the study, sacituzumab govitecan is now also recommended as a Category 1, preferred treatment for metastatic HR+/HER2- breast cancer by the National Comprehensive Cancer Network® (NCCN®) as defined in the Clinical Practice Guidelines in Oncology (NCCN Guidelines®)*
“Despite decades of advances, people living with pre-treated HR+/HER2- metastatic breast cancer need new treatment options. Nearly all people with this type of breast cancer will eventually develop resistance to endocrine-based therapies and progress on available chemotherapies,” noted Hope S. Rugo, MD, Professor of Medicine and Director, Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center, U.S. and principal investigator of the TROPiCS-02 study.
“This approval is significant for the breast cancer community. We have had limited options to offer patients after endocrine-based therapy and chemotherapy, and to see a clinically meaningful survival benefit of more than three months with a quality of life benefit for these women is exceptional,” Rugo added.
In the TROPiCS-02 study, sacituzumab govitecan demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit of 3.2 months versus comparator single-agent chemotherapy (treatment of physician’s choice; TPC) (median OS: 14.4 months vs. 11.2 months; hazard ratio [HR]=0.79; 95% CI: 0.65-0.96; p=0.02).
Sacituzumab govitecan also demonstrated a 34% reduction in risk of disease progression or death (median PFS: 5.5 versus 4.0 months; HR: 0.66; 95% CI: 0.53-0.83; p=0.0003).
Three times as many people treated with sacituzumab govitecan were progression free at one year versus those treated with chemotherapy (21% versus 7%). In a post-hoc analysis, data demonstrated sacituzumab govitecan-hziy’s efficacy across HER2-low and IHC0 status in pre-treated metastatic breast cancer patients in the TROPiCS-02 trial.
Sacituzumab govitecan-hziy also significantly improved additional secondary endpoint measures, including objective response rate and time to deterioration (TTD) assessed by the Global Health Status/Quality of Life and Fatigue scale per EORTC-QLQ-C30. No statistically significant difference in TTD in Pain Scale was observed.
“The FDA approval is an important step forward for both women and men living with metastatic breast cancer, especially for those individuals whose tumor is no longer responding to endocrine-based therapies and who are facing a poor prognosis,” explained Laura Carfang, Executive Director, SurvivingBreastCancer.org.
“We need to combat this terrible disease, and all options that potentially slow its progress and extend life for those living with metastatic breast cancer are welcomed,” Carfang said.
“We are pleased that sacituzumab govitecan could now provide new hope for people living with pre-treated HR+/HER2- metastatic breast cancer, building on the transformative role that Trodelvy is already playing for people with metastatic triple-negative breast cancer,” said Daniel O’Day, Chairman and Chief Executive Officer, Gilead Sciences.
“We thank the physicians, patients and their families who put their trust in the TROPiCS-02 study and helped make this milestone possible,” O’Day added.
The safety profile for sacituzumab govitecan was consistent with prior studies, with no new safety signals identified in this patient population. In TROPiCS-02 the most frequent serious adverse reactions (>1%) were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPiCS-02 study were reduced neutrophils and leukocytes. No patients treated with Trodelvy experienced interstitial lung disease.
Note * Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer Version 1.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed January 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
This review by the US FDA was conducted under Project Orbis and granted Priority Review. In addition, the European Medicines Agency (EMA) has also validated a Type II Variation Marketing Authorization Application for Trodelvy in HR+/HER2- metastatic breast cancer.
Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician’s Choice in Participants With HR+/HER2- Metastatic Breast Cancer (TROPiCS-02) – NCT03901339
Trial of Sacituzumab Govitecan in Participants With Refractory/Relapsed Metastatic Triple-Negative Breast Cancer (TNBC) (ASCENT) – NCT02574455
Highlights of Prescribing information
Sacituzumab govitecan-hziy (Trodelvy®; Gilead Sciences) [Prescribing Information]
Eribulin (Halaven®; Eisai)[Prescribing Information]
Capecitabine (Xeloda®; Genentech/Roche) [Prescribing Information]
Gemcitabine (Gemzar®; Eli Lilly & Co)[Prescribing Information]
Vinorelbine (Navelbine®; GSK)[Prescribing information]
 SEER Cancer Stat Facts: Female Breast Cancer Subtypes. SEER Program. National Cancer Institute (NCI). Online. last accessed on February 2, 2023.
 Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, Cronin KA. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014 Apr 28;106(5):dju055. doi: 10.1093/jnci/dju055. PMID: 24777111; PMCID: PMC4580552.
 Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O’Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021 Apr 22;384(16):1529-1541. doi: 10.1056/NEJMoa2028485. PMID: 33882206.
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