Several studies have investigated the safety and clinical efficacy of sacituzumab govitecan-hziy (SG) in the treatment of HR-positive/HER2-negative breast cancer.
Breast cancer is the most frequently diagnosed malignancy in women worldwide, with HR-positive/HER2-negative breast cancer being the most common subtype.1 Single-agent chemotherapy is a treatment option for endocrine-resistant or treatment-refractory illness; however, later-line therapies have low response rates.1
Trophoblast cell-surface antigen-2 (Trop-2) is a transmembrane calcium signal transducer that promotes cancer growth by boosting cellular proliferation, survival, and invasion and is increased in a variety of epithelial malignancies.1 In a number of solid tumors, higher levels of Trop-2 expression are linked to a poor prognosis.1 Trop-2 is overexpressed in all breast cancers, including HR-positive illness, and is related to a high mortality rate.1 The anti–Trop-2-SN-38 antibody–drug conjugate (ADC) SG has a high drug-to-antibody ratio of up to 8 SN-38 molecules per antibody.1 ADCs are a relatively new class of treatments that use the target selectivity of monoclonal antibodies to improve the delivery of therapeutic molecules to specific targets within the body.2
A phase 1/2 basket trial evaluated the safety and clinical efficacy of SG in patients with HR-positive/HER2-negative metastatic breast cancer who had disease progression after receiving ≥2 prior systemic therapies for metastatic illness, 1 of which had to be endocrine therapy and the other chemotherapy.1 Fifty-four women with HR-positive/HER2-negative metastatic breast cancer were treated between February 2015 and June 2017.1 On days 1 and 8 of a 21-day cycle, eligible patients with HR-positive/HER2-negative metastatic breast cancer received 10 mg/kg of SG as an intravenous infusion until disease progression, unacceptable toxicity, death, or withdrawal of consent.1
In this phase 1/2 basket study, 12 patients were still alive at the time of data cutoff.1 Neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%) were among the most common grade ≥3 treatment-related side effects.1 There were no deaths as a result of the treatment.1 The median progression-free survival (PFS) was 5.5 months, with a 12.0-month median overall survival (OS).1 These findings suggest that SG has potential in individuals with pretreated HR-positive/HER2-negative metastatic breast cancer with a tolerable adverse event profile.1
TROPiCS-02 is a multicenter, phase 3 trial comparing SG to the treatment of physician’s choice (TPC) in patients with HR-positive/HER2-negative metastatic breast cancer who have had ≥2 but not >4 previous courses of chemotherapy.2 The study is currently recruiting patients and opened for enrollment in April 2019.2 The primary end points of the trial are PFS and overall response rate (ORR).2 OS, duration of response, safety, quality of life, and blood and tumor biomarkers are all secondary end points.2
This trial will enroll 400 patients from 129 sites in the United States, Canada, the United Kingdom, France, Spain, Italy, Germany, Belgium, and the Netherlands.2 Participants will be randomly assigned to receive 10 mg/kg of SG delivered intravenously on days 1 and 8 of every 21-day cycle or single-agent standard-of-care TPC (eribulin, capecitabine, gemcitabine, or vinorelbine).2 The TROPiCS-02 phase 3 trial will demonstrate whether SG monotherapy can enhance PFS and ORR in patients with HR-positive/HER2-negative metastatic breast cancer who have already had 1 endocrine therapy and 2 to 4 lines of chemotherapy, compared with standard chemotherapy TPC.2
In HR-positive/HER2-negative metastatic breast cancer that is PD-L1–positive, a multicenter phase 2 trial is presently underway to determine whether adding pembrolizumab to SG improves PFS relative to SG alone.3 The study started in July 2020 and is estimated to be completed by April 2027. Key eligibility requirements include having received ≥1 prior hormone therapies and ≤1 prior chemotherapies for HR-positive metastatic breast cancer.3
A multicenter phase 3 trial is now underway (started in November 2020 and estimated to be completed in December 2023) in Asia to examine the efficacy and safety of SG versus TPC in patients with metastatic or locally recurrent HR-positive/HER2-negative metastatic breast cancer who have failed ≥2 and ≤4 prior chemotherapy regimens for metastatic illness.4 In a 1:1 ratio, approximately 330 eligible individuals will be randomly assigned to 1 of 2 therapy arms.4 On days 1 and 8 of a 21-day cycle, the investigational arm receives SG 10 mg/kg by intravenous injection.4 TPC (eribulin, capecitabine, gemcitabine, or vinorelbine) is used as the control arm.4 PFS is the primary outcome, with OS, ORR, and duration of response as secondary outcomes.4
Positive results from these studies may lead to the provision of a novel, successful treatment option for patients with HR-positive/HER2-negative metastatic breast cancer other than chemotherapy, addressing a significant unmet medical need in the area of breast oncology.
- Kalinsky K, Diamond JR, Vahdat LT, et al. Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm, basket trial. Ann Oncol. 2020;31:1709-1718.
- Rugo HS, Bardia A, Tolaney SM, et al. TROPiCS-02: a phase III study investigating sacituzumab govitecan in the treatment of HR+/HER2- metastatic breast cancer. Future Oncol. 2020;16:705-715.
- Garrido-Castro AC, Keenan TE, Li T, et al. Saci-IO HR+: randomized phase II trial of sacituzumab govitecan (SG) +/- pembrolizumab in PD-L1+ hormone receptor-positive (HR+)/HER2- metastatic breast cancer (mBC). J Clin Oncol. 2021;39(suppl_15):TPS1102.
- ClinicalTrials.gov. Asian study of sacituzumab govitecan (IMMU-132) in HR+/HER2- mBC. Updated February 2021. https://clinicaltrials.gov/ct2/show/NCT04639986. Accessed December 15, 2021.