Treatment with sacituzumab govitecan (Trodelvy®; Gilead Sciences), an antibody-drug conjugate (ADC), resulted in longer progression-free survival (PFS) compared to physician’s choice of chemotherapy in patients who have received many prior therapies and who had hormone-receptor positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer. [1]
This is the conclusion based on outcomes from the TROPiCS-02 phase 3 clinical trial, an industry sponsored study funded by Gilead Sciences, to be presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held from June 3-7, 2022 in Chicago, Il. [1]
HR+/HER2- is the most common subtype of advanced breast cancer and the most common cancer in women worldwide, accounting for approximately 70% of all breast cancer cases.[2]
IMMU-132-01 study
The Hormone Receptor positive (HR+) and HER2– metastatic breast cancer (MBC) cohort of the phase 1/2 IMMU-132-01 study with sacituzumab govitecan (n = 54) had an objective response rate (ORR) of 31.5%, median progression-free survival (PFS) of 5.5 months, median overall survival (OS) of 12 months, and a manageable safety profile. The TROPiCS-02 is a phase 3 randomized study was designed to confirm treatment outcomes of sacituzumab govitecan in HR+/HER2– advanced breast cancer.
Study design
The TROPiCS-02 phase III clinical trial randomly assigned patients at 113 international locations with HR+/HER2- unresectable locally advanced or metastatic breast cancer who had received two to four prior chemotherapy regimens for advanced disease to be given either sacituzumab govitecan or standard chemotherapy (capecitabine, eribulin, vinorelbine, or gemcitabine) until the disease progressed or the toxicity of the drugs became unacceptable. The primary endpoint was PFS with a secondary endpoint of OS.
Study findings
The trial results showed that use of sacituzumab govitecan, with more than 50% of patients had received three or more lines of chemotherapy, resulted in improved median PFS compared to standard chemotherapy (5.5 vs 4.0 mo; HR, 0.66; 95% CI, 0.53-0.83; P= 0.0003); PFS rates at 6 and 12 months were 46% vs. 30% and 21% vs. 7%, respectively.
Sacituzumab govitecan vs. standard chemotherapy showed a nonsignificant trend for improvement in OS (13.9 vs 12.3 months; HR, 0.84; P= 0.143) in the first of three planned OS analyses, with follow-up ongoing. The overall response rate (ORR; 21% vs. 14%) and clinical benefit rate (34% vs. 22%) were higher with sacituzumab govitecan vs. standard therapy and median duration of response was 7.4 vs. 5.6 months, respectively.
Overall, 74% vs. 60% of patients (sacituzumab govitecan vs. standard chemotherapy) had adverse events, including low white blood cell counts (51% vs. 39%) and diarrhea (10% vs. 1%). Adverse events leading to discontinuation of sacituzumab govitecan vs. standard chemotherapy were low (6% vs. 4%).
“It is very gratifying to see the benefit of sacituzumab govitecan for these patients who have had very limited treatment options,” said Hope S. Rugo, MD, FASCO, lead author, who is a professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Comprehensive Cancer Center.
“Longer follow-up is needed to determine the impact on overall survival, and additional prespecified analyses will help us understand the potential role of sacituzumab govitecan in a setting where there are currently no other targeted treatment options available.”
In the United States (U.S.), 5% to 10% of breast cancers are classified as aggressive and high-risk. In 2022, invasive breast cancer will be newly diagnosed in an estimated 287,850 women and 2,710 men. [3]
Adverse events
Overall, 74% vs 60% of patients (sacituzumab govitecan vs. standard chemotherapy) had grade ≥3 treatment-emergent adverse events (AEs); neutropenia (51% vs 39%) and diarrhea (10% vs 1%) were most common. AEs leading to discontinuation of sacituzumab govitecan vs. standard chemotherapy were low (6% vs 4%). There was 1 treatment-related death in the sacituzumab govitecan arm; none in the standard chemotherapy arm.
Metastatic breast cancer
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 30%. Treatment for HR+/HER2- metastatic breast cancer initially includes sequential endocrine therapy combined with targeted agents, and as the disease becomes resistant to endocrine-based therapy, treatment is limited to sequential single-agent chemotherapy with increasingly shorter durations of benefit. For patients treated with single-agent chemotherapy, the prognosis remains poor.
Antibody-drug Conjugate
Sacituzumab govitecan is an antibody-drug conjugate, which means that this drug consists of a protein, in this case a humanized antibody (hRS7) against tumor-associated calcium signal transducer 2 (TACSTD2 or TROP2) linked to the active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), a topoisomerase I inhibitor, that is uniquely delivered to cells that express the antibody target.[4]
The Trop-2 protein is a cell surface antigen highly expressed in several different kinds of cancer, including more than 90% of breast and bladder cancers. The antibody moiety of sacituzumab govitecan selectively binds to TROP2. After internalization and proteolytic cleavage, SN-38 selectively stabilizes topoisomerase I-DNA covalent complexes, resulting in DNA breaks that inhibit DNA replication and trigger apoptosis.[2]
Sacituzumab govitecan is approved for metastatic triple-negative breast cancer previously treated with two or more prior therapies, with at least one in the metastatic setting. If sacituzumab govitecan is approved by the U.S. Food and Drug Administration (FDA) to treat HR+/HER2- advanced breast cancer, it would be the first antibody-drug conjugate approved for use in this setting.
Next Steps
The patients in the study continue to be followed for OS and long-term safety endpoints. In adition, researchers are working to expand the patient benefit of sacituzumab govitecan beyond its current indications for second-line metastatic triple-negative breast cancer and accelerated approval in second-line metastatic bladder cancer. They are also pursuing studies across multiple tumor types and earlier lines of therapy.
Clinical trial
Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician’s Choice in Participants With HR+/HER2- Metastatic Breast Cancer (TROPiCS-02) – NCT03901339
Study of Sacituzumab Govitecan-hziy (IMMU-132) in Adults With Epithelial Cancer – NCT01631552
Highlights of prescribing information
Sacituzumab Govitecan (Trodelvy®; Gilead Sciences) [Prescribing Information]
Reference
[1] Rugo HS, Bardia A, Marmé F, Cortes J, Schmid P, Loirat D, Tredan O, et al. Primary results from TROPiCS-02: A randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer. J Clin Oncol 40, 2022 (suppl 17; abstr LBA1001) | DOI 10.1200/JCO.2022.40.17_suppl.LBA1001
[2] Breast Cancer Facts & Figures 2019-2020. Online. Last accessed on June 4, 2022.
[3] Cancer Facts & Figures 2022. Online. Last accesses on June 4, 2022.
[4] Pandey R, Gruslova A, Chiou J, Brenner AJ, Tiziani S. Stable Isotope Dilution LC-HRMS Assay To Determine Free SN-38, Total SN-38, and SN-38G in a Tumor Xenograft Model after Intravenous Administration of Antibody-Drug Conjugate (Sacituzumab Govitecan). Anal Chem. 2020;92(1):1260-1267. doi:10.1021/acs.analchem.9b04419
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