A Phase IIb, single arm, multicenter trial of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer who received at least two prior treatments

Refractory or relapsing metastatic triple-negative breast cancer (mTNBC) has a poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate, targeting human trophoblast cell-surface antigen 2 (Trop-2). This is the first report of SG's efficacy and safety in Chinese patients with mTNBC. EVER-132-001 (NCT04454437) was a multicenter, single-arm, Phase IIb study in


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EVEREST MEDICINES emergent adverse events (TEAEs) were reported in 71.3%, the most common were neutrophil count decreased (62.5%), white blood cell count decreased (48.8%) and anemia (21.3%); 6.3% discontinued SG because of TEAEs. SG demonstrated substantial clinical activity in heavily pretreated Chinese patients with mTNBC. The observed safety profile was generally manageable. What's new?
The novel antibody-drug conjugate sacituzumab govitecan (SG) targets human trophoblast cellsurface antigen, overexpression of which has been reported in various solid tumors, including breast cancer. This investigation examined the efficacy and safety of SG in Chinese patients with locally advanced or metastatic triple-negative breast cancer (mTNBC). SG demonstrated substantial clinical activity and manageable toxicity in heavily pretreated mTNBC patients. More than three-quarters of SG-treated patients exhibited tumor shrinkage and half had at least a 30% reduction in target lesion size. The results support the use of SG as a new standard of care for pretreated Chinese patients with mTNBC.

| INTRODUCTION
Breast cancer (BC) is the most commonly diagnosed tumor in females and is a leading cause of cancer-associated deaths. 1,2 In 2020, there were approximately 2.3 million newly diagnosed female BC cases, and nearly 700 000 deaths globally. 1 In China, BC is the most common cancer type among females and is estimated to have caused approximately 124 000 deaths in 2022. 2 Consequently, China is taking steps to combat its escalating cancer burden. 2 Triple-negative BC (TNBC) comprises 15-20% of all BCs and approximately 15% of invasive BC cases. 3,4 TNBC is characterized by a lack of expression of the estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2; is biologically aggressive; and with few targeted agents available, is associated with a worse prognosis compared to other subtypes of BC. 5,6 Metastatic triple-negative breast cancer (mTNBC) is an aggressive disease, with a median survival of 10-13 months. 7 Patients with pretreated mTNBC have low response rates (5-15%) to standard chemotherapy and short (2-3 months) progression-free survival (PFS). 3,8,9 Human trophoblast cell-surface antigen-2 (Trop-2; also called tumor-associated calcium signal transducer 2 [TACSTD2]), is a cellsurface membrane glycoprotein receptor encoded by the TACSTD2 gene. 10 Trop-2 is commonly expressed in various normal and cancerous epithelial cells, and is functionally linked to cell migration and anchorage-independent growth. 10 Increased Trop-2 expression has been reported in various solid tumors, including BC, promoting cell proliferation and migration, stimulating cancer growth and metastatic potential. 10 Trop-2 overexpression is more common in TNBC than other BC subtypes. 11 Trop-2 overexpression is associated with a poor prognosis, including overall survival (OS) and disease-free survival. 12 Consequently, Trop-2 has been considered and exploited as a target for anticancer therapies. 12,13 Antibody-drug conjugates (ADCs) are a subclass of emerging cancer therapeutics which combine cytotoxic chemotherapy with targeted antibodies. 14 Sacituzumab govitecan (SG; IMMU-132) is a third-generation novel ADC 10 approved by the Food and Drug Administration (April 2020), 15 European Medicines Agency (November 2021), 16

| Study design
This was a multicenter, single-arm, Phase IIb study conducted at 14 study centers across mainland China. The study objectives were to evaluate the efficacy and safety of SG in patients with locally advanced or mTNBC who were refractory or relapsing after ≥2 prior standard chemotherapy regimens. After a screening period of up to 28 days, patients received 10 mg/kg of SG intravenously on Days 1 and 8 of each 21-day treatment cycle. Treatment was continued until disease progression or unacceptable toxicity. CR patients were treated for at least 12 months and/or until disease progression or unacceptable toxicity.    Tumor shrinkage was reported in 61 (76.3%) patients after receiving SG and 40 (50%) patients had a ≥ 30% reduction in target lesion size according to the IRC assessment (Figure 2A

| Safety
All 80 (100.0%) patients experienced TEAEs (Table 3) 24 Cytotoxic chemotherapy is the dominant systemic treatment option for mTNBC. 25 In Western countries (United States, Canada and Germany) 65-67% of mTNBC patients receive monotherapy as their first-line treatment rather than combination regimens, which are more popular in Asia. 26 However, the overall efficacy of both monotherapy and combined chemotherapy for the treatment of mTNBC is limited. A meta-analysis of mTNBC subgroups from three Phase III first-line trials reported a pooled median ORR of 23%, OS of 17.5 months and median PFS of 5.4 months with single-agent chemotherapy. 27 No combination chemotherapy showed a superior OS. 27 TNBC is intrinsically chemo-sensitive, but is unfortunately prone to rapid release and resistance, known as the triple negative paradox. 24 In recent years, results from studies using novel therapies have brought new hope to mTNBC researchers and patients. For example, immunotherapy (KEYNOTE-355) and PARP inhibitors (OlympiAD trial). 28,29 The KEYNOTE-355 trial investigated pembrolizumab + chemotherapy vs placebo + chemotherapy in patients with previously untreated mTNBC. 29 In patients with a combined positive score of ≥10, the median PFS favored pembrolizumab with 9.6 vs 5.6 months (P = .0012, HR = 0.65). 24,29 The Phase III OlympiAD trial demonstrated a benefit in PFS but not OS in patients with BRCA-associated mTNBC treated with the PARP inhibitor Olaparib. 28    The study has some limitations. This was a single-arm study with a small sample size, with no direct comparison to other treatment and chemotherapy approaches, interpretations of efficacy and safety can be limited. However, ORR by the IRC was used as the primary endpoint, which is subject to less bias than PFS in a single group trial, and has been used for accelerated approval in other oncology trials. 3,38 In conclusion, these results demonstrate that SG provides a comparable benefit for heavily pretreated Chinese patients with mTNBC as previously reported in overseas studies. There were no unexpected safety issues in Chinese patients, and the observed safety profile was generally manageable.

ETHICS STATEMENT
The study was approved by the ethics committees of the National