Disease burden and treatment landscape
Breast cancer is the leading cause of death among Singaporean women and accounts for over 30% of all cancers diagnosed in women. It is a heterogenous disease comprised of distinct biological subtypes that carry both prognostic and therapeutic implications. Triple Negative Breast Cancer (TNBC) constitutes 15-20% of all breast cancer cases in Singapore and occurs more frequently among women in the 30s and 40s. The particularly aggressive and treatment-resistant subtype is characterised by an absence of oestrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor-2 (HER-2) expression. Therapeutics targeting ER, PR and HER2 thus have no role in the treatment of this disease and conventional treatment for TNBC involves surgery, chemotherapy and radiotherapy. Although immunotherapy has shown promising first-line clinical activity, single-agent chemotherapy remains standard for previously treated mTNBC. Survival after relapse is poor, with a median survival of little over a year.
Encouragingly, significant headway has been made in the last decade to identify novel strategies for the complex disease. A growing body of precision medicines which include immunotherapies, poly (ADP-ribose) polymerase (PARP) inhibitors and antibody-drug conjugates, have enjoyed clinical success in the setting of mTNBC.
Sacituzumab govitecan (Trodelvy) and its place in therapy
In January 2022, HSA approved the use of sacituzumab govitecan (Trodelvy) in the setting of ‘adult patients with unresectable locally advanced or metastatic triple negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease’. Sacituzumab govitecan is available in Singapore as a 180mg powder vial and is dosed at 10mg/kg as an intravenous infusion given once a week for 2 weeks. Each treatment cycle repeats every 21 days.
Market authorisation in Singapore follows US FDA’s full approval in April 2021, and signals a breakthrough for Singaporean patients in the high unmet-need setting with few treatment options. In tandem with the rapid clinical developments, sacituzumab govitecan has also been incorporated within clinical guidelines and is now considered the standard of care in pre-treated mTNBC, following late 2021 updates by the National Comprehensive Cancer Network (NCCN). NCCN recommends sacituzumab govitecan as a preferred regimen for treatment of adult patients with mTNBC who have received ≥ 2 prior therapies, ≥ 1 for metastatic disease. The NCCN also recommend sacituzumab govitecan as a second-line later therapy in patients with unresectable locally advanced or mTNBC.
Sacituzumab govitecan is a trophoblast cell surface antigen 2 (Trop-2) directed antibody-drug conjugate linked with SN-38, a topoisomerase-1 inhibitor. It targets Trop-2, a cell surface antigen which is overexpressed in the majority of TNBC, and delivers SN-38 directly to the tumours, causing cell death.
Sacituzumab govitecan’s regulatory and clinical approval is supported by efficacy and safety data from the Phase III ASCENT study (N=482), within which the drug demonstrated survival benefit with a significantly improved median progression free-survival (PFS) and median overall survival (OS) compared with chemotherapy of the physician’s choice. In addition, although greater efficacy was observed in patients who had a medium or high Trop-2 score, an improved PFS and OS was also observed irrespective of Trop-2 expression. The same benefit was also seen in all clinical and pre-specified subgroups, including patients who had received previous treatment with programmed death 1 (PD-1) or PD-L1 inhibitors. A separate exploratory analysis also confirmed that the drug benefits patients regardless of germline BRCA status.
From a safety perspective, the most common any-grade adverse event (AE) included nausea, neutropenia, diarrhoea, fatigue and anaemia. Neutropenia was managed with dose reduction, dose delay, or both with growth-factor support, which was required in 49% of patients on sacituzumab govitecan and 23% of patients on chemotherapy. There was a low incidence of treatment discontinuation (5%) due to AEs and patients received sacituzumab govitecan for a median of 4.4 months (maximum 22.9 months).
A summary of the pivotal trial is outlined in the table below.
| Study population | Study arms | Efficacy | Safety |
| ASCENT
N=529 (N=61 with brain mets; N=468 patients without brain mets) Median age: 54y (Range: 27 to 82) 100% previously treated with taxanes, 27% previously treated with PD-1 or PD-L1 inhibitors |
Randomized 1:1 to receive
Sacituzumab govitecan 10mg/kg (N=235) and Chemotherapy (N=233) of physician’s choice (54% eribulin, 20% vinorelbine, 13% capecitabine or 12% gemcitabine) |
At data cut-off, the median follow-up time from randomization was 17.7 months
Primary Endpoint Median PFS: Sacituzumab govitecan: 5.6 months Chemo: 1.7 months (HR for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001) Median OS: Sacituzumab govitecan 12.1 months Chemo: 6.7months (HR for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001) |
Key TEAEs grade ≥3 with sacituzumab govitecan vs chemo were neutropenia (51% vs 33%), leukopenia (10% vs 5%), diarrhoea (10% vs <1%), anaemia (8% vs 5%) and febrile neutropenia (6% vs 2%)
No deaths were considered sacituzumab govitecan-related |
Abbreviations – PFS: progression-free survival, HR: hazard ratio, OS: overall survival, PD-L1: programmed death ligand 1, CI: Confidence interval
Despite overwhelmingly impressive results reported in ASCENT, debate surrounds its open-label design which has been suggested to favour the experimental arm, the choice of PFS as the primary endpoint in the mTNBC setting which may lead to bias, and the substandard control arm which imposed certain restrictions that prevented use of more effective agents or combination of agents. Uncertainties thus remain in the extent to which the reported outcomes will translate in the real world. Further, patient access in terms of local pricing and reimbursement remains to be seen.
Notwithstanding, in heavily pre-treated patients with mTNBC, the antibody-drug conjugate sacituzumab govitecan was well tolerated and induced early and durable responses, providing significant hope for a treatment landscape plagued by poor prognosis and high unmet need.
Separately, sacituzumab govitecan is also approved for use under special regulatory pathways in China and the US for the treatment of metastatic urothelial cancer. It is also under investigation for potential use in other cancer settings including HR+/HER2- metastatic breast cancer, metastatic non-small cell lung cancer (NSCLC), metastatic small cell lung cancer (SCLC) and endometrial cancer.
