Breast cancer poses a significant threat to women's health and lives. Among its subtypes, triple-negative breast cancer (TNBC) stands out for its distinct biological behavior and aggressive clinical course, earning it the reputation of being the "most toxic" form of breast cancer. Due to the lack of effective therapeutic targets for TNBC, chemotherapy remains the primary systemic treatment. However, its effectiveness is often limited, and it is associated with considerable toxicity and side effects. Moreover, the prognosis for TNBC differs significantly from other breast cancer subtypes. Therefore, it is crucial to explore alternative therapeutic strategies to enhance clinical outcomes and patient benefit.

Sacituzumab tirumotecan (Sac-TMT) is an investigational TROP2-targeting antibody-drug conjugate (ADC) composed of a monoclonal antibody, a topoisomerase I inhibitor payload, and a novel hydrolyzable linker. TROP2 (trophoblast cell surface antigen 2) is highly expressed in epithelial tumors and is associated with proliferation and metastasis. Sac-TMT delivers its cytotoxic payload selectively to TROP2-positive cells and has shown promising clinical activity. It recently received marketing approval in China for adults with unresectable or metastatic triple-negative breast cancer (TNBC) after ≥2 prior systemic therapies.

The Phase II OptiTROP-Breast05 study (NCT05445908) evaluated sac-TMT as first-line treatment for patients with advanced/metastatic TNBC. The study also explored the impact of PD-L1 combined positive score (CPS) status. Patients with CPS, 10 (PD-L1-negative, IHC 22C3 pharmDx) have limited treatment options, representing a critical unmet need. As of 18 November 2024, a total of 41 patients (median age 55 years; 43.9% ECOG PS 1; 78.0% PD-L1 CPS ≥10) were enrolled. At baseline, 61.0% of patients had visceral metastases, 29.3% had de novo metastasis, 19.5% had a disease-free interval (DFI) of 6–12 months, and 51.2% had a DFI >12 months. The median follow-up was 18.6 months. 

For the overall cohort, the objective response rate (ORR) was 70.7%, and the disease control rate (DCR) was 92.7%. Median duration of response (mDoR) was 12.2 months, median progression-free survival (mPFS) was 13.4 months, and the 12-month PFS rate was 64.6%. 

Among the 32 patients with PD-L1 CPS ≥10, the ORR was 71.9% and the DCR was 93.8%. The mPFS in this subgroup was 13.1 months, with a 12-month PFS rate of 59.1%. 

Treatment-related adverse events (TRAEs) of grade 3 or higher occurred in 63.4% of patients. The most common grade ≥3 TRAEs (≥5% of patients) included decreased neutrophil count (46.3%), decreased WBC count (34.1%), anemia (12.2%), stomatitis (9.8%), decreased lymphocyte count (7.3%), and fatigue (7.3%). No treatment-related deaths occurred, and there were no reports of neuropathy or interstitial lung disease/pneumonitis.

KOL insights: 

“Sac-TMT demonstrated promising anti-tumor activity with a manageable safety profile as a first-line treatment for [patients] with a/mTNBC, independent of the PD-L1 status. A Phase III study comparing sac-TMT vs. investigator’s choice of chemotherapy in first-line PD-L1-negative (CPS < 10) a/mTNBC is currently underway.”– Expert Opinion.

Conclusion 

In 2023, the total incident cases of TNBC in the US were approximately 45k, according to DelveInsight’s analysis. Among the EU4 countries, Germany reported the highest number of TNBC incidence cases, with approximately 11K cases, followed by France and Italy. 

Competition in the TROP2 ADC space for TNBC is intensifying. While TRODELVY has been a leading treatment, Sacituzumab tirumotecan (Sac-TMT) is making strides, particularly with its approval in China and strong anti-tumor activity. Developed by Kelun-Biotech in collaboration with Merck, Sac-TMT has shown promising results as a first-line treatment for a/mTNBC, regardless of PD-L1 status, and is now being evaluated in a Chinese phase III trial for PD-L1-negative TNBC and PD-L1-positive patients who have undergone prior PD-1/L1 therapy.  Besides Sac-TMT, AstraZeneca and Daiichi Sankyo are pushing forward with their ADC candidate, Datroway, which is currently under investigation in two phase III trials. Given Sac-TMT’s remarkable response rate, experts have highlighted that it has the potential to surpass TRODELVY in efficacy. With multiple contenders vying for a position in the TNBC treatment landscape, innovation in TROP2-directed ADCs is moving fast, potentially reshaping therapeutic options for patients.