Sacituzumab tirumotecan (SKB-264/ MK-2870), developed by Kelun-Biotech and Merck, represents a groundbreaking TROP2-targeting antibody-drug conjugate (ADC) designed to combat the aggressive phenotype of TNBC. This innovative therapy, which combines a high-affinity monoclonal antibody with the potent T030 toxin through a stable CL2A linker, has been granted multiple Breakthrough Therapy Designations by China's NMPA for various advanced cancers, including TNBC. In March 2024, it received yet another BTD for first-line treatment of unresectable, locally advanced, recurrent, or metastatic PD-L1 negative TNBC.

TNBC, accounting for roughly 15% of all breast cancers, is characterized by its high aggressiveness and poor prognosis. Over 80% of TNBC cases exhibit high levels of TROP2 expression, a tumor-associated calcium signal transducer. According to DelveInsight’s estimates, the total incident cases of TNBC in the United States comprised ~44,000 cases in 2023.

The current standard of single-agent chemotherapy for TNBC is associated with dismal survival outcomes, highlighting the urgent need for more effective treatments. While NCCN guidelines recommend TRODELVY as a preferred second-line treatment, it is the only TROP2 ADC in advanced TNBC patients, there remains a significant unmet need for novel, optimized therapies.

Sacituzumab tirumotecan stands out as a promising TROP2 ADC, distinguished by its enhanced activity and bystander effect, facilitated by an irreversible linker that optimizes the release of its payload within and around tumor cells. This balance between safety and efficacy positions sacituzumab tirumotecan as a potential game-changer in the treatment landscape of advanced TNBC. Data from the Phase III OptiTROP-Breast01 trial, presented at the ASCO annual meeting, further underscores the potential of this ADC in transforming outcomes for patients with TNBC. 

Efficacy outcomes:

The study met its primary endpoint with a statistically significant improvement in PFS by central review. Sacituzumab tirumotecan significantly improves the PFS and the OS over chemotherapy.

Safety overview:

• Sacituzumab tirumotecan showed a manageable safety profile and had no unaccepted safety signals.

• The most common TRAES for both Sacituzumab tirumotecan and chemotherapy were hematologic toxicities

• TRAES leading to treatment discontinuation were low. Peripheral neuropathy and interstitial lung disease occurred with a low incidence.

KOL insights

“Sacituzumab tirumotecan demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) compared with chemotherapy, with a manageable safety profile, among heavily pretreated patients with advanced triple-negative breast cancer.” –Expert Opinion.

“OptiTROP-Breast01 study met the primary endpoint and the key secondary endpoint. Sacituzumab tirumotecansignificantly improves PFS, and overall survival over chemotherapy.”–Expert Opinion.

Conclusion- 

Sacituzumab tirumotecan (SKB264) has shown exceptional promise in treating advanced TNBC, significantly reducing the risk of progression or death with a tolerable safety profile. Interim analysis from June 21, 2023, revealed a median PFS of 5.7 months for SKB264 patients, more than double the 2.3 months seen in patients receiving chemotherapy. The 6-month PFS rates were 43.4% for SKB264 versus 11.1% for chemotherapy. In patients with high TROP2 expression, SKB264's median PFS was 5.8 months, compared to 1.9 months for chemotherapy. As of November 30, 2023, SKB264's median OS was not yet reached, contrasting with chemotherapy's 9.4 months. The objective response rate was a substantial 43.8% for SKB264, far exceeding chemotherapy's 12.8%. These results position SKB264 as a beacon of hope for advanced TNBC patients, offering a superior alternative to conventional chemotherapy.