Sacituzumab tirumotecan (sac-TMT) as first-line treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): Initial results from the phase II OptiTROP-Breast05 study.

1019 Background: TROP2 (trophoblast cell surface antigen 2) is highly expressed in TNBC and associated with poor survival. Sac-TMT (MK-2870/SKB264) is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. It is approved in China for pts with a/mTNBC who have received at least two prior chemotherapies, including one for metastatic disease. The Phase II OptiTROP-Breast05 study (NCT05445908) evaluated sac-TMT as first-line treatment for pts with a/mTNBC. The study also explored the impact of PD-L1 combined positive score (CPS) status. Pts with CPS < 10 (PD-L1-negative, IHC 22C3 pharmDx) have limited treatment options, representing a critical unmet need. Methods: Pts with a/mTNBC who had not received prior treatment for advanced disease were enrolled, regardless of PD-L1 or TROP2 status, to receive sac-TMT at 5 mg/kg Q2W until disease progression or unacceptable toxicity. For pts with recurrent TNBC, a disease-free interval (DFI) of at least 6 months was required for eligibility. Tumor assessment was performed every 6 weeks per RECIST v1.1 as assessed by investigator. Results: As of 18 Nov 2024, a total of 41 pts (median age 55 yrs; 43.9% ECOG PS 1; 78.0% PD-L1 CPS < 10) were enrolled; 61.0% of pts had visceral metastases at baseline, 29.3% of pts had de novo metastasis, 19.5% of pts had a DFI of 6-12 months (mos), and 51.2% of pts had a DFI > 12 mos. The median follow-up was 18.6 mo. The objective response rate (ORR) was 70.7% (29/41, 3 unconfirmed PR) and the disease control rate (DCR) was 92.7%. Median duration of response (mDoR) was 12.2 mo, while the median progression-free survival (mPFS) was 13.4 mo, and the 12-mo PFS rate was 64.6% (95% CI: 45.0%, 78.7%). Among the 32 pts with PD-L1 CPS < 10, the ORR was 71.9% (23/32, 3 unconfirmed PR) and the DCR was 93.8%. The mPFS in this subgroup was 13.1 mo, with a 12-mo PFS rate 59.1% (95% CI: 37.1%, 75.7%). Treatment-related adverse events (TRAEs) of grade 3 or higher occurred in 63.4% of pts. The most common ≥ grade 3 TRAEs (occurred in ≥5% of pts) were neutrophil count decreased (46.3%), WBC count decreased (34.1%), anemia (12.2%), stomatitis (9.8%), lymphocyte count decreased (7.3%) and fatigue (7.3%). No treatment-related deaths occurred, and there were no reports of neuropathy or interstitial lung disease/pneumonitis. Conclusions: Sac-TMT demonstrated promising anti-tumor activity with a manageable safety profile as a first-line treatment for pts with a/mTNBC, independent of the PD-L1 status. A Phase 3 study comparing sac-TMT vs investigator’s choice of chemotherapy in first-line PD-L1-negative (CPS < 10) a/mTNBC is currently underway (NCT06279364). Clinical trial information: NCT05445908 .