380MO SKB264 (MK-2870) in previously treated hormone receptor-positive (HR+)/ HER2-negative metastatic breast cancer (mBC): Results from a phase I/II, single-arm, basket trial

TROP2 is commonly overexpressed in HR+/HER2- mBC and associated with poor prognosis. SKB264 is a novel anti-TROP2 ADC developed using sulfonyl pyrimidine-CL2A-carbonate linker to conjugate its payload, a belotecan-derivative topoisomerase I inhibitor, to achieve an average Drug-to-antibody Ratio (DAR) of 7.4. This is the first report of results from a phase II cohort in patients (pts) with HR+/HER2- mBC. Pts with HR+/HER2- (including HER2-low and HER2-zero) mBC received SKB264 at a dose of 5 mg/kg Q2W until progression or unacceptable toxicity. Eligibility included progression on endocrine-based therapy and at least one prior chemotherapy for mBC. Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator. As of data cut-off (April 12, 2023), 41 pts (median age 50 yrs [34-66], 61% ECOG PS 1) were enrolled. Median follow-up was 8.2 months (mo). Treatment-related adverse events (TRAEs) of ≥ Grade 3 were reported in 48.8% (20/41) of pts. The most common ≥ Grade 3 TRAEs (≥ 5%) were neutrophil count decreased (36.6%), white blood cell count decreased (22%), anemia (14.6%), platelet count decreased (9.8%) and GGT increase (7.3%). TRAEs led to dose reduction in 17.1% (7/41) of pts. No neuropathy or drug-related ILD/pneumonitis was reported. No TRAEs led to treatment discontinuation or death. Of 38 pts evaluable for response assessment, 47% of pts had primary endocrine resistance; 79% of pts had received ≥2 prior chemotherapy for metastatic disease, and prior treatments included taxane (100%), and CDK 4/6 inhibitors (65.8%). The ORR was 36.8% (14/38, 12 confirmed PR and 2 unconfirmed PR) and DCR was 89.5%, median DoR was 7.4 mo (range, 4.2 to 14.9+), 6-mo DoR rate was 80%. Median PFS was 11.1 mo (95% Cl: 5.4, 13.1), and 6-mo PFS rate was 61.2%. SKB264 at 5 mg/kg demonstrates a manageable safety profile and promising antitumor activity in pts with pre-treated HR+/HER2- mBC. Two phase 3 studies are currently planned in HR+/HER2- mBC, one in China for pts after at least one chemo for mBC and a second global for pts previously untreated with chemo for mBC, both comparing SKB264 vs investigator selected chemo.