Sacituzumab tirumotecan (sac-TMT) is a novel Trop2-directed antibody–drug conjugate utilizing a proprietary linker for conjugation with a belotecan-derived topoisomerase I inhibitor payload. In prior phase 1/2 trials, sac-TMT demonstrated promising antitumor activity in pretreated patients with hormone receptor (HR)-positive/HER2-negative metastatic breast cancer (mBC). This study reports that sac-TMT showed a statistically significant and clinically relevant improvement in PFS compared with investigator-selected chemotherapy (ICC).
The randomized phase 3 OptiTROP-Breast02 (NCT06081959) trial enrolled patients with HR-positive/HER2-negative breast cancer who had progressed on cyclin-dependent kinase (CDK)4/6 inhibitors and had received 1 to 4 prior lines of chemotherapy in the advanced or metastatic setting. Patients were randomized (1:1) to receive either sac-TMT (5 mg/kg every 2 weeks) or physician’s choice of ICC (eribulin, vinorelbine, capecitabine, or gemcitabine). The primary endpoint was PFS. Secondary endpoints included investigator-assessed progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and duration of response. Efficacy measures are reported for the intent-to-treat population.
A total of 399 patients were enrolled (sac-TMT, n=200; ICC, n=199 [eribulin (n=122), gemcitabine (n=43), vinorelbine (n=24), and capecitabine (n=10)]), with a median age of 54 years. At baseline, in the sac-TMT cohort, 54.0% had HER2-zero disease, 96.5% had visceral metastases, and 56.5% had received ≥2 prior lines of chemotherapy. In the ICC cohort, 51.8% had HER2-zero disease, 95.0% had visceral metastases, and 56.8% had received ≥2 prior lines of chemotherapy. At the data cutoff (January 22, 2025), 113 patients in the sac-TMT group and 58 in the ICC group remained on treatment. The median follow-up was 7.4 months. Significantly improved median PFS was observed with sac-TMT compared with ICC (8.3 vs 4.1 months; hazard ratio, 0.35; 95% confidence interval [CI], 0.26-0.48; P<.0001). The 6-month PFS rate was 61.4% with sac-TMT versus 25.7% with ICC. A consistently longer PFS was observed for sac-TMT over ICC across all predefined subgroups. Longer PFS in the sac-TMT group was observed irrespective of HER2 expression (HER2-zero: hazard ratio, 0.39; 95% CI, 0.26-0.57; HER2-low: hazard ratio, 0.31; 95% CI, 0.20-0.48). Although OS data were immature at a median follow-up of 7.4 months, sac-TMT showed a trend toward improved OS compared with ICC, 41.5% vs 24.1% (hazard ratio, 0.33; 95% CI, 0.18-0.61). In the sac-TMT cohort, DCR was 86.0% and ORR was 41.5%, and in the ICC cohort, DCR was 68.3% and ORR was 24.1%. The absolute improvement in DCR between sac-TMT and ICC was 17.8% (95% CI, 9.8-25.8) and the absolute improvement in ORR between sac-TMT and ICC was 17.4% (95% CI, 8.4-26.3).
Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 62.0% of sac-TMT-treated patients and 64.8% of ICC-treated patients. The most common grade ≥3 TRAEs with sac-TMT and ICC, respectively, were decreased neutrophil counts (45.0% vs 52.0%) and decreased white blood cell counts (31.0% vs 32.0%). TRAEs led to treatment discontinuation in 0% of patients in the sac-TMT group and 0.5% in the ICC group. Grade 1 to 2 pneumonitis was observed in 1.5% and 1.0% of patients in the sac-TMT and ICC arms, respectively.
Sac-TMT demonstrated a statistically significant and clinically meaningful improvement in PFS compared with ICC, with consistent efficacy across HER2 expression subgroups (HER2-zero and HER2-low). The safety profile of sac-TMT was manageable, with no new safety signals identified. These findings support sac-TMT as a promising new treatment option for patients with HR-positive/HER2-negative mBC who have progressed on CDK4/6 inhibitors and prior chemotherapy. Further follow-up for OS data is ongoing.
Source: Li M, Fan Y, Li H, et al. Sacituzumab tirumotecan (sac-TMT) vs investigator's choice of chemotherapy (ICC) in previously treated locally advanced or metastatic hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer (BC): Results from the randomized, multi-center phase III OptiTROP-Breast02 study. Presented at: ESMO Congress 2025. October 18, 2025; Berlin, Germany. Abstract LBA23.