Sacituzumab Tirumotecan Shows Promising Antitumor Activity with Manageable Toxicity in Solid Tumors

Findings from the first-in-human phase 1/2 trial (NCT04152499) of sacituzumab tirumotecan (sac-TMT) demonstrate that the investigational antibody-drug conjugate has a manageable toxicity profile and promising antitumor activity. This was observed in patients with unresectable locally advanced or metastatic solid tumors who were refractory to standard therapies.¹

In the phase 1 portion of the trial, 30 patients received escalating doses of the agent at 2, 4, 5, 5.5, and 6.0 mg/kg. Overall, 5 patients experienced dose-limiting toxicities (DLTs): 1 patient (14%) in the 4-mg/kg group had grade 3 stomatitis, 1 patient (14%) in the 5-mg/kg group had grade 3 rash, 1 patient (20%) in the 5.5-mg/kg group had grade 3 stomatitis, and 2 patients (29%) in the 6-mg/kg group had grade 3 urticaria or grade 3 stomatitis.

No further dose escalation occurred beyond the 6 mg/kg dosage based on DLT assessment criteria and the safety profile.

Overall, 28 patients (93%) reported 1 or more adverse events (AEs), all deemed to be treatment-related per the investigators. These were grade 3 or 4 in 17 patients (57%); none were grade 5. The most common treatment-related AEs (TRAEs) were nausea (63%), alopecia (57%), and anemia (50%). There was only 1 patient who discontinued treatment because of a TRAE: 1 patient in the 2-mg/kg group due to grade 2 treatment-related pneumonitis, as assessed by the investigator. Additionally, pneumonia was also reported in this patient during the period with the treatment-related pneumonitis event. Overall, TRAEs led to treatment interruption in 13 patients and dose reduction in 6 patients, and the most commonly occurring TRAEs included nausea, alopecia, anemia, stomatitis, and vomiting.

Phase 2

The recommended dose for expansion (RDE) in phase 2 were the 4 mg/kg and 5 mg/kg doses. Fifty-nine patients with triple negative breast cancer (TNBC) or HR-positive/HER2-negative breast cancer were treated. For patients in the dose expansion portion, the objective response rate (ORR) was 34.8% (95% CI, 16.4%–57.3%) in the 4-mg/kg group (n = 23) and 38.9% (95% CI, 23.1%–56.5%) in the 5-mg/kg group (n = 36) for TNBC. In patients with HR-positive/HER2-negative breast cancer, the ORR was 31.7% (95% CI, 18.1%-48.1%; n = 41).

Study Details

In phase 1, 30 patients were enrolled across 10 sites between March 16, 2020, and November 1, 2021. The doses were 2 mg/kg (n = 4), 4 mg/kg (n = 7), 5 mg/kg (n = 7), 5.5 mg/k (n = 5), and 6 mg/kg (n = 7). At the time of data cutoff, all patients had discontinued study treatment, primarily due to progressive disease. In addition to breast cancer, other patients had ovarian cancer, pancreatic cancer, urothelial carcinoma, non–small cell lung cancer, gastric or gastroesophageal junction cancer, and endometrial cancer.

The agent was administered as a single intravenous infusion every 2 weeks on days 1 and 15 of each 4-week cycle at doses of 2, 4, 6, 9, and 12 mg/kg in dose-escalating cohorts. In phase 2, sac-TMT was administered every 2 weeks on days 1 and 15 of each 4-week cycle per the recommended doses identified in phase 1 of the study. Treatment continued until disease progression, unacceptable toxicity, patient withdrawal, or death.

The primary end points for phase 1 were maximum tolerated dose (MTD) of sac-TMT and establishing RDEs (phase 1) and determining ORR per RECIST v1.1 by investigator assessment (phase 2). The secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Demographics

In phase 1, the overall median age was 56 years (range, 32-72), 87% were women, and most patients (73%) had an ECOG performance status of 1. Patients were Asian (50%), White (40%), other (7%), and Black (3%). The median tumor burden was 85.4 mm (range, 25.0-220.0 mm).

In patients with TNBC in phase 2 (n = 59), the median age was 49.0 years (range, 31.0-73.0), all patients were women and from China, and most (75.0%) had an ECOG performance status of 1. This population was heavily pretreated, with the majority (39.0%) treated with 5 or more lines of therapy.

In patients with HR-positive/HER2-negative disease, the median age was 50.0 years (range, 34.0–66.0) and all patients were women from China. Most (61.0%) had an ECOG performance status of 1, and 76% had previously been treated with 5 or more lines of therapy.

In patients with metastatic TNBC, the ORR was 37% across all patients, 35% in the 4-mg/kg group, and 39% in the 5-mg/kg group. Median DOR was 11.5 months (range, 5.4-22.1+) and 11.5 months (range, 3.7–19.3+), respectively. Median PFS was 5.7 months among all patients, 5.8 months in the 4-mg/kg group, and 5.5 months in the 5-mg/kg group (Fig. 3). Median OS was 15.7, 12.1, and 17.1 months, respectively.

In patients with HR-positive/HER2-negative breast cancer, the ORR was 32%. Median DOR was 9.5 months (range, 4.2–17.0+), the median PFS was 8.0 months, and the median OS was 13.9 months.

The median duration of treatment exposure in patients with metastatic TNBC was 5.3 months (range, 0–26) in the 4-mg/kg group and 3.6 months (range, 0–22) in the 5-mg/kg group. All patients reported 1 or more treatment-related adverse event (TRAE). Thirty-six patients (61%) reported grade 3 or 4 TRAEs, including 12 (52%) in the 4-mg/kg group and 24 (67%) in the 5-mg/kg group; none were grade 5. The most common TRAEs in both dosing groups were anemia (4 mg/kg, 74%; 5 mg/kg, 89%), decreased white blood cell count (4 mg/kg, 74%; 5 mg/kg, 78%), and decreased neutrophil count (4 mg/kg, 61%; 5 mg/kg, 72%).

In patients who were HR-positive/HER2-negative, the median duration of treatment exposure was 5.0 months (range, 0-19) and all patients reported 1 or more TRAEs. Twenty-two patients (54%) reported grade 3 or 4 TRAEs and there were no grade 5 TRAEs reported. The most common TRAEs were decreased white blood cell count (88%), anemia (85%), and decreased neutrophil count (85%).

Sacituzumab tirumotecan (sac-TMT) is an antibody–drug conjugate composed of an anti-TROP2 monoclonal antibody coupled to a cytotoxic belotecan-derived topoisomerase I inhibitor (KL610023) via a novel linker. Previous studies have evaluated the antitumor activity in other TROP2-directed ADCs. In studies of patients with relapsed or refractory metastatic TNBC, sacituzumab govitecan (Trodelvy) was associated with ORRs between 33% and 35%, median PFS of 5.5 to 5.6 months and median OS of 12.1 to 13.0 months.^2,3

These findings support further assessment of sac-TMT in phase 3 trials.

REFERENCES:

1. Ouyang Q, Rodon J, Liang Y, et al. Results of a phase 1/2 study of sacituzumab tirumotecan in patients with unresectable locally advanced or metastatic solid tumors refractory to standard therapies. J Hematol Oncol. 2025;18(1):61. doi:10.1186/s13045-025-01705-2

2. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213

3. Bardia A, Messersmith WA, Kio EA, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol. 2021;32(6):746-756. doi:10.1016/j.annonc.2021.03.005