SHR-A1921, an antibody-drug conjugate (ADC), has shown promising early efficacy and manageable safety in patients with platinum-resistant ovarian cancer, according to data from a phase 1 study presented at the 2024 ESMO Congress. The first-in-human trial (NCT05154604) evaluated the agent in heavily pretreated patients with limited treatment options.
Efficacy Results
In the cohort receiving SHR-A1921 at a dose of 3.0 mg/kg once every three weeks (n = 26), the overall response rate (ORR) was 42.3% (95% CI, 23.4%-63.1%), including a complete response (CR) rate of 3.8% and a partial response (PR) rate of 38.5%. Stable disease (SD) was observed in 57.7% of patients, resulting in a disease control rate (DCR) of 100.0% (95% CI, 86.8%-100.0%). The median duration of response (DOR) was 9.9 months (95% CI, 4.5-not reached [NR]), and the median progression-free survival (PFS) was 7.9 months (95% CI, 4.2-NR).
Patients treated with a dose of 2.0 mg/kg twice every three weeks (n = 17) experienced an ORR of 58.8% (95% CI, 32.9%-81.6%), with a PR rate of 58.8%. Stable disease was observed in 35.3% of patients, while 5.9% experienced progressive disease. The DCR in this group was 94.1% (71.3%-99.9%), with a median DOR of 6.3 months (95% CI, 3.0-NR) and a median PFS of 6.9 months (95% CI, 4.2-9.6).
Mechanism of Action and Prior Research
SHR-A1921 comprises a humanized anti-TROP-2 IgG1 monoclonal antibody linked to a DNA topoisomerase I inhibitor via a tetrapeptide-based cleavable linker. Platinum-resistant ovarian cancer is characterized by poor prognosis and limited effective treatment options after failure of platinum-based chemotherapy, which approximately 85% of patients with epithelial ovarian cancer eventually develop resistance to. Prior research established the maximum tolerated dose of SHR-A1921 at 4.0 mg/kg every three weeks, leading to the selection of 3.0 mg/kg once every three weeks and 2.0 mg/kg twice every three weeks for dose optimization.
Study Design and Patient Population
The study enrolled patients with histologically confirmed recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who experienced disease progression during or within six months after completing platinum-based therapy. Key inclusion criteria included measurable disease per RECIST 1.1, an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, acceptable organ function, and the availability of tumor tissue for TROP-2 expression analysis.
Patients received intravenous SHR-A1921 at 3.0 mg/kg on day 1 of each 21-day cycle or at 2.0 mg/kg on days 1 and 8 of each 21-day cycle until disease progression, intolerable toxicity, patient withdrawal, or investigator decision.
Safety Profile
Treatment-related adverse events (TRAEs) of any grade occurred in 100% of patients in both the 3.0-mg/kg and 2.0-mg/kg groups. Grade 3 or 4 TRAEs were observed in 42.3% and 60.0% of patients, respectively. TRAEs leading to treatment interruption occurred in 38.5% and 65.0% of patients, while dose reductions were required in 23.1% and 30.0% of patients, respectively. Serious TRAEs were reported in 15.4% and 35.0% of patients in the respective groups. No fatal TRAEs occurred in either group.
The most common grade 3 or 4 TRAEs included stomatitis (11.5%; 50.0%), anemia (3.8%; 15.0%), vomiting (7.7%; 0%), and nausea (0%; 5.0%) in the 3.0-mg/kg and 2.0-mg/kg groups, respectively.
Ongoing Phase 3 Trial
The efficacy and safety of SHR-A1921 are currently being evaluated in a phase 3 trial (NCT06394492) comparing it to investigator's choice of chemotherapy in patients with platinum-resistant epithelial ovarian cancer. This trial is actively recruiting participants.
