Kelun-Biotech's Sacituzumab tirumotecan (Sac-TMT) has been granted marketing authorization by China's National Medical Products Administration (NMPA) for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received at least two prior systemic therapies. This marks a significant milestone as the first domestically developed TROP2-directed antibody-drug conjugate (ADC) to receive full approval in China.
The approval is based on the results of the Phase III OptiTROP-Breast01 study, a randomized, controlled trial that demonstrated a statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) with Sac-TMT compared to chemotherapy in patients with advanced TNBC who had received at least two prior systemic therapies. These findings were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.
Clinical Efficacy and Safety
The OptiTROP-Breast01 trial enrolled patients with locally recurrent or metastatic TNBC whose disease had relapsed following or was refractory to two or more prior chemotherapy regimens. Patients were randomized to receive intravenous Sac-TMT at 5 mg/kg every two weeks or physician's choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine).
The primary endpoint was PFS by blinded independent central review (BICR). Secondary endpoints included OS, investigator-assessed PFS, overall response rate (ORR), duration of response (DOR), and safety.
Data from the trial showed that patients receiving sacituzumab tirumotecan (n = 130) achieved a median PFS per BICR of 5.7 months (95% CI, 4.3-7.2) compared with 2.3 months (95% CI, 1.6-2.7) among patients who received investigator’s choice of chemotherapy (n = 133; HR, 0.31; 95% CI, 0.22-0.45; P < .00001). Additionally, patients with high TROP2 expression (HR, 0.29; 95% CI, 0.19-0.46) and those with low/medium TROP2 expression (HR, 0.35; 95% CI, 0.21-0.56) achieved a significant PFS benefit with sacituzumab tirumotecan vs chemotherapy.
Interim OS analysis showed a median OS that was not yet reached (NR; 95% CI, 11.2-not evaluable) in the Sac-TMT arm compared to 9.4 months (95% CI, 8.5-11.7) in the chemotherapy arm (HR, 0.53; 95% CI, 0.36-0.78; P = .0005). The 12-month OS rates were 57.8% vs 35.2%, respectively. The ORRs were 45.4% vs 12.0%, respectively, and the respective median DORs were 7.1 months vs 3.0 months (HR, 0.50; 95% CI, 0.22-1.13).
Regarding safety, all patients in the Sac-TMT arm experienced a treatment-related adverse event (TRAE) compared to 96.2% in the chemotherapy arm. Grade 3 or higher TRAEs were similar between arms (57.7% vs 56.8%, respectively).
Mechanism of Action
Sac-TMT is a novel human TROP2 ADC comprising a recombinant anti-TROP2 humanized monoclonal antibody conjugated to a belotecan-derivative topoisomerase I inhibitor (KL610023) via a novel linker. The drug has a drug-to-antibody ratio (DAR) of 7.4. Upon binding to TROP2 on tumor cells, Sac-TMT is internalized, releasing KL610023 intracellularly, which induces DNA damage, cell cycle arrest, and apoptosis. The released KL610023 is membrane permeable, enabling a bystander effect, killing adjacent tumor cells.
Future Development
In addition to the TNBC approval, the NMPA is reviewing supplemental new drug applications (sNDAs) for Sac-TMT monotherapy in locally advanced or metastatic EGFR-mutant NSCLC following progression on EGFR-TKI therapy, or both EGFR-TKI and platinum-based chemotherapy.
Outside of Greater China, MSD (Merck & Co., Inc.) holds exclusive rights to develop, manufacture, and commercialize Sac-TMT under a licensing agreement with Kelun-Biotech.
