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Phase I study of Y101D, a bispecific antibody targeting PD-L1 and TGF-β in patients with advanced solid tumors
Haishuang Sun1, Gang Chen1, Jinhui Xue2
1Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Background:
Y101D is a novel bispecific antibody targeting PD-L1 and TGF-β. This multicenter phase I study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of Y101D in patients with metastatic or locally advanced solid tumors.
Methods:
Patients who failed standard therapies were enrolled. In the dose-escalation and -expansion phases, Y101D was administered intravenously every 2 weeks (Q2W) at 1, 3, 10, 20, and 30 mg/kg. Primary objectives were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) in escalation, safety, and objective response rate (ORR) in expansion. Secondary objectives included pharmacokinetics/pharmacodynamics parameters, and immunogenicity.
Results:
Among 50 enrolled patients, the most common treatment-related adverse events (TRAEs) were aspartate aminotransferase elevation (20.0%), gingival bleeding (18.0%), alanine aminotransferase elevation (14.0%), rash (14.0%), and proteinuria (14.0%). Grade ≥ 3 TRAEs occurred in 10.0% of patients, with no grade 4/5 TRAEs. Immune-related adverse events (irAEs) occurred in 22.0%, predominantly grades 1-2. No DLTs were observed, and MTD was not reached. One extensive-stage small cell lung cancer (ES-SCLC) patient (20 mg/kg Q2W) achieved a confirmed partial response (ORR: 2.1%, 95% CI, 0.1%-11.3%). Median progression-free survival and overall survival were 1.3 months (95% CI, 0.9-1.3) and 10.5 months (95% CI, 6.6-12.7), respectively. The pharmacokinetic characteristics of single and multiple doses of 20 mg/kg Q3W and 1200 mg Q3W supported the administration schedule of once every 3 weeks. PD-L1 target occupancy exceeded 95% at 2 h post-dose across all cohorts and remained sustained pre-dose.
Conclusions:
Y101D monotherapy exhibited a manageable safety profile and on-target pharmacodynamic activity, with limited antitumor activity as a single agent. Further evaluation in disease-focused cohorts and rational combination regimens is warranted, including in ES-SCLC.
Clinical Trial Number Registration:
NCT05028556.
Insights
Y101D, a novel bispecific antibody targeting PD-L1 and TGF-β, showed a manageable safety profile in solid tumor patients. Limited antitumor activity was observed as a single agent, warranting further combination studies.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Y101D is a novel bispecific antibody designed to simultaneously target PD-L1 and TGF-β.
- This study investigates Y101D in patients with advanced solid tumors who have exhausted standard treatment options.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of Y101D.
- To determine the maximum tolerated dose (MTD) and objective response rate (ORR) of Y101D.
Main Methods:
- A multicenter phase I dose-escalation and expansion study.
- Y101D was administered intravenously every two weeks at doses ranging from 1 to 30 mg/kg.
- Safety assessments included dose-limiting toxicities (DLTs) and treatment-related adverse events (TRAEs).
Main Results:
- No DLTs were observed, and the MTD was not reached, indicating good tolerability.
- Common TRAEs included elevated liver enzymes and rash; Grade ≥3 TRAEs occurred in 10% of patients.
- A partial response was observed in one patient with extensive-stage small cell lung cancer (ES-SCLC); ORR was 2.1%.
Conclusions:
- Y101D monotherapy demonstrated a manageable safety profile and achieved on-target PD-L1 pharmacodynamic effects.
- Limited antitumor activity suggests Y101D may be more effective in combination therapies.
- Further investigation in specific cancer types like ES-SCLC and combination regimens is recommended.
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