Safety and efficacy of a novel PD-L1/4-1BB bispecific antibody QLF31907 in previously-treated patients with advanced melanoma: Results from a phase 2 study.

2527 Background: QLF31907, a bispecific antibody that simultaneously block PD-1/L1 immunosuppressive pathway on cancer cells and conditionally activate 4-1BB co-stimulatory pathway on tumor-specific T cells, was designed to restrict 4-1BB agonism to the tumor microenvironment, which might overcome resistance to PD-(L)1 inhibitor and reduce hepatoxicity as traditional 4-1BB monoclonal antibodies reported. Although immunotherapy (IO) has revolutionized the treatment of melanoma, a significant proportion of patients (pts), particularly those with mucosal and acral subtypes, either fail to respond initially or experience disease relapse after treatment. Here, we present results of QLF31907 in previously-treated pts with advanced melanoma, including IO-exposed. Methods: This phase 2 trial was comprised of safety observation stage and efficacy expansion stage. Pts with unresectable locally advanced or metastatic melanoma who failed, were intolerable to, or refused standard treatment were recruited and administered QLF31907 via intravenous infusion from 5 mg/kg to 20 mg/kg every 2 weeks (Q2W) or 3 weeks (Q3W). The primary endpoints were dose-limiting toxicity (DLT) and safety in safety observation stage, and was objective response rate (ORR) per RECIST v1.1 assessed by investigator in efficacy expansion stage. Results: As of Dec 31, 2025, 59 pts were enrolled (median age: 57.0 years; male: 47.5%; ECOG PS of 1: 42.4%; stage IV: 93.2%). The mucosal subtype accounted for the most (40.7%), followed by acral (33.9%), cutaneous (non-acral; 18.6%) and primary unknown (6.8%). Median prior lines of therapies were 2.0 (range, 1–5). Fifty-five (93.2%) pts received prior immunotherapy, including 50 (87.7%) pts received prior anti-PD-1/PD-L1 agents. No DLT occurred. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 34 (57.6%) pts. The most common grade ≥3 TEAEs (≥10%) were liver injury (18.6%), neutrophil count decreased (15.3%), anemia (13.6%), white blood cell count decreased (11.9%). In 57 efficacy-evaluable pts, seven had partial response. The ORR and disease control rate (DCR) was 12.3% (95% confidence interval [CI], 5.1%-23.7%) and 56.1% (95% CI, 42.4%-69.3%), respectively. The median progression-free survival, duration of response, and overall survival was 2.6 months (95% CI, 1.6-3.7), 5.8 months (95% CI, 2.3-not evaluable [NE]), and 15.3 months (95% CI, 11.6-NE), respectively. Conclusions: QLF31907 showed potential anti-tumor activity and acceptable safety profile in heavily-treated pts with advanced melanoma, including IO-exposed pts. These results warrant validation in further clinical trials. Clinical trial information: NCT05823246 .