9516 Background: Mucosal melanoma (MM) is a rare and aggressive cancer with a poor prognosis. Unlike its more common counterpart, cutaneous melanoma, MM responds poorly to standard single-agent immunotherapy, such as anti-PD-1 monoclonal antibodies (mAbs), limiting treatment options. This clinical challenge underscores the need for more effective strategies, making combination therapies a clear future direction. The aim is to overcome resistance by targeting multiple pathways simultaneously. The main objective of this study is to explore and compare two distinct immunotherapy backbones—targeting the PD-1/CTLA-4 and VEGF pathways—for their potential in future rational combinations against MM. Methods: This is a phase Ib, dose de-escalation and cohort-expansion, open-label trial. The combination dose of axitinib will utilize a "3+3" dose de-escalation design. The starting dose is 5 mg. If dose-limiting toxicity (DLT) is observed at this dose level, the dose for subsequent cohorts will be reduced to 3 mg. Patients with metastatic melanoma receive 10 mg/kg cadonilimab Q3W (cohort 1) or 20 mg/kg ivonescimab Q3W (cohort 2) in combination with 5 mg axitinib BID. Primary endpoints are rate of dose-limiting toxicities (DLTs) and safety. Secondary endpoints are objective response rate (ORR) by investigator assessment, duration of response (DOR), progression-free survival (PFS), overall survival (OS) and overall safety. Results: As of December 25, 2025, a total of 28 patients have been enrolled in the study (14 cohort 1; 14 cohort 2). Median follow-up of 13 months. The distribution of primary tumor sites was as follows: oral cavity 14.3%, esophagus17.9%, rectum 32.1%, and cervix 35.7%. 21% had elevated LDH. BRAF status, known for 71% of patients, was positive in 25%. No DLT or treatment related death was observed，Axitinib was selected as 5 mg BID. 71.4% patients experienced treatment related AE (TRAE) and 17.9% patients experienced Grade 3-4 TRAEs. In cohort 1，the most common TRAEs include hypothyroidism, hypertension, diarrhea, anorexia and rash. In cohort 2, the most common TRAEs include proteinuria, myalgia, hyperthyroidism, hypertension, abnormal transaminase levels, anorexia and hyperlipidemia. No patient discontinued treatment due to TRAE. ORR, DOR, DCR, and median PFS for all cohorts are shown in Table. Conclusions: The combination therapy involving cadonilimab or ivonescimab plus axitinib demonstrates a promising safety and efficacy profile. These findings suggest that such dual-antibody-based regimens could provide synergistic anti-tumor activity with an improved therapeutic index, warranting further clinical investigation. Clinical trial information: NCT06424626 . Secondary Endpoint Cohort 1 （n=14） Cohort 2 （n=14） PR 5 5 SD 4 5 PD 5 4 ORR 35.7% 35.7% DCR 64.3% 71.4% DOR (mo) 6.7 6.4 mPFS (mo) 5.8 8.7 mOS (mo) NA NA
Mao et al. (Thu,) studied this question.