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Background ASKG915 is a bifunctional fusion protein of PD-1 antibody fused with an IL-15 prodrug. Preclinical studies demonstrated its efficacy in neoplastic models. Here, we present initial safety and efficacy results from a first-in-human, dose escalation and dose expansion of ASKG915 monotherapy in patients (pts) with advanced solid tumors.Methods This open-label, multicenter, Phase 1/2 study in adult pts with advanced solid tumors ( NCT05867420) comprised two parts: dose escalation and dose expansion. Pts with advanced solid tumors that were resistant/refractory to current standard treatment, and with at least 1 measurable lesion per RECIST 1.1, were eligible. The primary objective was safety. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity.Results As of June 09, 2025, 46 pts were enrolled at dose-escalation phase (n=16) and dose expansion phase (n=30). Primary tumor types included NSCLC (n=17, 37%), colorectal cancer (n=13, 28%), ovarian cancer (n=8, 17%), cervical cancer (n=4, 9%) and others (n=4, 9%). Most pts (39/46, 85%) had received more than two lines of prior treatment, and 30 pts (65%) had undergone previous immunotherapy.No dose-limiting toxicity was observed and the maximum tolerated dose has not been reached. Grade 3 and above ASKG915-related treatment emergency adverse event(TEAE)s occurred in five pts (31.3%). Serious TEAEs were reported in four pts (25.0%). Based on overall safety data, two doses were selected for further exploring at dose expansion phase. During the dose expansion phase, anemia (9/30, 30%), rash (7/30, 23.3%) and pyrexia (6/30, 20%) were the most frequently reported TEAEs; grade 3 ASKG915-related TEAEs only occurred in three pts (10%), including abnormal liver function , rash and blood pressure elevated. All toxicities were manageable/reversible.The ORR and DCR were 8.3% and 47.2% across all dose levels of ASKG915 monotherapy. Three partial responses were observed (2 MSS CRC and 1 NSCLC). In 3rd line and above MSS CRC subgroup at the mid dose level or above (n=10), the ORR were 20% in all pts regardless of liver metastasis (LM) status and 33.3% in pts (n=6) without LM. CD8+ T and NK cells in pts receiving mid dose at or above showed an increasing trend towards proliferation and expansion, alongside elevated levels of INF-γ. The total plasma drug exposure in pts increased dose-dependently within the range of study doses after the initial administration.Conclusions ASKG915 monotherapy showed a tolerable safety profile and promising antitumor activity in heavily pretreated advanced solid tumors. These results support further evaluation of ASKG915.Acknowledgements We thank the patients and their families for their participation in the study, and we thank all research personnel for their support of this trial. The study was funded by ASKgene pharm, Inc.Trial Registration Clinical trial information: NCT05867420Ethics Approval The protocol and all amendments were approved by the independent ethics committee at each participating study site. The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.