Background: DB-1303 is an antibody-drug conjugate (ADC) consisting of a humanized anti-HER2 IgG1 monoclonal antibody, covalently linked to proprietary DNA topoisomerase I inhibitor (P1003) via a maleimide tetrapeptide-based cleavable linker, with a high drug-to-antibody ratio (~8). Methods: This is a global first-in-human, dose-escalation and -expansion study in patients (pts) with advanced/metastatic solid tumors. Pts (ECOG 0-1) with HER2 – (high or low) expressing or mutant cancers who failed previously systemic therapies were recruited and received DB-1303 intravenously Q3W as monotherapy. The objectives were safety, tolerability, maximum tolerated dose (MTD) or recommended phase 2 dose (PR2D), pharmacokinetics (PK), and preliminary antitumor activity. Here we report the results from dose-escalation. Results: As of Jan 13, 2023, 85 pts received DB-1303 at 6 dose levels (2.2, 4.4, 6.0, 7.0, 8.0, and 10.0 mg/kg) and received a median of 7 (range, 1-27) prior lines of therapy, including previous anti-HER2 ADC therapy in 32.9% of pts. The median duration of treatment was 63.0 (range, 21-211) days, and 68 pts (80.0%) remained on treatment. Treatment-emergent adverse events (TEAEs) and ≥ grade (G) 3 TEAEs occurred in 74 pts (87.1%) and 18 pts (21.2%), respectively; the most common TEAEs were nausea (51.8%, 3.5% ≥ G3), vomiting (43.5%, 1.2% ≥ G3), platelet count decreased (35.3%, 3.5% ≥ G3), and anemia (29.4%, 5.9% ≥ G3). Few pts experienced neutropenia (10 [11.8%]) and alopecia (3 [3.5%]). There was no DLT or TEAEs leading to death. Interstitial lung disease occurred in 2 pts (2.4%, G1), without any ≥ G2. The exposure parameters (C_max and AUC) of DB-1303 ADC increased with ascending doses from 2.2 to 10.0 mg/kg. The half-life of DB-1303 ADC is approximately 6-7 days for 6.0-8.0 mg/kg dose cohorts. The exposure of serum release payload was magnitudes lower than that of DB-1303 ADC, demonstrating stability of the ADC in systemic circulation. A total of 52 pts had undergone at least one post-baseline tumor scan. Twenty-three pts (44.2%, 23/52) had objective partial tumor response per RECIST 1.1: Thirteen HER2+ breast cancer (BC) (50.0%, 13/26, including 5 pts with brain metastases [55.6%, 5/9]), 5 HER2 low BC (38.5%, 5/13), 2 colorectal cancer (66.7%, 2/3), 1 endometrial carcinoma (33.3%, 1/3), 1 esophageal cancer (50.0%, 1/2), and 1 ovarian cancer (50.0%, 1/2). Among all the pts, the DCR was 88.5% (46/52); for pts with HER2+ BC and HER2-low BC, the DCRs were 96.2% (25/26) and 84.6% (11/13), respectively. Conclusions: DB-1303 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2+ BC and brain metastasis as well as in HER2-low BC. Expansion is ongoing in selected tumor pts treated at the RP2D. Clinical trial information: NCT05150691.