Background: The combination of immune checkpoint inhibitors with chemotherapy has become the first-line treatment for advanced non-squamous NSCLC with negative driver genes, but not for driver gene-positive tumors. PM8002 is a bispecific antibody targeting both PD-L1 and VEGF-A. Previous published data indicated that PM8002 has a tolerable safety profile and potential anti-tumor activity in a variety of solid tumors (SITC2022 abstract #725 and ASCO2023 abstract #2536). Here, we report results of PM8002 in advanced NSCLC patients in an ongoing Phase Ib/IIa trial. Methods: Patients with previously untreated advanced non-squamous NSCLC (EGFR/ALK wild-type and PD-L1+; Cohort 6), advanced non-squamous with EGFR mutations who had failed prior EGFR-TKI treatment (Cohort 7), or EGFR/ALK wild-type who had failed anti-PD-1/L1 therapy and platinum-based chemotherapy regiments (NSCLC IO- and PBC-treated) were enrolled into a Phase I/IIa trial. All patients received PM8002 until observations of unacceptable toxicity, disease progression, or consent withdrawal. Tumor responses were evaluated every 6 weeks. The primary endpoint was objective response rate (ORR), with disease control rate (DCR), progression-free survival (PFS), and safety, as secondary endpoints. Results: As of Dec 20, 2023, 61 patients with advanced NSCLC were enrolled and had at least one tumor assessment. Among 61 evaluable patients 16 partial response (PR) and 32 stable diseases (SD) were observed (all cohorts; see individual cohorts in the table below). Any-grade treatment-related adverse events (TRAEs) occurred in 85.2% patients (52/61) with those ≥ Grade 3 at 18% (11/61). Immune-related AEs (irAEs) occurred in 37.7% patients (23/61). Serious adverse events (SAEs) and treatment-related SAEs were observed in 23% (14/61) and 9.8% (6/61) of patients, respectively. The most common TRAEs (≥15%) were hypertension, hypothyroidism, proteinuria, hypoalbuminemia, hypocalcemia, aspartate aminotransferase increase, and lactate dehydrogenase increase. 8.2% (5/61) of patients discontinued PM8002 due to TRAEs. Conclusions: PM8002 showed preliminary antitumor activity and acceptable safety in patients with advanced NSCLC. Monotherapy and combination trials with chemotherapy for different indications are still ongoing. Clinical trial information: NCT05918445.