Background: Since the initial approval of bevacizumab (bev) with chemo in NSCLC, the subsequent focus of bev use in combination with PD1 therapy for first line metastatic disease has largely focused on non-squamous (non-SCC) histology. Ivonescimab is a novel anti-PD-1/VEGF bispecific antibody. The bispecific approach to these targets has the potential to recalibrate the malignant immuno-architecture in favor of a more immune-responsive and anti-tumor microenvironment. Cooperative VEGF binding with the bispecific has been shown to elevate affinity of ivonescimab to PD-1 by more than 10-fold. Ivonescimab has a mean T_1/2 of 6-7 days while bev T_1/2 is 20 days. Therefore, we aimed to assess the efficacy and safety of ivonescimab combined with chemotherapy for first line advanced or metastatic NSCLC in patients (pts) with squamous (SCC) or non-SCC NSCLC. Methods: An open-label, multi-center phase II study evaluating the efficacy and safety of ivonescimab combined with chemotherapy in pts with advanced or metastatic NSCLC. Pts were enrolled into 3 cohorts based on prior therapy and presence of AGA. Data from pts with prior therapy for advanced or metastatic disease were presented in ASCO 2022 and here we report additional pts and longer-term data from pts with NSCLC without AGA receiving first line therapy for advanced/metastatic disease. Pts were treated with 10 or 20 mg/kg ivonescimab once every 3wks combined with carboplatin and pemetrexed (non-SCC) or carboplatin and paclitaxel (SCC). The primary endpoint was ORR per RECIST by investigator. Results: 135 pts with advanced or metastatic NSCLC received ivonescimab plus chemotherapy including 63 with SCC and 72 with non-SCC. Median age was 61 yrs (. 78% male, 3% and 97% pts had ECOG PS 0 and 1, respectively, and 20% pts had baseline brain metastasis. Median follow-up was 11.5 mo. Pts with SCC experienced a 75% ORR with median DOR 15.4 mo, 95% DCR, the 9-mo PFS and OS rate was 67% and 93%, respectively. Pts with non-SCC experienced a 55% ORR, DOR was not reached, 100% DCR, the 9-mo PFS rate and OS rate was 61% and 81%, respectively. The most common treatment related adverse events (TRAEs)≥ 10% were epistaxis, proteinuria, rash, amylase increased, anemia, ALT increased, infusion related reaction, AST increased, pruritus, decreased appetite, and WBC decreased. Grade ≥3 TRAEs occurred in 28.1% TRAE leading to discontinuation occurred in 6.7% of pts. Conclusions: Ivonescimab, plus chemotherapy has shown promising anti-tumor activity in pts with advanced/metastatic NSCLC without AGA and can be administered safely in combination with platinum doublet chemotherapy to patients with SCC and non-SCC histology. Clinical trial information: NCT04736823.