Background: SI-B001 is a first-in-class novel EGFR×HER3 bispecific antibody. The objective of this phase II study was to investigate the efficacy and safety of SI-B001 in combination with chemotherapy in pts with locally advanced or metastatic EGFR/ALK wild-type NSCLC. Methods: This phase II study enrolled patients with locally advanced or metastatic EGFR/ALK wild-type NSCLC who had failed first-line anti-PD-1/L1 therapy, with or without platinum-based chemotherapy (PBC). This study consisted of three cohorts: In Cohort A pts received SI-B001 plus PBC as second-line treatment after failure to first-line anti-PD-1/L1 antibody monotherapy; Cohort B pts received SI-B001 plus docetaxel as second-line treatment after failure to first-line anti-PD-1/L1 therapy plus PBC; Cohort C pts received SI-B001 plus docetaxel as third-line or higher treatment after failure to first-line anti-PD-1/L1 therapy and PBC. This study evaluated SI-B001 in three distinct dosing schedules: Schedule 1 (16+9mg/kg once weekly), Schedule 2 (14mg/kg on Days 1 and 8 every 3 weeks), and Schedule 3 (21+12mg/kg once weekly). The primary endpoints of the study were to determine the objective response rate (ORR) in evaluable patients and to identify the optimal dose. The secondary endpoints included assessment of progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), and safety. Results: As of November 11, 2022, 55 pts have been enrolled in the study, including 1 pt in Cohort A, 45 pts in Cohort B, 8 pts in Cohort C, and one pt enrolled based on the investigator's discretion. Of the 55 pts, 48 were evaluable for efficacy; ORR (n/N, [95%CI]) of 31.3% (15/48, [18.7, 46.3]), DCR of 77.1% (37/48, [62.7, 88.0]). In Cohort B, 23 pts were enrolled in schedule 1, 21 pts were enrolled in schedule 2, and 1 pt was enrolled in schedule 3. Of the 45 pts enrolled in Cohort B, 38 were evaluable for efficacy. Among 22 evaluable pts in schedule 1 the ORR was 45.5% (10/22, [24.5, 67.8]) and the DCR was 68.2% (15/22, [45.1, 86.1]). 18 out of the 22 had no actionable genomic alterations (AGA), the ORR was 50.0% (9/18, [26.0, 74.0]), the DCR was 72.2% (13/18, [46.5, 90.3]), and the mPFS has not been reached. The most common grade ≥3 treatment-related adverse events (TRAEs) were myelosuppression (17%), decreased neutrophil count (15%), and decreased white blood cell count (12%). There was no drug-related death. Conclusions: SI-B001 plus docetaxel demonstrated antitumor activity in locally advanced or metastatic NSCLC EGFR/ALK wild-type pts who failed on prior first-line anti-PD-1/L1 antibody plus PBC, especially without AGA. The toxicity of SI-B001 + docetaxel was manageable. These findings support the continued investigation of SI-B001 and docetaxel as a treatment option in NSCLC. Clinical trial information: NCT05020457.