Background: SI-B001 is an EGFR×HER3 bispecific antibody. We present the efficacy and safety results from two ongoing studies of SI-B001, S209 and S206, in recurrent and metastatic HNSCC. Methods: S209 included pts with recurrent and metastatic HNSCC progressed on prior anti-PD-1/L1 plus platinum-based chemotherapy (PBC). Pts were treated with SI-B001 16mg/kg IV QW. S206 included pts with recurrent and metastatic HNSCC progressed on prior anti-PD-1/L1 with or without PBC and received no more than two lines of treatment. Pts enrolled in S206 were divided into two groups: Group A, pts without prior exposure to paclitaxel were treated with SI-B001 (12mg/kg IV QW) plus paclitaxel (80mg/m² IV QW); Group B, pts with prior exposure to paclitaxel were treated with SI-B001 (12mg/kg IV QW) plus docetaxel (35mg/m² IV D1D8D15 Q4W). The study endpoints of the two studies were identical. The primary endpoint was objective response rate (ORR) by investigator per RECIST v1.1. Secondary endpoints were ORR by independent central review, progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall Survival (OS), and safety. Results: As of Dec 31, 2022, 11 pts in S209 received SI-B001. Pts had a median of 4 prior lines of therapy. In 9 out of 11 pts who have at least 1 post baseline tumor assessment in S209, ORR (n/N) was 22.2% (2/9), mPFS [95%CI] was 2.7 [1.8-7.9] mo. 29 pts in S206 received SI-B001 plus chemotherapy, including 19 pts in Group A and 10 pts in Group B. In 22 pts who had at least 1 post baseline tumor assessment, ORR was 45.5% (10/22), mPFS was 5.1 [3.7-5.6] mo. 1 nasal sinus cancer pt enrolled had stable disease (SD). 14 out of the 18 pts who have at least 1 post baseline tumor assessment in Group A, ORR was 64.3% (9/14) mPFS was 5.6 [5.1-6.3] mo. 8 out of 10 pts who have at least 1 post baseline tumor assessment in Group B, ORR was 12.5% (1/8), mPFS was 1.9 [1.2-3.7] mo. The most common grade 3 and above treatment-related adverse events (TRAEs) in S209 was Hypomagnesaemia (9%). The most common grade 3+ TRAEs in S206 were rash (16%), anaemia (8%) and white blood cell count decreased (8%). No SI-B001 drug-related deaths occurred in either study. Conclusions: SI-B001 plus paclitaxel demonstrated potential improvements in ORR and DCR compared with SI-B001 monotherapy in recurrent and metastatic HNSCC. The toxicity of SI-B001 plus chemotherapy in HNSCC is manageable and tolerable. Clinical trial information: NCT05044897; NCT05054439.