Background: Penpulimab is a novel human immunoglobulin G1 (IgG1) anti-programmed cell death-1 (PD-1) antibody. The effect of antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis was eliminated completely by the modification of crystallizable fragment to avoid the FcγR binding. ALTN-AK105-II-01 (NCT04203719) is a single-arm, multi-cohort, multicenter phase 2 study to explore the efficacy and safety of penpulimab plus anlotinib, a multikinase inhibitor inhibiting angiogenesis and tumor cell proliferation simultaneously, in the treatment of various advanced cancers. Here we report the results of the cohort 1 for patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Methods: Eligible pts were diagnosed with histologically confirmed R/M HNSCC and had failed at least one line of platinum-based chemotherapy. Other inclusion criteria included aged 18 years or older, ECOG PS 0-1, and previous anti-angiogenic agents or immune checkpoint inhibitors treatment-naïve. Pts were given penpulimab 200mg intravenously on day 1 and oral anlotinib 12mg once daily from day 1 to day 14 every 3 weeks until disease progression or unacceptable toxicities. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR), and safety. Results: From June 1, 2020 to November 22, 2021, 38 pts were enrolled in 8 cencers in China. The sites of primary tumors included oral cavity (15/38, 42.9%), oropharynx (6/38, 15.8%), hypopharynx (4/38 4.5%), larynx (10/38, 26.3%) and others (3/38, 7.9%). As of January 6, 2022 (data cut-off),The study met its primary endpoint that 13 pts achieved partial response (PR) and the ORR (confirmed at least 4 weeks after initial response) was 34.21%. 14 pts obtained stable disease (SD) lasting for at least 4 weeks, given a DCR of 76.32%. After a median follow-up of 6.96 months (95%CI: 4.40, 8.80). PFS events were observed in 17 pts and the median PFS was 8.35 months (95%CI: 5.45, 13.11). The PFS at 6 months was 62.5%. 9 pts died and the median OS was not reached (95% CI: 9.43，NE). For pts with tumor response, the median DoR was not reached (95% CI: 2.37, NE). Treatment-related adverse events (TRAEs) occurred in 89.47% pts, TRAE of grade 3 or above occurred in 39.47% of pts. The most common TRAEs were hypertension (28.95%) and hypothyroidism (28.95%). Conclusions: The combination of penpulimab and anlotinib demonstrated promising efficacy and manageable toxicities in R/M HNSCC pts who failed standard first-line therapy. Further investigation is warranted. Clinical trial information: NCT04203719.