e16079 Background: Neoadjuvant chemoradiation therapy followed by radical surgery has been extensively recommended for locally advanced esophageal squamous cell carcinoma (ESCC). However, toxicities and challenges to the subsequent surgery limit its wide clinical application. Immune checkpoint inhibitors combined with antiangiogenesis have synergistic effects and have shown good therapeutic effects in previous studies, as well as fewer side effects. Here, we tested a novel combination of anlotinib (an antiangiogeneic kinase inhibitor) and penpulimab (an anti-PD-1 antibody), devoid of radio- or chemo-therapy, for the neoadjuvant therapy of locally advanced ESCC. Methods: In this prospective, single-arm, phase II clinical trial (ChiCTR2200064848), patients(pts) with resectable locally advanced ESCC (clinical stage III-IVa) were recruited. The study was designed using a two-stage minimax approach. The planned sample size was 40 pts would provide 80% power at a one-sided alpha error of 5%, threshold pathological complete response (pCR) of 16% and expected pCR of 30%. Pts received neoadjuvant therapy with anlotinib (8 mg, po, D1-14, Q3W) combined with penpulimab (200 mg, ivgtt, Q3W) for 2 cycles. Six to eight weeks later, pts underwent radical surgery after exclusion of contraindications. The primary endpoint was pCR rate. Secondary endpoints included tumor regression grade (TRG), R0 resection rate, objective response rate (ORR) and safety profile. Results: From Jan 2023 to Nov 2023, 25 pts (19 males and 6 females) were enrolled with a median age of 67 years (range: 50-74). A concerning 92% were diagnosed with lymph node metastasis. Moreover, 85% (22/25) pts exhibited medical contraindications, including pure red cell aplasia, compromised pulmonary function, and poor nutritional status, etc.) rendering them ineligible for standard neoadjuvant chemoradiotherapy or chemotherapy. All pts were available for efficacy assessment, ORR and DCR were 48.0% and 96.0%, respectively. Of these, 21 pts underwent esophagectomy, with an R0 resection rate of 90.5% (19/21). The study's initial phase successfully achieved its primary endpoint, with a pCR rate of 19.0% (4/21). Furthermore, the major pathological response (MPR) was 28.6% (6/21). The most common TRAEs (≥10%) included hypertension (28.0%), hand-foot syndrome (20%), fatigue (20%), abdominal pain (12%), toothache (12%). Grade 3-4 TRAEs were observed in 12.0% of the patients (3/25), and no reports of grade 5 TRAEs. Conclusions: Preliminary results from the initial stage suggest that anlotinib combined with penpulimab as a neoadjuvant treatment for ESCC showed promising safety and efficacy, especially for those deemed unsuitable for neoadjuvant chemoradiation or chemotherapy. More ESCC pts would be recruited in the future. Clinical trial information: ChiCTR2200064848.