Background: Combination therapy of anti-PD1 agent with VEGFR inhibitor is a promising therapeutic approach in unresectable or metastatic mucosal melanoma. We conducted this study evaluating neoadjuvant lenvatinib and pembrolizumab in pts with resectable mucosal melanoma. Methods: This was a single-arm, open-label, single-center, ongoing phase 2 study conducted from Sep 2021. Eligible pts were adults (18-75 yr) with histologically confirmed, resectable mucosal melanoma. Pts received lenvatinib 20mg qd and pembrolizumab 200mg q3w for 2 cycles, followed by surgery. Pembrolizumab (200mg q3w) continued post operatively for further 15 cycles. The primary endpoint was complete pathologic response (pCR). Secondary endpoints were Event free survival (EFS), Overall survival (OS) and safety. Results: As of Dec 2022, 19 pts were enrolled with a median follow-up of 49 wks (95%CI, 38 -60). Median age was 57 yrs, 14 were female. Primary sites included: 8 female genital, 6 ano-rectal, 4 head & neck (1 nasal, 3 oral),1 esophageal. 12 pts were localized disease,7(37%) were regional lymphatic disease. KIT or NRAS mutations were presented in 2 and 3 pts, respectively. 15 pts underwent surgery, 2 pts had a pCR (13.3 %), 1 MPR, 3 pPR, with a pathologic response rate of 40%(6/15,95%CI 16-67%). 4 pts did not proceed with planned surgery for pts preference. Median EFS has not been reached. IHC data of the resected tumor showed higher CD8+ T cells density in responders (R=pCR+ MPR + pPR) than non-responders (NR=pNR) (p = 0.04). In 6 pts(one pPR and 5pNR) with paired pre and post treatment samples, CD3+ and CD8+ T cells were significantly increased following treatment (p =0.03). Most common AEs were proteinuria (6, 32%), hypothyroidism (6, 32%), dysphonia (5, 26%). One pt(5%, 1/19) had grade 3 ALT elevation. No grade 4-5 toxicities were observed. Conclusions: The combination of pembrolizumab plus lenvatinib as neoadjuvant therapy in resectable MM is safe. The preliminary data has shown promising pathologic response with increased CD8+ T cell infiltration, supporting further investigation of neoadjuvant treatment in MM. Acknowledgement: Investigational funding and products are granted from Merck Sharp & Dohme LLC. Clinical trial information: NCT04622566.