Background: Metastatic acral melanoma is very difficult to treat. Unlike cutaneous melanoma, acral melanoma responds poorly to checkpoint inhibitors in monotherapy. OrienX010 is a granulocyte-macrophage colony-stimulating factor expressing herpes simplex type-1 derived oncolytic virus. It has shown robust efficacy in metastatic acral melanoma, and may improve the response to checkpoint inhibitors. To evaluate the role of OrienX010 in combination with checkpoint inhibitors in acral melanoma, we conducted a Phase Ib neoadjuvant trial of OrienX010 in combination with the anti-PD-1 monoclonal antibody toripalimab in resectable stage IIIB-IVM1a acral melanoma (NCT04197882). Methods: Patients with resectable stage IIIB-IV M1a acral melanoma received neoadjuvant intratumoral OrienX010 up to 10 mL of 8 x 10⁷ pfu/mL and intravenous toripalimab 3 mg/kg every 2 weeks for 4 – 6 doses prior to surgical resection. After resection, adjuvant toripalimab 3 mg/kg was administered every 3 weeks for up to 1 year. The primary endpoints were radiographic response rate per RECIST 1.1 and pathological response rate (pCR and pPR). The secondary endpoints were 1- and 2-year recurrence-free survival, and safety. Results: Between July 2019 and Jan 2021, 30 patients with regional metastatic acral melanoma were enrolled. Median age was 56.5 years, 14 (47%) were male, 19 (63%) had recurrent disease, and stage IIIB 12 (40%), IIIC 14 (47%), and IVM1a 4 (13%). Median tumor burden was 28mm (range, 10-80mm), and only 5 (17%) patients had melanoma mutations (2 cKIT, 1 NRAS, 2 BRAF). To date, of 24 patients who completed neoadjuvant treatment, 21 (88%) underwent surgery. Three (12%) patients did not undergo surgery due to disease progression prior to surgery and 6 patients are still receiving neoadjuvant treatment. Radiographic responses were seen in 10 (33%) patients. However, 17 of 21 (81%) patients showed pathologic responses in resected metastases, with 3 (14%) showing a pCR and 14 (67%) a pPR. Pathologic responses were associated with greater lymphoid infiltrate, hyaline fibrosis, and decrease in Ki-67 expression in the metastasis. At a median follow-up of 8.9 months, none of the patients who underwent resection have recurred. The neoadjuvant treatment was well tolerated, with all patients experiencing at least 1 treatment related adverse event (TRAE) and Grade 1 fever was most common. Three (10%) patients had a grade 3-4 TRAE, including 1 alanine aminotransferase increase and 2 wound infections. Conclusions: Neoadjuvant treatment with OrienX010 and toripalimab in resectable stage IIIB-IVM1a acral melanoma was well tolerated and produced a high pathologic response rate. To date, no patients have recurred, and recurrence-free survival evaluation is ongoing. This combination therapy warrants further evaluation in acral melanoma. Clinical trial information: NCT04197882