The phase 1 clinical trial of anti–PD-1 ab plus intrahepatic injection of oncolytic virus (OH2) combined radiotherapy of liver metastasis in stage IV melanoma.

9547 Background: Patients with melanoma and liver metastases generally exhibit reduced responses to systemic immunotherapy. Oncolytic herpes simplex virus 2 (OH2), is an oncolytic virus with potential therapeutic benefits. Preliminary clinical trials have demonstrated the efficacy of combining PD-1 antibody therapy with intrahepatic intralesional injections of OH2. Additionally, liver metastasis radiotherapy may modulate the tumor microenvironment, potentially enhancing the efficacy of immunotherapy combinations. In this phase I study, we aim to evaluate the safety and efficacy of OH2 and Pucotenlimab, in combination with liver metastasis-directed radiotherapy in patients with melanoma. Methods: Eligible pts included those over 18 with injectable liver metastasis confirmed by biopsy with or without extra-hepatic metastasis; the ocular melanoma and brain metastasis were excluded. Pts received intravenous Pucotenlimab Q3W combined with ultrasound guided intrahepatic injection of OH2 Q2W (10 7 CCID50/mL, 8ml per injection) after SBRT (24-30Gy/3Fx) of liver metastasis. The primary endpoint was ORR. Clinical trial: NCT05068453. Results: From Dec 2021 to Jan 2025, 20 pts were enrolled. 77.8% had received at least one prior treatment; 52.9% presented with extrahepatic metastases. The median size of enrolled lesions was 34.56 mm (13.0–271.0 mm). The median number of liver metastases was 5.5. Among these patients, 17 were evaluable for efficacy. One iCR, four iPR, resulting in an ORR of 29.4% and a DCR of 52.9%. Nearly 60.0% of pts exhibited a reduction in target lesions, including 65.2% of intrahepatic lesions, and 41.7% of extrahepatic lesions with a maximum reduction of 100.0%. Among injection target lesions, 58.3% demonstrated shrinkage,. In non-injection target lesions, 54.5% exhibited shrinkage. The median follow-up was 17.0m. The 1-year survival rate observed was 60.0%, while the 2-year was 51.4%. The OS has not been reached. Interestingly, no clear correlation has been established between imaging evaluations and patient prognosis. Among the pts classified as having PD, 10 individuals continued treatment due to clinical benefits. Notably, their OS was comparable to that of the overall population, with 2-year survival rate 60.0%. No treatment-related deaths reported. Adverse events were minimal, with only two grade 3 TRAEs observed: pneumonia and colitis. Biopsies of 17 pts with injected lesions were analyzed 8 to 12 weeks after the first injection. Of these, five pts (1 iCR, 1 iPR, and 3 SD) showed no residual tumor cells, accompanied by TIL infiltration. All five pts exhibited long PFS. Conclusions: The combination of systemic anti-PD-1 therapy with intralesional injection of an oncolytic virus and radiotherapy has demonstrated a remarkable ORR and excellent OS in patients with melanoma and liver metastases, with manageable toxicity. Clinical trial information: NCT05068453 .