Axitinib in combination with anti–PD-1 ab (pucotenlimab) plus intra-hepatic injection of oncolytic virus (OH2), in patients with mucosal melanoma and liver metastasis: An open-label phase I trial.
Authors: Wang Xuan , Cui Chuanliang , Yin Shanshan , Cong Yue , Lian Bin , Li Caili , Si Lu , Chi Zhihong , Sheng Xinan , Kong Yan , Mao Lili , Zhou Li , Tang Bixia , Yan Xieqiao , Li Siming , Dai Jie , Li Juan , Wei Xiaoting , Guo Jun 
Published: July 2024

e21524

Background: The combination of anti-PD-1 plus axitinib as systemic therapy had promising antitumor activity in mucosal melanoma, but with limit effect in mucosal melanoma with liver metastasis, which might due to immunosuppression in liver metastasis. Oncolytic virus can heighten the immune response and turn over the immunosuppressive state, which has shown its efficacy in liver metastaic as Intra-hepatic injection. So we initiated this phase I study to evaluate axitinib combination with anti–PD-1 ab plus oncolytic virus in liver metastasis mucosal melanoma. Methods: Eligible pts included those over 18 years old, mucosal melanoma with injectable liver metastasis confirmed by biopsy with or without extra-hepatic metastasis. Pts received intravenous pucotenlimab Q3W combined plus axitinib 5 mg orally twice a day, combined with ultrasound guided intratumoral injection of OH2 Q2W (107CCID50/mL, 8ml per injection). Liver biopsy would be performed at first tumor evaluation (8-12weeks). The primary endpoint was ORR; secondary endpoints included toxicity, disease control rate (DCR), PFS and OS. Results: From Dec 2021 to Jan 2024, 20 pts were eligible and enrolled. Baseline characteristics: median age 56 yrs; 70% got previous treatment, (35% PD-1 resistant). 90% got extra-hepatic metastasis: regional or distant lymph node 45%, lung 40%,; LDH>ULN 50%; median size of target lesions: 61.5mm(12-155mm); median number of liver metastasis: 3(1-18) with median liver lesions 42.5mm(13-230mm). Till the last flow up, 15 pts were evaluable with a median follow-up of 9.39 months. The global ORR was 26.7% (4/15) with 42.9% lesionshrink, injection lesions decrease (43.8%) and non-injection lesion 23.1%. The DCR was 46.7% (7/15). There are still 8 pts on treatment at last follow up. The median PFS was 4.5m, and no pts who had response showed progression till last follow up, the mean DOR was 11.0m. Median OS is not reached. Biopsies of 13 pts for injected lesions at 8 to 12 weeks after first injection were examined to determine the situation of tumor regression and TIL infiltration. Among them, 3 pts (2 PD and 1 PR) had no melanoma cells residual by immunohistochemistry with impressive TIL infiltration. The biopsy showed better pathological response than radiological response which might explain some pts still got survival benefit on treatment after radiological PD. Most adverse events (AE) were grade 1-2 and manageable. Grade 3-4 treatment-related AE showed 30% pts, with diarrhea and oral ulceration as the most common. No treatment-related deaths occurred. Conclusions: Systemic anti-PD-1 plus axitinib combined intralesional injection of Oncolytic virus has shown preliminary efficacy in mucosal melanoma pts with liver metastases with manageable toxicity. Clinical trial information: NCT04206358 , NCT05070221 .