A phase 1b clinical trial of anti-PD-1 ab (Toripalimab) plus intralesional injection of OrienX010 in stage melanoma with liver metastases.
Authors: Jun Guo, Chuanliang Cui, Xuan Wang, Bin Lian, Shanshan Yin, Yue Cong, Zhihong Chi, Lu Si, Xinan Sheng, Bixia Tang, Lili Mao, Xue Bai, Xieqiao Yan, Siming Li, Li Zhou
Journal: Journal of Clinical Oncology (2021)

9559 Background: Liver metastasis was associated with reduced responses and PFS in melanoma patients (pts) treated with anti-PD-1 monotherapy, which is probably due to reduced marginal CD8+ T cell infiltration. Oncolytic virotherapy was found to increase CD8+ T cell infiltration in the injected lesions and improve the efficacy of anti-PD-1 ab in a phase 1b trial. We hypothesized that intratumoral oncolytic virus injection for liver metastasis in melanoma combined with systemic anti-PD-1 therapy might improve the efficacy, thus conducting this phase 1b trial with intratumoral OrienX010 - a HSV-1-derived oncolytic virotherapy with expression of GM-CSF combined toripalimab in liver metastatic melanoma pts. Methods: Eligible pts included those over 18 with injectable liver metastasis confirmed by biopsy with or without extra-hepatic metastasis; ocular melanoma and brain metastasis were excluded. Pts received intravenous toripalimab Q2W combined with ultrasound guided intratumoral injection of OrienX010 Q2W (8×10 7 pfu/ml, 10ml per injection) until intolerance or disease progression per iRECIST criteria. Liver biopsy would be performed at baseline and first tumor evaluation (8-12weeks). The primary endpoint was toxicity; secondary endpoints included ORR, DCR and PFS. Clinical trial information: NCT04206358. Results: From Jul 2019 to Dec 2020, 15 pts were eligible and enrolled. Baseline characteristics: median age 62 yrs; primary: mucosal 60%, cutaneous 20%, unknown primary 13.3%, acral 6.7%; gene mutation status: Braf 20%, Nras 6.7%; 73.3% got extra-hepatic metastasis: regional or distant lymph node 46.7%, lung 20.0%; LDH＞ULN 20%; median size of injected lesions: 32mm(10-83mm); median number of liver metastasis: 4(1-10); median number of injection: 10 (3-36). AEs were all grade 1/2: pyrexia 86.7%, rigor 66.7%, elevated transaminase 53.3%, nausea/vomiting 40.0%, fatigue 26.7%. No grade 3-4 AEs. The ORR by investigator was 13.3% (2/15), DCR 46.7% (7/15); the response rate was 40%(6/15) for injected lesions, 28.5%(4/14) for non-injected lesions in liver, and 23% (3/13) for extra-hepatic metastasis. For biopsies of injected lesions at 8 to 12weeks, 30%( 2 PR and 3 SD) showed no melanoma cells residual by immunohistochemistry, 46.7% got impressive TIL infiltration (Brisk n = 4 and Nonbrisk n = 3 according to the definition of AJCC 8th edition) compared with baseline in which all showed absence of TIL infiltration, also a large number of plasma cells, histiocyte and pigment were found with hyaline fibrosis. The PFS has reached 72 weeks for one PR pt. The median PFS was not reached. Conclusions: Systemic toripalimab combined with intrahepatic OrienX010 injection has shown remarkable pathological responses with good tolerance in melanoma liver metastases. Survival is still in follow-up. Clinical trial information: NCT04206358.