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

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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 (8×107 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.