Clinical outcomes from a phase I clinical trial of a novel oncolytic virus VG161 in patients with hepatocellular carcinoma (HCC) refractory after 2 prior lines of therapy including checkpoint inhibitors (CPI).
Authors: Shen Yinan , Liang Xingmei , Jin Xinyan , Tan Qian , Zhao Ronghua , Wei Guyue , Fang Tian , Li Yuwei , Wang Lei , Rahimian Shah , Ding Jun , Jia William , Singh Manu , Murad Yanal , Huang Maoliang , Zhang Yuntao , Shi Guoming , Kaufman Howard L. , Bai Xueli , Liang Tingbo 
Published: June 2024

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Background: This study aims to investigate the safety and anti-tumor activity of VG161 expressing IL12, IL15/IL15 receptor α unit, and PD-L1 blocking peptide in patients with HCC refractory to standard therapies. Methods: The study was conducted as a multicenter phase I trial with fast titration and 3+3 dose escalation part (A) and expansion part (B), which enrolled patients with primary liver cancer refractory to standard therapies. Patients in part A were dosed in 5 cohorts on days 1, 2 and 3 by image-guided intratumoral injections with dosing ranges from 1.0×10^8 to 5×10^8 PFU per 28 days treatment cycles. Part B used a single arm Simon's two-stage design at the recommended phase 2 dose (RP2D). The study endpoints were safety, and efficacy assessed by objective response rate (ORR) and Disease Control Rate (DCR) by RECIST1.1 and mRECIST (HCC), PFS and OS. Pretreatment HCC tumor samples were collected and analyzed by RNAseq. Results: 44 patients including 40 HCC (Male/Female: 37/3; median age: 58years) were dosed and no DLTs were reported. The most common Treatment-Related Adverse Events (TRAEs) was fever, which was resolved with symptomatic treatment. RP2D was determined as 1ⅹ10^8 PFU daily on day 1, 2 and 3 of each cycle. Of 40 HCC patients, 35 failed after 2 prior lines of therapy and were eligible for tumor assessment. ORR was 17.14% (6/35), DCR was 60.00% (21/35). The median PFS and OS were 2.90 (95%CI: 1.85-3.95) and 9.40 (95%CI: 0.47-18.33) months respectively. Statistically significant OS prolongation was observed in a subgroup of 22 HCC patients who progressed after receiving at least 3 months of CPI (PreCPI>3 m) as compared to those who received CPI for ≤3 months (PreCPI ≤ 3 m). The median OS was 17.30 months (95%CI: 5.35-29.25) vs. 7.40 months (95%CI: 5.11-9.69), HR: 0.32 (95%CI: 0.10 to 0.98) (p<0.05). Patients who received targeted or CPI therapies after VG161 survived longer than those who did not receive any anticancer treatment although they all previously failed such therapies [20.10 months (95%CI: 13.19-27.01) vs. 8.80 months (95%CI: 6.34-11.26), HR: 0.30 (95%CI: 0.10-0.88), P<0.05]. PreCPI>3 m and anti-cancer treatment after VG161 were the 2 independent factors with significant impact on OS (P<0.05). A gene signature was identified based on RNAseq data which predicted the prolonged OS in the study patients (P<0.01) but not in patients retrieved from TCGA database. Conclusions: VG161 was well tolerated and demonstrated comparable ORR and DCR with other CPIs data in 2L HCC. VG161 also prolonged survival in a subgroup of patients identified by prior treatment or gene signature, supporting further studies with enrichment of patients who may benefit from the treatment. The implications of pre/post VG161 CPI treatment on OS underscore a combination strategy for improving outcomes. Clinical trial information: NCT04806464 .