Introduction Intratumoral administration of pexa-vec (pexastimogene devacirepvec), an oncolytic and immunotherapeutic vaccinia virus, given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy. Methods This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival, overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥1 dose of study treatment. Results The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib: 234, sorafenib: 225). At the interim analysis, the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to the early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups. Conclusion Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies.

中文翻译：

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PHOCUS：一项针对晚期肝细胞癌患者使用 Pexa-Vec (JX-594) 和索拉非尼序贯治疗的 3 期、随机、开放标签研究。


简介 pexa-vec (pexastimogene devacirepvec) 是一种溶瘤和免疫治疗痘苗病毒，给予肝细胞癌 (HCC) 患者，瘤内给药与局部和远处肿瘤反应相关。我们假设索拉非尼的后续治疗可以表现出优异的疗效。方法 这项随机 III 期开放标签研究评估了先用 pexa-vec 再用索拉非尼序贯治疗与索拉非尼治疗晚期 HCC 且既往未接受全身治疗的患者的情况。主要终点是总生存期（OS）。关键的次要终点包括进展时间（TTP）、无进展生存期、总体缓解率（ORR）和疾病控制率（DCR）。对接受≥1 剂研究治疗的所有患者进行安全性评估。结果 该研究在 16 个国家的 142 个地点进行。从2015年12月30日到2019年8月2日的中期分析，459名患者被随机分配（pexa-vec加索拉非尼：234例，索拉非尼：225例）。在中期分析中，pexa-vec 加索拉非尼组的中位 OS 为 12.7 个月（95% CI：9.89，14.95），索拉非尼组为 14.0 个月（95% CI：11.01，18.00）。这导致该研究提前终止。中位 TTP 为 2.0 个月（95% CI：1.77，2.96）和 4.2 个月（95% CI：2.92，4.63）； ORR 分别为 19.2%（45 名患者）和 20.9%（47 名患者）； pexa-vec 加索拉非尼组和索拉非尼组的 DCR 分别为 50.0%（117 名患者）和 57.3%（129 名患者）。 pexa-vec 加索拉非尼组的 117 名患者（53.7%）和索拉非尼组的 77 名患者（35.5%）报告了严重不良事件。肝衰竭是两组中最常报告的。 结论 序贯 pexa-vec 加索拉非尼治疗并未显示出晚期 HCC 临床获益的增加，并且与单独索拉非尼相比表现更差。检查点抑制剂附加值的出现应该会指导溶瘤病毒治疗策略的进一步发展。