Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3–11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment.

靶向 PD-1/L1 的免疫检查点抑制剂作为单一药物对肝细胞癌的疗效有限。靶向膜磷脂酰丝氨酸可能会诱导促炎和免疫刺激作用，从而增强免疫治疗活性。这一假设在一项单臂 2 期试验中得到了检验，该试验评估了一线 Bavituximab（一种磷脂酰丝氨酸靶向抗体）加派姆单抗（抗 PD-1）治疗不可切除的肝细胞癌患者的效果 (NCT03519997)。主要终点是研究者评估的可评估患者的客观缓解率，次要终点包括无进展生存期、不良事件发生率、总生存期和缓解持续时间。在 28 名可评估患者中，确认缓解率为 32.1%，达到预先指定的终点，中位无进展生存期为 6.3 个月（95% CI，1.3-11.3 个月）。 45.7% 的患者发生任何级别的治疗相关不良事件，14.3% 的患者发生 3 级或以上不良事件。 33 名患者（94.3%）观察到任何原因的不良事件，其中 11 名患者（31.4%）出现 3 级或以上不良事件。对基线肿瘤样本的预先设定的探索性分析表明，B 细胞的消耗、间质中纤维化组织的存在和免疫检查点的表达与肿瘤反应相关。这些结果表明，靶向磷脂酰丝氨酸可能会与 PD-1 阻断产生协同效应，而不增加毒性率，并且这种治疗策略的未来研究可能会受到治疗前肿瘤微环境特征的生物标志物的指导。