Zhang Ting, Du Sicheng, Zhang Ying, Liu Rongrui, Li Juan, Zhao Chuanhua, Xu Jianming
Chinese People's Liberation Army (PLA) Medical School, Beijing, China.
Department of Gastrointestinal Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
Cancer Med. 2025 Mar;14(6):e70713. doi: 10.1002/cam4.70713.
The relationship between treatment-related adverse events (TRAEs) and efficacy in patients receiving immune checkpoint inhibitors (ICIs) combined with anti-angiogenic therapy remains unclear. This study aims to investigate the potential correlation between TRAEs and efficacy in patients with unresectable hepatocellular carcinoma (uHCC) treated with the combination of camrelizumab and apatinib.
We conducted an analysis of efficacy and safety data obtained from 189 patients with uHCC enrolled in a phase II trial. All patients received intravenous camrelizumab 200 mg every 2 weeks and oral apatinib 250 mg once daily in 4-week cycles. Efficacy was evaluated based on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). We described the profiles of TRAEs and analyzed the correlation between TRAEs and treatment efficacy. To mitigate the impact of immortal time bias, landmark analysis and time-dependent Cox regression analysis were employed to assess the correlation between immune-related adverse events (irAEs) and survival outcomes.
As of March 10, 2021, irAEs of any grade were reported in 88 (46.6%) patients, with 17 (9.0%) patients experiencing grade 3-4 irAEs. The median onset time for any grade irAEs was 17.4 weeks. Apatinib-related adverse events (AEs) of any grade were reported in 188 (99.5%) patients. Among them, 139 (73.5%) patients experienced any grade of apatinib-related hypertension, while 65 (34.4%) patients had grade 3-4 hypertension. Patients who experienced irAEs exhibited significantly higher ORR and DCR, but the onset of irAEs occurred later than the time of PR or CR in 75.0% (30/40) of patients. Furthermore, in the landmark analysis and time-dependent Cox regression analysis, no significant differences in survival outcomes were observed between patients with irAEs and those without. Notably, patients with apatinib-related hypertension demonstrated better ORR (38.1% vs. 18.0%, p = 0.009) and DCR (84.2% vs. 60.0%, p < 0.001), as well as longer PFS (6.5 vs. 3.7 months, p = 0.001) and OS (23.0 vs. 15.1 months, p = 0.03).
In this study, the occurrence of irAEs did not predict the efficacy of camrelizumab in combination with apatinib, likely due to the decreased incidence and delayed occurrence. On the other hand, apatinib-related hypertension was associated with improved treatment efficacy.
接受免疫检查点抑制剂（ICI）联合抗血管生成治疗的患者中，治疗相关不良事件（TRAEs）与疗效之间的关系尚不清楚。本研究旨在探讨卡瑞利珠单抗联合阿帕替尼治疗不可切除肝细胞癌（uHCC）患者中TRAEs与疗效之间的潜在相关性。
我们对参加一项II期试验的189例uHCC患者的疗效和安全性数据进行了分析。所有患者每2周静脉注射200mg卡瑞利珠单抗，每日口服250mg阿帕替尼，每4周为一个周期。基于客观缓解率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）和总生存期（OS）评估疗效。我们描述了TRAEs的特征，并分析了TRAEs与治疗疗效之间的相关性。为减轻永生时间偏倚的影响，采用了地标性分析和时间依赖性Cox回归分析来评估免疫相关不良事件（irAEs）与生存结果之间的相关性。
截至2021年3月10日，88例（46.6%）患者报告了任何级别的irAEs，17例（9.0%）患者发生3-4级irAEs。任何级别的irAEs的中位发病时间为17.4周。188例（99.5%）患者报告了任何级别的阿帕替尼相关不良事件（AEs）。其中，139例（73.5%）患者发生任何级别的阿帕替尼相关高血压，65例（34.4%）患者发生3-4级高血压。发生irAEs的患者表现出显著更高的ORR和DCR，但75.0%（30/40）的患者irAEs的发生时间晚于PR或CR时间。此外，在地标性分析和时间依赖性Cox回归分析中，有irAEs的患者和没有irAEs的患者在生存结果上没有观察到显著差异。值得注意的是，发生阿帕替尼相关高血压的患者表现出更好的ORR（38.1%对18.0%，p=0.009）和DCR（84.2%对60.0%，p<0.001），以及更长的PFS（6.5对3.7个月，p=0.001）和OS（23.0对15.1个月，p=0.03）。
在本研究中，irAEs的发生并不能预测卡瑞利珠单抗联合阿帕替尼的疗效，可能是由于其发生率降低和发生延迟。另一方面，阿帕替尼相关高血压与治疗疗效改善相关。
