Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Eur J Cancer. 2022 Sep;172:387-399. doi: 10.1016/j.ejca.2022.05.042. Epub 2022 Jul 12.
Investigations for programmed cell death-1 (PD-1) blockade-induced hyperprogressive disease (HPD) have not been stringently conducted in patients with advanced gastric cancer (AGC). We explored the occurrence of HPD and its clinical implications in patients with AGC and treated with PD-1 inhibitors.
We enrolled 169 patients with AGC and treated with either the PD-1 blockade (nivolumab or pembrolizumab; N = 112) or irinotecan monotherapy (N = 57) as a single agent. Tumour growth dynamics based on tumour growth kinetics and tumour growth rate (TGR) and time to treatment failure were analysed to define HPD. The incidence, clinical consequences and predictive markers of HPD were investigated.
The optimal criteria for HPD were 4-fold increases in both tumour growth kinetics and TGR ratios and a 40% increase in TGR based on the analysis for patients treated with irinotecan. In total, 10.7% (12/112) of patients experienced HPD after PD-1 inhibitor treatment. Patients with HPD had both shorter progression-free survival (hazard ratio: 2.318; 95% confidence interval: 1.205-4.460) and overall survival (hazard ratio: 2.542; 95% confidence interval: 1.314-4.918) than patients with progressive disease without HPD, losing opportunities for subsequent systemic treatments. Although other variables including PD-L1 expression were not associated with the occurrence of HPD, hypoalbuminemia (<3.25 mg/dL) at baseline was significantly associated with the occurrence of HPD (P < 0.001) and inferior survival outcomes.
HPD occurs in a proportion of patients with AGC and treated with PD-1 inhibitors. PD-1 inhibitor-induced HPD is associated with worse outcome, loss of eligibility for subsequent treatment and hypoalbuminemia, warranting further investigation.
程序性细胞死亡受体-1（PD-1）阻断诱导的超进展性疾病（HPD）在晚期胃癌（AGC）患者中的研究尚未得到严格开展。我们探讨了接受 PD-1 抑制剂治疗的 AGC 患者中 HPD 的发生及其临床意义。
我们纳入了 169 名接受 PD-1 抑制剂（nivolumab 或 pembrolizumab；N=112）或伊立替康单药治疗（N=57）的 AGC 患者。根据肿瘤生长动力学和肿瘤生长率（TGR）以及治疗失败时间分析肿瘤生长动态，以定义 HPD。研究了 HPD 的发生率、临床后果和预测标志物。
基于伊立替康治疗患者的分析，HPD 的最佳标准为肿瘤生长动力学和 TGR 比值增加 4 倍，以及 TGR 增加 40%。共有 10.7%（12/112）接受 PD-1 抑制剂治疗的患者发生 HPD。与无 HPD 的进展性疾病患者相比，HPD 患者的无进展生存期（风险比：2.318；95%置信区间：1.205-4.460）和总生存期（风险比：2.542；95%置信区间：1.314-4.918）均更短，从而失去了后续系统治疗的机会。尽管其他变量（包括 PD-L1 表达）与 HPD 的发生无关，但基线时低白蛋白血症（<3.25mg/dL）与 HPD 的发生显著相关（P<0.001），并与较差的生存结局相关。
HPD 在接受 PD-1 抑制剂治疗的 AGC 患者中一定比例存在。PD-1 抑制剂诱导的 HPD 与不良预后、丧失后续治疗资格和低白蛋白血症相关，需要进一步研究。
