Background Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity and survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally-funded basket trial ((NCT02834013) for patients with rare cancers (N = 684) to evaluate associations between irAEs and overall survival and progression-free survival. Methods Patients were treated with nivolumab and ipilimumab; the trial was opened at > 1000 sites. Landmark Cox regression models were used to assess first cycle irAE associations with progression-free and overall survival. Results We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer overall survival (OS) (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p < .001) compared to no treatment-related irAE, while grade 3-4 irAEs were associated with shorter OS (HR = 1.41, 95% CI = 1.04-1.90, p = .025). Similar, but weaker, associations were observed with progression-free survival (PFS) and grade 1-2 treatment-related irAEs: HR = 0.83, 95% CI = 0.67-1.01, p = .067 and grade 3-4: HR = 1.35, 95% CI = 1.02-1.78, p = .037 compared to no treatment-related irAEs. Grade 1-2 dermatologic toxicity was associated with improved OS compared to other grade 1-2 toxicities (HR = 0.67, 95% CI = 0.52-0.85, p = .002). There was no significant OS difference between patients with Grade 1-2 fatigue, gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities vs other Grade 1-2 toxicities. Conclusions In this large cohort of patients with rare tumors receiving checkpoint inhibitor therapy, grade of irAE in the first cycle was predictive for survival.

中文翻译：

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接受检查点抑制剂治疗的罕见癌症患者的第一周期毒性和生存率


背景 检查点抑制剂治疗的免疫相关不良事件 （irAE） 与结果之间的关联先前已经评估过，大多数先前的研究发现毒性与生存之间存在正相关。先前的研究通常报告了更常见的肿瘤类型。我们使用联邦资助的针对罕见癌症患者 （N = 684） 的篮子试验 （（NCT02834013） 的独特数据资源来评估 irAEs 与总生存期和无进展生存期之间的关联。方法 患者接受 nivolumab 和 ipilimumab 治疗;在 > 1000 个站点开始试验。使用 Landmark Cox 回归模型评估第一周期 irAE 与无进展生存期和总生存期的相关性。结果我们发现，与无治疗相关的 irAE 相比，第一周期治疗中 1-2 级治疗相关的 irAEs 与较长的总生存期 （OS） 相关 （多变量风险比，95% 置信区间，p 值：0.61,0.49-0.75，p < .001），而 3-4 级 irAEs 与较短的 OS 相关 （HR = 1.41,95% CI = 1.04-1.90，p = .025）。与无进展生存期 （PFS） 和 1-2 级治疗相关 irAE 观察到相似但较弱的关联：HR = 0.83,95% CI = 0.67-1.01，p = .067 和 3-4 级：HR = 1.35,95% CI = 1.02-1.78，p = .037与无治疗相关的 irAE 相比。与其他 1-2 级毒性相比，1-2 级皮肤毒性与 OS 改善相关 （HR = 0.67,95% CI = 0.52-0.85，p = .002）。1-2 级疲劳、胃肠道、代谢、肝脏、内分泌和甲状腺毒性患者与其他 1-2 级毒性患者之间无显著 OS 差异。 结论 在接受检查点抑制剂治疗的一大批罕见肿瘤患者中，第一个周期的 irAE 分级可预测生存。