Departments of Cutaneous Oncology and Immunology, H. Lee Moffitt Cancer Center and Research Center Inc, Tampa, Florida, USA
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
J Immunother Cancer. 2021 May;9(5). doi: 10.1136/jitc-2021-002535.
The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood.
E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034).
Occurrence of grades 1-2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1-2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1-2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1-2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1-2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3-4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3-4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1-2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found.
Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3-4 irAEs.
目前，免疫相关不良事件（irAEs）的发生与辅助免疫治疗的使用及其管理对无复发生存率（RFS）和总生存率（OS）的影响尚未得到很好的理解。
E1609 纳入了 1673 例接受切除术的高危黑色素瘤患者，并评估了辅助用伊匹单抗 3mg/kg（ipi3）和 10mg/kg（ipi10）与干扰素-α的疗效。我们研究了 irAEs 的发生与免疫抑制剂的使用与接受伊匹单抗治疗患者的 RFS 和 OS 的关系（n=1034）。
发生 1-2 级 irAEs 与 RFS 相关（5 年：52%（95%CI 47%至 56%）vs 无 AE 组的 41%（95%CI 31%至 50%）；p=0.006），且 OS 有改善趋势（5 年：75%（95%CI 71%至 79%）与无 AE 组的 67%（95%CI 56%至 75%）相比；p=0.064）。在特定的 irAEs 中，1-2 级皮疹与 RFS（p=0.002）和 OS（p=0.003）最显著相关。在调整预后因素的多变量模型中，1-2 级皮疹与 RFS（p<0.001，HR=0.70）和 OS（p=0.01，HR=0.71）的相关性最显著，1-2 级皮疹与内分泌相关的 irAEs 与 RFS（p<0.001，HR=0.66）和 OS（p=0.008，HR=0.7）的相关性也最显著。总体而言，1-2 级 irAEs 在 RFS 和 OS 方面的预后最好，而 3-4 级 irAEs 获益的 RFS 较少，与无 irAE 相比，OS 无优势。发生 3-4 级 irAE 的患者比发生 1-2 级 irAE 的患者接受皮质类固醇和免疫抑制剂的暴露率显著更高（92%比 60%；p<0.001），但未发现皮质类固醇和免疫抑制剂的使用与 RFS 或 OS 之间存在显著相关性。在研究非皮质类固醇免疫抑制剂的影响时，尽管 RFS 和 OS 有倾向于不暴露的更好，但未发现显著相关性。
皮疹和内分泌 irAEs 是接受辅助伊匹单抗治疗患者 RFS 和 OS 的独立预后因素。发生较低级别的 irAEs 的患者获益最多，但我们未发现有证据表明更常用于治疗 3-4 级 irAEs 的高剂量皮质类固醇和免疫抑制剂有负面影响。
