Morgan Claire, Kurland John, Patel Mayur, O'Brien Cathy, Concepcion Pamela, Doherty Gary J, Hois Stephan, Negro Alejandra, Pavlovic Dejan, Robbins Karen A
Global Patient Safety, Oncology, AstraZeneca, Gaithersburg, Maryland, USA
Late-stage Development Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA.
J Immunother Cancer. 2025 May 30;13(5):e011140. doi: 10.1136/jitc-2024-011140.
Durvalumab (D; anti-programmed cell death ligand 1 (PD-L1)) monotherapy or in combination with tremelimumab (T; anti-cytotoxic T lymphocyte antigen-4 (CTLA-4)) have demonstrated efficacy in advanced cancers. However, higher incidences of adverse events (AEs) and immune-mediated AEs (imAEs) were observed with D+T compared with D monotherapy in clinical trials. While safety data have been published from individual clinical trials of D with or without T, we report a comprehensive safety analysis of D and D+T in a broad population and across multiple tumor types.
A retrospective analysis was conducted using safety data pooled from phase I to III clinical trials in patients with advanced non-small cell lung cancer (NSCLC), recurrent or metastatic squamous cell carcinoma of the head and neck, unresectable hepatocellular carcinoma (uHCC), gastric adenocarcinoma, or metastatic urothelial carcinoma, who received either D monotherapy (N=4,045; 13 clinical trials) or D+T (N=3,319; 14 clinical trials).
Compared with D monotherapy, patients treated with D+T had higher incidences of maximum grade 3 or 4 AEs (49.5% vs 39.6%), treatment-related AEs of maximum grade 3 or 4 (22.1% vs 11.5%), any imAE (30.2% vs 17.4%), and imAEs of maximum grade 3 or 4 (11.0% vs 4.3%). The majority of imAEs were non-serious, low grade and manageable in both datasets. Higher incidences of imAEs with D+T were mainly driven by diarrhea/colitis (7.6% vs 1.9%) and dermatitis/rash (4.7% vs 1.6%). Fatal imAEs were infrequent and similar between D+T and D monotherapy (0.4% vs 0.3%). Across tumor types, hypothyroid events were the most frequently reported imAE of any grade (D+T: 9.7%; D monotherapy: 7.6%). As expected, given organ involvement, pneumonitis was most frequently reported in NSCLC (D+T: 5.4%; D monotherapy: 4.7%), while hepatic events were most frequently reported in uHCC (D+T: 7.9%; D monotherapy: 6.1%).
Higher incidences of imAEs were observed with D+T compared with D monotherapy across tumor types; however, fatal imAEs were infrequent and similar in both datasets. ImAEs in the D+T dataset were consistent with the safety profiles of the individual agents and dual PD-(L)1 and CTLA-4 inhibition. Overall, the safety profiles of D monotherapy and D+T were tolerable and manageable across tumor types.
度伐利尤单抗（D；抗程序性细胞死亡配体1（PD-L1））单药治疗或与曲美木单抗（T；抗细胞毒性T淋巴细胞抗原4（CTLA-4））联合治疗已在晚期癌症中显示出疗效。然而，在临床试验中，与度伐利尤单抗单药治疗相比，度伐利尤单抗联合曲美木单抗（D+T）治疗的不良事件（AE）和免疫介导的不良事件（imAE）发生率更高。虽然已经公布了度伐利尤单抗联合或不联合曲美木单抗的个别临床试验的安全性数据，但我们报告了在广泛人群和多种肿瘤类型中对度伐利尤单抗和度伐利尤单抗联合曲美木单抗进行的全面安全性分析。
使用从I期至III期临床试验汇总的安全性数据进行回顾性分析，这些试验的受试者为晚期非小细胞肺癌（NSCLC）、复发性或转移性头颈部鳞状细胞癌、不可切除的肝细胞癌（uHCC）、胃腺癌或转移性尿路上皮癌患者，他们接受了度伐利尤单抗单药治疗（N=4045；13项临床试验）或度伐利尤单抗联合曲美木单抗治疗（N=3319；14项临床试验）。
与度伐利尤单抗单药治疗相比，接受度伐利尤单抗联合曲美木单抗治疗的患者3/4级AE的最高发生率更高（49.5%对39.6%）、最高3/4级治疗相关AE的发生率更高（22.1%对11.5%）、任何imAE的发生率更高（30.2%对17.4%）以及最高3/4级imAE的发生率更高（11.0%对4.3%）。在两个数据集中，大多数imAE不严重、级别低且易于处理。度伐利尤单抗联合曲美木单抗治疗imAE发生率较高主要由腹泻/结肠炎（7.6%对1.9%）和皮炎/皮疹（4.7%对1.6%）所致。致命性imAE很少见，度伐利尤单抗联合曲美木单抗治疗与度伐利尤单抗单药治疗相似（0.4%对0.3%）。在所有肿瘤类型中，甲状腺功能减退事件是任何级别中报告最频繁的imAE（度伐利尤单抗联合曲美木单抗治疗：9.7%；度伐利尤单抗单药治疗：7.6%）。不出所料，鉴于器官受累情况，肺炎在NSCLC中报告最频繁（度伐利尤单抗联合曲美木单抗治疗：5.4%；度伐利尤单抗单药治疗：4.7%），而肝脏事件在uHCC中报告最频繁（度伐利尤单抗联合曲美木单抗治疗：7.9%；度伐利尤单抗单药治疗：6.1%）。
与度伐利尤单抗单药治疗相比，在所有肿瘤类型中，度伐利尤单抗联合曲美木单抗治疗的imAE发生率更高；然而，致命性imAE很少见，且在两个数据集中相似。度伐利尤单抗联合曲美木单抗治疗的数据集中的imAE与各药物的安全性特征以及双重PD-（L）1和CTLA-4抑制作用一致。总体而言，度伐利尤单抗单药治疗和度伐利尤单抗联合曲美木单抗治疗的安全性特征在所有肿瘤类型中均可耐受且易于处理。
