EMD Serono, Billerica, Massachusetts, USA.
the healthcare business of Merck KGaA, Darmstadt, Germany.
Clin Transl Sci. 2024 Mar;17(3):e13730. doi: 10.1111/cts.13730.
Like other monoclonal antibodies, immune checkpoint inhibitors may be immunogenic in some patients, potentially affecting pharmacokinetics (PKs) and clinical outcomes. In post hoc analyses, we characterized antidrug antibody (ADA) development with avelumab monotherapy in patients with metastatic Merkel cell carcinoma (mMCC) from the JAVELIN Merkel 200 trial (first-line [1L; N = 116] and second-line or later [≥2L; N = 88] cohorts) or with advanced urothelial carcinoma (aUC) from the JAVELIN Bladder 100 (1L maintenance [N = 350]) and JAVELIN Solid Tumor (≥2L [N = 249]) trials. Treatment-emergent ADAs developed in a numerically higher proportion of patients with aUC (1L maintenance, 19.1%; ≥2L, 18.1%) versus mMCC (1L, 8.2%; ≥2L, 8.9%); incidences within tumor types were similar by line of therapy. In PK analyses, numerically lower avelumab trough concentration and higher baseline clearance were observed in treatment-emergent ADA+ versus ADA- subgroups; however, differences were not clinically relevant. Numerical differences in overall survival, progression-free survival, or objective response rate by ADA status were observed; however, no clinically meaningful trends were identified. Proportions of patients with treatment-emergent adverse events (TEAEs; any grade or grade 3/4), serious TEAEs, TEAEs leading to treatment discontinuation, or infusion-related reactions were similar, with overlapping 80% confidence intervals between ADA subgroups. Efficacy and safety observations were similar in subgroups defined by early development of ADA+ status during treatment. In conclusion, no meaningful differences in PKs, efficacy, and safety were observed between subgroups of avelumab-treated patients with different ADA status. Overall, these data suggest that ADAs are not relevant for treatment decisions with avelumab.
与其他单克隆抗体一样，免疫检查点抑制剂在某些患者中可能具有免疫原性，从而潜在影响药代动力学（PKs）和临床结局。在事后分析中，我们对 JAVELIN Merkel 200 试验（一线[1L；N=116]和二线或以上[≥2L；N=88]队列）中转移性 Merkel 细胞癌（mMCC）患者或 JAVELIN Bladder 100 试验（1L 维持[N=350]）和 JAVELIN Solid Tumor 试验（≥2L[N=249]）中晚期尿路上皮癌（aUC）患者接受avelumab 单药治疗后抗药抗体（ADA）的发展情况进行了特征描述。与 mMCC（1L，8.2%；≥2L，8.9%）相比，aUC（1L 维持，19.1%；≥2L，18.1%）中治疗出现 ADA 的患者比例更高；不同治疗线的肿瘤类型中发生率相似。在 PK 分析中，与 ADA-亚组相比，治疗出现 ADA+的患者avelumab 谷浓度数值较低，基线清除率较高；然而，差异无临床意义。观察到 ADA 状态对总生存期、无进展生存期或客观缓解率的数值差异；然而，未发现有临床意义的趋势。ADA 亚组间治疗出现的不良事件（TEAEs；任何等级或 3/4 级）、严重 TEAEs、导致治疗中断的 TEAEs 或输注相关反应的患者比例相似，置信区间重叠度为 80%。在治疗期间早期出现 ADA+状态的亚组中，疗效和安全性观察结果相似。总之，不同 ADA 状态的 avelumab 治疗患者亚组间，在 PKs、疗效和安全性方面未观察到有意义的差异。总体而言，这些数据表明 ADA 对于avelumab 的治疗决策无相关性。
