Lung Clinic Grosshansdorf, Airway Research Center North, German Center of Lung Research, Grosshansdorf, Germany.
State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.
J Thorac Oncol. 2022 Sep;17(9):1122-1129. doi: 10.1016/j.jtho.2022.05.016. Epub 2022 Jun 25.
In the phase 1/3 IMpower133 study, atezolizumab plus carboplatin and etoposide (CP/ET) followed by maintenance atezolizumab for first-line treatment of extensive-stage SCLC (ES-SCLC) led to improvement in both overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET followed by maintenance placebo. We explored the benefit of atezolizumab versus placebo in the subset of patients who reached the IMpower133 maintenance phase and the safety profile of maintenance therapy.
Patients with untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo, followed by maintenance atezolizumab or placebo. The primary end points were OS and investigator-assessed PFS. A multivariate Cox model from the start of maintenance treatment was used to evaluate the treatment effect and account for lead-time bias; a generalized linear model was used to identify prognostic or predictive characteristics for reaching the maintenance phase.
A similar proportion of patients in each arm received at least the first dose of maintenance therapy (atezolizumab: 77%, n = 154 of 201; placebo: 81%, n = 164 of 202) and were included in the maintenance analysis population. An Eastern Cooperative Oncology Group performance status of 0 and absence of liver metastases at baseline were identified as prognostic factors for reaching the maintenance phase. The positive treatment effect with atezolizumab remained after adjusting for baseline characteristics. Median OS and PFS from the start of maintenance therapy in the atezolizumab versus placebo arm were 12.5 versus 8.4 months (hazard ratio = 0.59, 95% confidence interval: 0.43-0.80) and 2.6 versus 1.8 months (hazard ratio = 0.63 [95% confidence interval: 0.49-0.80]), respectively. Treatment-related adverse events from the start of maintenance therapy occurred in 41% (n = 64 of 155) and 25% (n = 41 of 163) of safety-evaluable patients in the atezolizumab and placebo arms, respectively, and were grade 3 or 4 in 28% (n = 43 of 155) and 23% (n = 37 of 163) of the respective populations; no patient in the atezolizumab arm and one patient in the placebo arm had a grade 5 treatment-related adverse event.
These data in the context of other immunotherapy trials in ES-SCLC suggest that induction with atezolizumab plus CP/ET and maintenance treatment with atezolizumab are important components that contributed to the OS benefit observed in IMpower133. Safety results from randomization and from the start of maintenance therapy were similar between the treatment arms despite the continuation of atezolizumab in the maintenance phase.
在 1/3 期 IMpower133 研究中，阿特珠单抗联合卡铂和依托泊苷（CP/ET）加一线治疗广泛期小细胞肺癌（ES-SCLC）后的维持治疗阿特珠单抗与安慰剂加 CP/ET 加安慰剂相比，均显著提高了总生存期（OS）和无进展生存期（PFS）。我们探讨了阿特珠单抗在达到 IMpower133 维持阶段的患者亚组中的疗效，以及维持治疗的安全性。
未经治疗的 ES-SCLC 患者以 1:1 的比例随机分配接受四个 21 天周期的 CP/ET 加阿特珠单抗或安慰剂，随后是阿特珠单抗或安慰剂的维持治疗。主要终点为 OS 和研究者评估的 PFS。从维持治疗开始的多变量 Cox 模型用于评估治疗效果并考虑领先时间偏倚；广义线性模型用于确定达到维持阶段的预后或预测特征。
在每个治疗组中，相似比例的患者至少接受了第一剂维持治疗（阿特珠单抗：77%，n=201 中的 154；安慰剂：81%，n=202 中的 164），并纳入维持分析人群。在基线时，东部肿瘤协作组的表现状态为 0 分和无肝转移被确定为达到维持阶段的预后因素。在调整基线特征后，阿特珠单抗的阳性治疗效果仍然存在。从维持治疗开始，阿特珠单抗组的中位 OS 和 PFS 分别为 12.5 个月与 8.4 个月（风险比=0.59，95%置信区间：0.43-0.80）和 2.6 个月与 1.8 个月（风险比=0.63 [95%置信区间：0.49-0.80]）。从维持治疗开始，在可评估安全性的患者中，分别有 41%（n=64/155）和 25%（n=41/163）的患者出现与治疗相关的不良事件，且分别有 28%（n=43/155）和 23%（n=37/163）的患者出现 3 级或 4 级与治疗相关的不良事件；阿特珠单抗组无 5 级治疗相关不良事件，安慰剂组有 1 例。
这些数据在 ES-SCLC 的其他免疫治疗试验背景下表明，阿特珠单抗联合 CP/ET 的诱导治疗和阿特珠单抗的维持治疗是导致 IMpower133 中观察到的 OS 获益的重要组成部分。尽管在维持阶段继续使用阿特珠单抗，但治疗组之间随机分组和维持治疗开始时的安全性结果相似。
