tarlatamab联合PD-L1抑制剂作为广泛期小细胞肺癌(delphi303)化疗免疫治疗后一线维持治疗的安全性和活性:一项多中心、非随机、1b期研究

Kelly G Paulson, Sally C M Lau, Myung-Ju Ahn, Mor Moskovitz, Michael Pogorzelski, Simon Häfliger, Amanda Parkes, Yuyang Zhang, Ali Hamidi, Corbin G Thompson, Martin Wermke
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We evaluated the safety and activity of tarlatamab in combination with atezolizumab or durvalumab as first-line maintenance therapy in patients with extensive-stage (ES)-SCLC.<h3>Methods</h3>In this multicentre, non-randomised, phase 1b study, patients aged 18 years and older, with Eastern Cooperative Oncology Group performance status of 0–1 and without disease progression after four to six cycles of platinum–etoposide chemotherapy plus a programmed cell death ligand 1 (PD-L1) inhibitor (if available), received tarlatamab 10 mg intravenously once every 2 weeks, after an initial tarlatamab 1 mg dose, with atezolizumab intravenously (1680 mg once every 4 weeks) or durvalumab intravenously (1500 mg once every 4 weeks) as maintenance until disease progression. Patients were enrolled from 30 centres in 13 countries. The primary objective was to evaluate safety and to determine the recommended phase 2 dose or maximum tolerated dose of tarlatamab in combination with a PD-L1 inhibitor through assessment of dose-limiting toxicities, treatment-emergent adverse events, treatment-related adverse events, and changes in vital signs, electrocardiograms, and clinical laboratory tests. All patients who received at least one dose of tarlatamab were included in the analyses. Because overall survival data were immature at the primary analysis, in this Article, we report a non-specified interim analysis to provide an updated examination of overall survival and longer-term safety. This study is registered with <span><span>ClinicalTrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>, <span><span>NCT05361395</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>; the EU Clinical Trials registry, 2021-005462-17; and EudraCT, 2024-511021-58.<h3>Findings</h3>Between Aug 31, 2022, and Jan 30, 2024, 88 patients received tarlatamab with atezolizumab or durvalumab after standard-of-care first-line chemo-immunotherapy. The median time from start of standard-of-care first-line chemo-immunotherapy to start of tarlatamab maintenance was 3·6 months (IQR 3·2–4·3). 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引用次数: 0

摘要

tarlatamab是一种delta-样配体3 (DLL3)导向的双特异性t细胞参与免疫疗法,可提高先前治疗过的小细胞肺癌(SCLC)患者的生存率。我们评估了tarlatamab联合atezolizumab或durvalumab作为大分期(ES)-SCLC患者一线维持治疗的安全性和活性。在这项多中心、非随机、1b期研究中,年龄在18岁及以上的患者,在接受4 - 6个周期的铂-依托泊苷化疗+程序性细胞死亡配体1 (PD-L1)抑制剂(如果有)后,表现状态为0-1,无疾病进展,在初始剂量为1 mg的塔拉他单抗后,每2周静脉注射一次10 mg塔拉他单抗。静脉滴注atezolizumab (1680 mg,每4周1次)或静脉滴注durvalumab (1500 mg,每4周1次)作为维持直至疾病进展。患者来自13个国家的30个中心。主要目的是评估安全性,并通过评估剂量限制性毒性、治疗发生不良事件、治疗相关不良事件、生命体征、心电图和临床实验室检查的变化,确定tarlatamab与PD-L1抑制剂联合使用的推荐2期剂量或最大耐受剂量。所有接受至少一剂塔拉他单的患者都被纳入分析。由于在初步分析中总生存期数据不成熟,因此在本文中,我们报告了一项非指定的中期分析,以提供对总生存期和长期安全性的最新检查。本研究已在ClinicalTrials.gov注册,编号NCT05361395;欧盟临床试验注册,2021-005462-17;[j] .科学通报,2016,(4):481 - 481。在2022年8月31日至2024年1月30日期间,88名患者在标准护理一线化疗免疫治疗后接受了塔拉他单抗和阿特唑单抗或杜伐单抗。从开始标准治疗的一线化疗免疫治疗到开始塔拉他单抗维持治疗的中位时间为3.6个月(IQR为3.2 - 4·3)。从维持开始的中位随访时间为18.4个月(15.2 - 23.0),tarlatamab的中位暴露时间为35周(8-75)。最常见的3-4级不良事件是低钠血症(88例患者中9例[10%])、贫血(88例患者中7例[8%])和中性粒细胞减少症(88例患者中6例[7%])。88例患者中有50例(57%)发生严重不良事件。最常见的严重不良事件是细胞因子释放综合征(88例患者中21例[24%])、发热(88例患者中6例[7%])、免疫效应细胞相关神经毒性综合征(88例患者中4例[5%])和肺炎(88例患者中4例[5%])。没有因治疗相关不良事件而死亡。中位总生存期为25.3个月(95% CI为20.3,无法估计)。tarlatamab + PD-L1抑制剂作为一线化学免疫治疗后的维持,显示出可控的安全性和有希望的抗癌活性,支持正在进行的3期试验(NCT06211036)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Safety and activity of tarlatamab in combination with a PD-L1 inhibitor as first-line maintenance therapy after chemo-immunotherapy in patients with extensive-stage small-cell lung cancer (DeLLphi-303): a multicentre, non-randomised, phase 1b study

Background

Tarlatamab is a delta-like ligand 3 (DLL3)-directed bispecific T-cell engager immunotherapy that has improved survival in patients with previously treated small-cell lung cancer (SCLC). We evaluated the safety and activity of tarlatamab in combination with atezolizumab or durvalumab as first-line maintenance therapy in patients with extensive-stage (ES)-SCLC.

Methods

In this multicentre, non-randomised, phase 1b study, patients aged 18 years and older, with Eastern Cooperative Oncology Group performance status of 0–1 and without disease progression after four to six cycles of platinum–etoposide chemotherapy plus a programmed cell death ligand 1 (PD-L1) inhibitor (if available), received tarlatamab 10 mg intravenously once every 2 weeks, after an initial tarlatamab 1 mg dose, with atezolizumab intravenously (1680 mg once every 4 weeks) or durvalumab intravenously (1500 mg once every 4 weeks) as maintenance until disease progression. Patients were enrolled from 30 centres in 13 countries. The primary objective was to evaluate safety and to determine the recommended phase 2 dose or maximum tolerated dose of tarlatamab in combination with a PD-L1 inhibitor through assessment of dose-limiting toxicities, treatment-emergent adverse events, treatment-related adverse events, and changes in vital signs, electrocardiograms, and clinical laboratory tests. All patients who received at least one dose of tarlatamab were included in the analyses. Because overall survival data were immature at the primary analysis, in this Article, we report a non-specified interim analysis to provide an updated examination of overall survival and longer-term safety. This study is registered with ClinicalTrials.gov, NCT05361395; the EU Clinical Trials registry, 2021-005462-17; and EudraCT, 2024-511021-58.

Findings

Between Aug 31, 2022, and Jan 30, 2024, 88 patients received tarlatamab with atezolizumab or durvalumab after standard-of-care first-line chemo-immunotherapy. The median time from start of standard-of-care first-line chemo-immunotherapy to start of tarlatamab maintenance was 3·6 months (IQR 3·2–4·3). The median follow-up from the start of maintenance was 18·4 months (15·2–23·0) and the median exposure to tarlatamab was 35 weeks (8–75). The most common grade 3–4 adverse events were hyponatraemia (nine [10%] of 88 patients), anaemia (seven [8%] of 88 patients), and neutropenia (six [7%] of 88 patients). Serious adverse events occurred in 50 (57%) of 88 patients. The most common serious adverse events were cytokine release syndrome (21 [24%] of 88 patients), pyrexia (six [7%] of 88 patients), immune effector cell-associated neurotoxicity syndrome (four [5%] of 88 patients), and pneumonia (four [5%] of 88 patients). There were no deaths due to treatment-related adverse events. Median overall survival was 25·3 months (95% CI 20·3–not estimable).

Interpretation

Tarlatamab plus a PD-L1 inhibitor as maintenance after first-line chemo-immunotherapy showed a manageable safety profile with promising anticancer activity, supporting the ongoing phase 3 trial (NCT06211036).

Funding

Amgen.
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