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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02808-y

摘要内容如下：

对于目前没有靶向分子改变的非小细胞肺癌（NSCLC）肿瘤患者，标准治疗方案是单独使用抗PD-（L）1检查点抑制剂或联合铂-双联疗法的免疫疗法。然而，并不是所有的患者都能获得持久的益处，对免疫检查点阻断的抵抗是常见的。了解耐药机制（可能包括DNA损伤反应和修复途径的缺陷、STK11/LKB1的改变或功能性突变、抗原呈递途径的改变以及肿瘤微环境中的免疫抑制细胞亚群）并开发有效的治疗方法来克服它们，仍然是尚未满足的需求。在此，2期Umbrella Hudson研究评估了含抗PD-（L）1免疫疗法和铂双联疗法失败后晚期NSCLC的合理联合方案。共有268名患者接受了durvalumab（抗PD-L1单克隆抗体）-ceralasertib（ATR激酶抑制剂）、durvalumab-olaparib（PARP抑制剂）、durvalumab-danvatirsen（STAT3反义寡核苷酸）或durvalumab-oleclumab（抗CD73单克隆抗体）治疗。Durvalumab-Ceralasertib的临床获益最大；客观缓解率（主要转归）为13.9%（11/79）对其他方案的2.6%（5/189），合并的中位无进展生存期（次要转归）为5.8（80%可信区间4.6-7.4）对2.7（1.8-2.8）个月，中位总生存期（次要转归）为17.4（14.1-20.3）对9.4（7.5-10.6）个月。在已知的免疫治疗难治性亚组中，Durvalumab-Ceralasertib的获益是一致的。在假设对ATR抑制具有易感性的ATM改变患者中，客观缓解率为26.1%（6/23），中位无进展生存期/中位总生存期为8.4/22.8个月。Durvalumab-Ceralasertib的安全性/耐受性可控。生物标志物分析表明，抗PD-L1/ATR抑制诱导免疫变化，恢复抗肿瘤免疫。Durvalumab-Ceralasertib在免疫治疗难治性NSCLC中正在进一步研究中。ClinicalTrials.gov标识符：NCT03334617。

英文原文如下：

Abstracts

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.

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