ASS1 缺陷型非鳞状非小细胞肺癌患者中 pegargiminase 联合培美曲塞和顺铂的 1 期药代基因组学剂量扩增研究。
Phase 1, pharmacogenomic, dose-expansion study of pegargiminase plus pemetrexed and cisplatin in patients with ASS1-deficient non-squamous non-small cell lung cancer.
机构信息
Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI) - A Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, UK.
Department of Medical Oncology, Barts Health NHS Trust, St Bartholomew's Hospital, London, UK.
出版信息
Cancer Med. 2021 Oct;10(19):6642-6652. doi: 10.1002/cam4.4196. Epub 2021 Aug 12.
INTRODUCTION
We evaluated the arginine-depleting enzyme pegargiminase (ADI-PEG20; ADI) with pemetrexed (Pem) and cisplatin (Cis) (ADIPemCis) in ASS1-deficient non-squamous non-small cell lung cancer (NSCLC) via a phase 1 dose-expansion trial with exploratory biomarker analysis.
METHODS
Sixty-seven chemonaïve patients with advanced non-squamous NSCLC were screened, enrolling 21 ASS1-deficient subjects from March 2015 to July 2017 onto weekly pegargiminase (36 mg/m ) with Pem (500 mg/m ) and Cis (75 mg/m ), every 3 weeks (four cycles maximum), with maintenance Pem or pegargiminase. Safety, pharmacodynamics, immunogenicity, and efficacy were determined; molecular biomarkers were annotated by next-generation sequencing and PD-L1 immunohistochemistry.
RESULTS
ADIPemCis was well-tolerated. Plasma arginine and citrulline were differentially modulated; pegargiminase antibodies plateaued by week 10. The disease control rate was 85.7% (n = 18/21; 95% CI 63.7%-97%), with a partial response rate of 47.6% (n = 10/21; 95% CI 25.7%-70.2%). The median progression-free and overall survivals were 4.2 (95% CI 2.9-4.8) and 7.2 (95% CI 5.1-18.4) months, respectively. Two PD-L1-expressing (≥1%) patients are alive following subsequent pembrolizumab immunotherapy (9.5%). Tumoral ASS1 deficiency enriched for p53 (64.7%) mutations, and numerically worse median overall survival as compared to ASS1-proficient disease (10.2 months; n = 29). There was no apparent increase in KRAS mutations (35.3%) and PD-L1 (<1%) expression (55.6%). Re-expression of tumoral ASS1 was detected in one patient at progression (n = 1/3).
CONCLUSIONS
ADIPemCis was safe and highly active in patients with ASS1-deficient non-squamous NSCLC, however, survival was poor overall. ASS1 loss was co-associated with p53 mutations. Therapies incorporating pegargiminase merit further evaluation in ASS1-deficient and treatment-refractory NSCLC.
简介
我们通过一项包含探索性生物标志物分析的 1 期剂量扩展试验，评估了精氨酸耗竭酶聚乙二醇化天冬酰胺酶（ADI-PEG20；ADI）联合培美曲塞（Pem）和顺铂（Cis）（ADIPemCis）在 ASS1 缺陷型非鳞状非小细胞肺癌（NSCLC）中的作用。
方法
67 例未经化疗的晚期非鳞状 NSCLC 患者接受了筛选，其中 21 例 ASS1 缺陷患者于 2015 年 3 月至 2017 年 7 月入组，接受每周一次的 PEG （36mg/m2）联合培美曲塞（500mg/m2）和顺铂（75mg/m2）治疗，每 3 周（最多 4 个周期）为一个疗程，随后接受培美曲塞或 PEG 维持治疗。评估了安全性、药代动力学、免疫原性和疗效；通过下一代测序和 PD-L1 免疫组化对分子生物标志物进行注释。
结果
ADIPemCis 具有良好的耐受性。血浆精氨酸和瓜氨酸水平存在差异，PEG 抗体在第 10 周达到平台期。疾病控制率为 85.7%（21/25；95%CI 63.7%-97%），部分缓解率为 47.6%（21/25；95%CI 25.7%-70.2%）。中位无进展生存期和总生存期分别为 4.2（95%CI 2.9-4.8）和 7.2（95%CI 5.1-18.4）个月。两名 PD-L1 表达阳性（≥1%）的患者接受了帕博利珠单抗免疫治疗后仍存活（9.5%）。肿瘤 ASS1 缺陷患者中 p53（64.7%）突变更为富集，与 ASS1 功能正常的疾病相比，中位总生存期更差（10.2 个月；n=29）。KRAS 突变（35.3%）和 PD-L1（<1%）表达无明显增加。在一名进展患者（n=3）中检测到肿瘤 ASS1 的重新表达。
结论
ADIPemCis 在 ASS1 缺陷型非鳞状 NSCLC 患者中安全且具有高度活性，但总体生存情况较差。ASS1 缺失与 p53 突变相关。包含 PEG 的治疗方案值得在 ASS1 缺陷和治疗耐药的 NSCLC 中进一步评估。
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