PO.CL07.02 · 临床研究

液体活检指导的精准肿瘤学临床试验：评估ctDNA基因组分析在晚期或转移性实体瘤患者治疗优化中的应用价值

Liquid biopsy-informed precision oncology clinical trial to evaluate the utility of ctDNA genomic profiling for therapy optimization in patients with advanced or metastatic solid tumors

编号 3908 展板 14 时间 4/20 02:00–05:00 区域 Section 47 主讲 Amna Jamali, MBBS

分会场 Molecular Targeted Therapy

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作者与单位 Authors & Affiliations

Amna Jamali¹, Jaime Wehr¹, Jenna VanLiere Canzoniero¹, Maria Fatteh¹, Katerina Karaindrou¹, Michael Conroy¹, Ilias Ziakas¹, Mohamed Sherief¹, Timsy Wanchoo¹, Faith Too¹, Lily Scharpf¹, Ruth Moges¹, Dana Petry¹, Kala Visvanathan¹, Ellen Verner², Amy Greer², Kory Kreimeyer¹, Jonathan Spiker¹, Rachel Karchin¹, Christine L. Hann¹, Vincent K. Lam¹, Joseph Christopher Murray¹, Josephine Feliciano¹, Kristen Marrone¹, Julie R. Brahmer¹, Ming-Tseh Lin³, Taxiarchis Botsis¹, Hao Wang¹, Mark Sausen², Christopher D. Gocke³, Rena Xian³, Jessica Tao¹, Valsamo (Elsa) K. Anagnostou¹

¹Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD,²Labcorp, Baltimore, MD,³Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD

摘要 Abstract

中文摘要

背景：通过液体活检（LB）进行的基因组分析推动了精准肿瘤学的决策制定；然而，一项重大挑战在于如何审慎地解读LB数据，以改善基因型特异性治疗的选择与用药顺序。方法：我们报告一项观察性生物标志物试验首次计划分析的最新结果，该试验旨在评估序贯LB在晚期或转移性实体瘤患者中的临床应用价值（NCT05585684）。主要终点评估可行性、可干预改变的患病率以及接受基因型匹配治疗的患者比例。次要终点包括无进展生存期（PFS）、总生存期（OS）以及LB与肿瘤二代测序（NGS）之间的一致性。在基线、治疗早期（1-3周）及疾病进展时进行序贯LB，采用经临床验证的33基因panel NGS检测（Labcorp Plasma Focus）。配对的白细胞（WBC）NGS用于识别克隆性造血（CH）来源的变异。采用多资源程序化方法评估突变的可干预性，并赋予证据等级（1-4级），随后在约翰霍普金斯分子肿瘤委员会（JH MTB）进行审议。结果：在50例患者中，MTB审议了45份基线LB和12份进展期LB。JH MTB将72.5%（n=50）的基线改变归类为肿瘤来源。在19例具有存档组织NGS的患者中，基线LB检出32个变异，其中78.1%在组织NGS中也被检出。此外，基线时23.2%（n=16）、治疗早期20.0%（n=6）及进展时13.0%（n=3）的LB改变为CH来源。经MTB审议，基线时29.2%、治疗早期21.9%及进展时26.1%的变异被归类为可干预（58.8%为1级、11.8%为2级、11.8%为3级、17.6%为4级证据）。在45例接受审议的患者中，38例获得了治疗建议，57.9%启动了推荐治疗。与接受标准治疗的患者相比，接受MTB推荐治疗的患者中位PFS和OS显著更长（分别为p=0.027和p=0.00062）。在校正性别、吸烟状态、年龄及既往系统治疗线数等临床协变量的多因素分析中，MTB推荐的治疗选择与PFS和OS独立相关（分别为p=0.043和p=0.006）。接受基因型匹配MTB推荐治疗的患者亚组，与接受标准治疗者相比，中位PFS和OS显著更长（分别为p=0.026和p=0.0074）。结论：我们的研究结果强调了在多学科MTB框架内、由程序化工作流驱动的精准肿瘤学干预的重要性，这一干预依托全面的LB分子信息以指导治疗选择并改善患者结局。

查看英文原文 English abstract

Background: Genomic profiling via liquid biopsies (LB) has advanced precision oncology decision-making; however, a major challenge is critically interpreting LB data to improve the selection and order of genotype-specific therapies. Methods: We present updated results from the first planned analysis of an observational biomarker trial, aimed at assessing the clinical utility of serial LB in patients with advanced or metastatic solid tumors (NCT05585684). Primary endpoints assessed feasibility, prevalence of actionable alterations, and fraction of patients receiving genotype-matched therapies. Secondary endpoints encompassed progression-free survival (PFS), overall survival (OS), and concordance between LB and tumor next-generation sequencing (NGS). Serial LBs at baseline, early (1-3 weeks) on therapy, and at progression, employed a clinically validated 33-gene panel NGS assay (Labcorp Plasma Focus). Matched white blood cell (WBC) NGS was used to identify clonal hematopoiesis (CH)-derived variants. Mutation actionability was evaluated using a multi-resource programmatic approach, and levels of evidence (1-4) were assigned, followed by review at the Johns Hopkins Molecular Tumor Board (JH MTB). Results: Among 50 patients, 45 baseline and 12 progression LBs were reviewed at MTB. JH MTB classified 72.5% (n=50) of baseline alterations as tumor-derived. In 19 patients with archival tissue NGS, 32 variants were detected in the baseline LB, of which 78.1% were also detected in tissue NGS. Furthermore, 23.2% (n=16) of LB alterations at baseline, 20.0% (n=6) early on-therapy, and 13.0% (n=3) at progression were CH derived. Upon MTB review, 29.2% variants at baseline, 21.9% at early on-therapy and 26.1% at progression were classified as actionable (58.8% level 1, 11.8% level 2, 11.8% level 3 and 17.6% level 4 evidence). Of 45 patients reviewed, 38 received therapeutic recommendations and 57.9% initiated recommended therapy. Patients treated with MTB recommended therapies had significantly longer median PFS and OS compared to those who received standard of care (p=0.027 and p=0.00062 respectively). MTB-recommended therapy selection was independently associated with PFS and OS, in multivariate analyses adjusting for clinical covariates including sex, smoking status, age, and prior lines of systemic therapy (p=0.043 and p=0.006, respectively). Subset of patients treated with genotype-matched MTB recommendations had significantly longer median PFS and OS compared to those who received standard of care (p=0.026 and p=0.0074 respectively). Conclusion: Our findings emphasize the importance of precision oncology interventions driven by programmatic workflows within a multidisciplinary MTB, supported by comprehensive LB molecular information to guide therapy selection and improve patient outcomes.

利益披露 Disclosure

A. Jamali, None.. J. Wehr, None. J. V. Canzoniero, Foundation Medicine ). Astra Zeneca Other, Honoraria. Johns Hopkins University Patent. Haystack Diagnostics ). M. Fatteh, None.. K. Karaindrou, None.. M. Conroy, None.. I. Ziakas, None.. M. Sherief, None.. T. Wanchoo, None.. F. Too, None.. L. Scharpf, None.. R. Moges, None.. D. Petry, None.. K. Visvanathan, None. E. Verner, Labcorp Employment, Stock. A. Greer, Labcorp Employment, Stock. K. Kreimeyer, None.. J. Spiker, None.. R. Karchin, None. C. L. Hann, Astra Zeneca ), Other, Consultant. Daiichi Sankyo Europe GmbH ), Other, Consultant. Genentech Other, Consultant. Amgen ). V. K. Lam, GlaxoSmithKline ). Astra Zeneca ), Other, Consultant. Merck ). Nuvalent ). Bristol Myers Squibb ), Other, Consultant. Iovance Biotherapeutics Other, Consultant, Data safety and monitoring board member. Lilly Other, Consultant. Takeda Other, Consultant. Nuvation Bio Other, Consultant. Guardant Health Other, Consultant. Genentech/Roche Other, Consultant. Pfizer Other, Consultant. J. C. Murray, Janssen (Johnson & Johnson) Other, Consultant. Astra Zeneca Other, Consultant. Curio Science Other, Honoraria. Caris Life Sciences Other, Honoraria. ION Oncology Practice Network Other, Honoraria. Nebraska Oncology Society Other, Honoraria. PRIME Other, Honoraria. iTeos Therapeutics Other, Advisory board member. Doximity Stock Option. NIH/NCI ). CDC ). Maryland Cigarette Restitution Fund ). Merck ). J. Feliciano, Astra Zeneca ), Other, Consultant. Pfizer ). Bristol Myers Squibb ). Regeneron Other, Consultant. Coherus Other, Consultant. Eli Lilly Other, Consultant. Genentech Other, Consultant. Takeda Other, Consultant. Janssen Other, Consultant. Daiichi Sankyo Other, Consultant. K. Marrone, Astra Zeneca Other, Consultant, Honoraria. Amgen Other, Consultant. Janssen Other, COnsultant. Mirati Therapeutics ), Other, Consultant. Daiichi Sankyo/Lilly Other, Consultant. Puma Biotechnology Other, Consultant. Bristol Myers Squibb ). J. R. Brahmer, Astra Zeneca ), Other, Consultant. Bristol Myers Squibb ). RAPT Therapeutics Other, Consultant. Mestag Other, Consultant. GlaxoSmithKline Other, Consultant. Amgen Other, Consultant. Sanofi Aventis Other, Consultant. Summit Therapeutics Other, Consultant. Genentech Other, Consultant. Beyer Other, Consultant. Genmab Other, Data safety and monitoring board member. M. Lin, None.. T. Botsis, None.. H. Wang, None. M. Sausen, Labcorp Employment, Stock. C. D. Gocke, None.. R. Xian, None.. J. Tao, None. V. K. Anagnostou, Astra Zeneca ), Other, Advisory board member. Bristol-Myers Squibb ). Personal Genome Diagnostics/Labcorp ), Other, Honoraria. Delfi Diagnostics ). Neogenomics Other, Advisory board member. Foundation Medicine Other, Honoraria. Roche Other, Honoraria. ThermoFisher Other, Honoraria. Guardant Health Other, Honoraria.

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