PO.CL01.05 · 临床研究

帕博利珠单抗治疗复发性胶质瘤中无进展生存的分子相关因素

Molecular correlates of progression-free survival in recurrent gliomas treated with pembrolizumab

编号 5253 展板 19 时间 4/21 09:00–12:00 区域 Section 42 主讲 Shameel Shafqat, MBBS

分会场 Biomarkers Predictive of Therapeutic Benefit 5

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作者与单位 Authors & Affiliations

Shameel Shafqat¹, Muhammad Asad Maqbool¹, Hussam Al Kateb², Terry C. Burns³, Jian L. Campian⁴, Shannon P. Fortin Ensign⁵, Evanthia Galanis⁴, Julie E. Hammack⁶, Cristaine M. Ida², Mitch L. Klebig², Timothy J. Kaufmann⁷, Autumn C. Moon², Maciej M. Mrugala⁸, Bryan J. Neth⁹, Alyx B. Porter⁸, Michael W. Ruff⁹, Ugur T. Sener⁹, Wendy J. Sherman⁶, Joon H. Uhm⁹, Rachael A. Vaubel², Sani H. Kizilbash⁴

¹Comprehensive Cancer Center, Mayo Clinic, Rochester, MN,²Department of Laboratory and Pathology Medicine, Mayo Clinic, Rochester, MN,³Department of Neurological Surgery, Mayo Clinic, Rochester, MN,⁴Department of Oncology, Mayo Clinic, Rochester, MN,⁵Department of Oncology, Mayo Clinic, Phoenix, AZ,⁶Department of Neurology, Mayo Clinic, Jacksonville, FL,⁷Department of Radiology, Mayo Clinic, Rochester, MN,⁸Department of Neurology, Mayo Clinic, Phoenix, AZ,⁹Department of Neurology, Mayo Clinic, Rochester, MN

摘要 Abstract

中文摘要

背景：帕博利珠单抗已越来越多地被超说明书用于复发性胶质瘤，但预测应答的生物标志物仍定义不清。胶质瘤在胶质母细胞瘤、IDH野生型(GBM)，星形细胞瘤、IDH突变型(A-IDHm)和少突胶质细胞瘤、1p/19q共缺失型(OLIGO)之间表现出显著的分子异质性，这可能影响免疫治疗疗效。本研究旨在识别接受帕博利珠单抗治疗的复发性胶质瘤患者无进展生存(PFS)的分子预测因子。方法：回顾性纳入Mayo Clinic各中心在2014-2024年间接受≥2个周期帕博利珠单抗治疗的≥18岁复发性胶质瘤成人患者。审阅了二代测序(NGS)报告，并在可获得时分析了帕博利珠单抗起始前切除的存档肿瘤组织。使用Mayo Clinic实体瘤检测组套进行全面分子分析，该组套采用Illumina Tru-Sight Oncology 500高通量NGS检测。使用RANO 2.0标准评估进展。采用Kaplan-Meier方法评估基因组改变(临床相关序列和/或拷贝数变异)，并使用log-rank检验比较PFS差异。结果：共纳入33例患者[中位(范围)年龄：44.0(21-76)岁；63.6%为男性]。肿瘤组织取样与帕博利珠单抗起始之间的间隔为9.9(0.9-176.1)个月，中位治疗时长为2.8(1.4-10.4)个月。整个队列的中位PFS为2.4(0.8-15.2)个月，自帕博利珠单抗起始的中位总生存为6.9(0.9-48.2)个月。OLIGO患者(n=8)的PFS[4.6(1.9-15.2)个月]长于A-IDHm[n=11；PFS 2.1(1.1-4.4)个月]或GBM[n=14；PFS 2.3(0.8-9.2)个月]。在OLIGO中，CDKN2A/B杂合缺失(n=3)预示更短的PFS(3.9 vs 10.9个月；p=0.0462)，而在A-IDHm中，FANC突变(n=2)与更长的PFS相关(4.17 vs 1.61个月；p=0.0224)。所评估的其他改变基因或通路与PFS均未观察到显著关联，包括但不限于肿瘤突变负荷、EGFR、RB1、TP53、FUBP1、NF 1或2、PTEN、PDGFRA、PIK3CA、PIK3R1、CDK4、KRAS、MLH1、MLH2、MSH6基因组改变或CDKN2A/B纯合缺失(均p>0.05)。结论：帕博利珠单抗在复发性胶质瘤中总体疗效有限，然而探索性分析识别出若干可能与PFS相关的亚型特异性基因组改变。这些具有假设生成意义的发现凸显了潜在肿瘤生物学对免疫治疗应答的潜在影响，值得在更大规模的前瞻性队列中进一步验证。

查看英文原文 English abstract

Background: Pembrolizumab has been increasingly used off label for recurrent gliomas, yet biomarkers predicting response are poorly defined. Gliomas exhibit substantial molecular heterogeneity across Glioblastoma, IDH-wildtype (GBM), Astrocytoma, IDH-Mutant (A-IDHm), and Oligodendroglioma, 1p/19q co-deleted (OLIGO), which may influence immunotherapy efficacy. This study aimed to identify molecular predictors of progression-free survival (PFS) in recurrent glioma patients treated with pembrolizumab. Methods: Adults ≥18 years with recurrent glioma receiving ≥2 cycles of pembrolizumab between 2014 - 2024 were retrospectively identified across Mayo Clinic. Next-generation sequencing (NGS) reports were reviewed and archival tumor tissue resected prior to pembrolizumab initiation was analyzed when available. Comprehensive molecular profiling was performed using the Mayo Clinic Solid Tumor Panel which employs the Illumina Tru-Sight Oncology 500 High-Throughput NGS assay. Progression was assessed using RANO 2.0 criteria. Genomic alterations (clinically relevant sequences and/or copy-number variants) were evaluated using the Kaplan-Meier method, with differences in PFS compared using the log-rank test. Results: Thirty-three patients were included [median (range) age: 44.0 (21-76) years; 63.6% male]. The interval between tumor tissue sampling and pembrolizumab initiation was 9.9 (0.9-176.1) months, and median treatment duration was 2.8 (1.4-10.4) months. Median PFS for the overall cohort was 2.4 (0.8-15.2) months, and median overall survival from pembrolizumab initiation was 6.9 (0.9-48.2) months. Patients with OLIGO (n=8) had a longer PFS [4.6 (1.9-15.2) months] than either A-IDHm [n=11; PFS 2.1 (1.1-4.4) months] or GBM [n=14; PFS 2.3 (0.8-9.2) months]. Within OLIGO, CDKN2A/B heterozygous deletion (n=3) predicted a shorter PFS (3.9 vs 10.9 months; p=0.0462), while in A-IDHm, FANC mutation (n=2) was associated with a longer PFS (4.17 vs 1.61 months; p=0.0224). No significant associations with PFS were observed for other altered genes or pathways evaluated, including but not limited to Tumor Mutational Burden, EGFR, RB1, TP53, FUBP1, NF 1 or 2, PTEN, PDGFRA, PIK3CA, PIK3R1, CDK4, KRAS, MLH1, MLH2, MSH6 genomic alterations or CDKN2A/B homozygous deletion (all p>0.05). Conclusions: Pembrolizumab shows limited overall efficacy in recurrent gliomas, however, exploratory analyses identified several subtype-specific genomic alterations that may correlate with PFS. These hypothesis-generating findings highlight the potential influence of underlying tumor biology on immunotherapy response and warrant further validation in larger, prospective cohorts.

利益披露 Disclosure

S. Shafqat, None.. M. Maqbool, None.. H. Al Kateb, None.. T. C. Burns, None.. J. Campian, None.. S. P. Fortin Ensign, None.. E. Galanis, None.. J. E. Hammack, None.. C. M. Ida, None.. M. L. Klebig, None.. T. J. Kaufmann, None.. A. C. Moon, None.. M. M. Mrugala, None.. B. J. Neth, None.. A. B. Porter, None.. M. W. Ruff, None.. U. T. Sener, None.. W. J. Sherman, None.. J. H. Uhm, None.. R. A. Vaubel, None.. S. H. Kizilbash, None.

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