PO.CL05.06 · 临床研究

III-IV期黑色素瘤中IPI/NIVO/RELA联合sarilumab的血清药效学生物标志物:一项Simon II期试验的第1阶段结果(NCT05428007)

Serum pharmacodynamic biomarkers of IPI/NIVO/RELA plus sarilumab in Stage III-IV melanoma: Stage 1 results of a Simon Phase II trial (NCT05428007)

编号 6453 展板 1 时间 4/21 02:00–05:00 区域 Section 41 主讲 Teruyuki Mizutani, MD;PhD

分会场 Clinical Correlates of Immunotherapy

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作者与单位 Authors & Affiliations

Teruyuki Mizutani¹, Amrutesh Puranik¹, Inderjit Mehmi², Judith Goldberg¹, Maya Dimitrova¹, Perla Arriola¹, Stanzin Idga¹, Xiaochun Li¹, Benjamin Levinson¹, Justine Cohen³, Elizabeth I. Buchbinder³, Donald Lawrence⁴, Alissa Kalyan¹, Morgan Simons¹, F. Stephen Hodi³, Ryan J. Sullivan⁴, Omid Hamid², Michelle Krogsgaard¹, Janice M. Mehnert¹

¹NYU Langone Health Perlmutter Cancer Ctr., New York, NY,²The Angeles Clinic and Research Institute, Los Angeles, CA,³Dana-Farber Cancer Institute, Boston, MA,⁴Harvard Medical School/Massachusetts General Hospital, Boston, MA

摘要 Abstract

中文摘要

背景:评估预测应答的生物标志物对于优化免疫检查点抑制剂(ICI)治疗黑色素瘤至关重要。在此背景下,随时间监测细胞因子动态提供了一种合理的策略,以确定用sarilumab进行IL-6R抑制是否具有生物学活性,并识别与临床结局相关的药效学特征。在此,我们聚焦于使用Luminex检测的纵向血清细胞因子谱,以在一项II期试验中探索应答的药效学生物标志物,该试验在不可切除或晚期黑色素瘤患者中联合使用nivolumab(3 mg/kg)、ipilimumab(1 mg/kg)、IL-6受体抑制剂sarilumab(150 mg)和LAG-3抗体relatlimab(160 mg)(INR + S)。方法:我们分析了33例接受INR + S治疗的黑色素瘤患者的血清细胞因子,使用来自基线、第4周、第6周、第12周、第18周和第28周(停用sarilumab后的最终时间点)的样本,并根据应答和毒性对患者进行分类。患者被分为PR/CR、SD和PD组,以及1-2级与3级或更高毒性组。使用Luminex检测对血清细胞因子进行分析,测量23种分析物。共分析了来自33例患者的152份样本。使用Mann-Whitney U检验、配对t检验和Kruskal-Wallis检验进行统计分析,显著性水平设为0.05。结果:最佳总体应答率为63.6%。到第24周,12%的患者发生3-5级免疫相关不良事件(irAE)。在基线时,未识别出对治疗应答或>3级irAE的任何治疗前预测因素。在所有患者中,与基线相比,在一个或多个时间点观察到IL-6、IL-6R、OSM、CXCL10、IL-4、IL-10、G-CSF和M-CSF数种与临床获益相关的显著治疗后模式。值得注意的是,PR/CR患者随时间显示IL-6升高和IL-6R降低,并在停用sarilumab后恢复到基线水平。当比较基线与第4周时,疾病进展与OPN和IL-8的显著增加相关,而PR/CR患者显示IL-6R、IL-4和G-CSF降低。结论:本研究的纵向分析揭示了IL-6升高和IL-6R降低。这些动态变化可能反映了一种更活跃的IL-6R阻断模式,并可能促进了临床结局的改善。该试验的下一阶段是对INR +/- S的随机比较,将分析来自该随机比较的生物标本以在我们的发现基础上进一步深入研究。

查看英文原文 English abstract

Background: Assessing biomarkers to predict response is crucial for optimizing melanoma treatment with immune checkpoint inhibitors (ICIs). In this context, monitoring cytokine dynamics over time provides a rational strategy to determine whether IL-6R inhibition with sarilumab is biologically active and to identify pharmacodynamic signatures associated with clinical outcomes. Here, we focus on longitudinal serum cytokine profiling using Luminex assays to explore pharmacodynamic biomarkers for response in a phase II trial combining nivolumab (3 mg/kg), ipilimumab (1 mg/kg), the IL-6 receptor inhibitor sarilumab (150 mg), and the LAG-3 antibody relatlimab (160 mg) (INR + S) in patients with unresectable or advanced melanoma. Methods: We analyzed serum cytokines from 33 melanoma patients treated with INR + S using samples from baseline, week 4, week 6, week 12, week 18, and week 28 (final timepoint after discontinuation of sarilumab), and categorized patients according to response and toxicity. Patients were classified into PR/CR, SD, and PD groups, as well as grade 1-2 versus grade 3 or greater toxicity. Serum cytokines were profiled using Luminex assays, measuring 23 analytes. In total, 152 samples from 33 patients were analyzed. Statistical analyses were conducted using Mann-Whitney U test, paired t-test, and Kruskal-Wallis test, with the significance level set at 0.05. Results: The best overall response rate was 63.6%. Grade 3-5 irAEs occurred in 12% of patients by week 24. At baseline, no pretreatment predictive factors for either treatment response or > grade 3 irAEs were identified. Across all patients, several significant post-treatment patterns that correlated with clinical benefit were observed compared with baseline at one or more time points for IL-6, IL-6R, OSM, CXCL10, IL-4, IL-10, G-CSF, and M-CSF. Notably, PR/CR patients showed increased IL-6 and decreased IL-6R levels over time, which returned to baseline levels after discontinuation of sarilumab. When comparing baseline with week 4, progressive disease was associated with marked increases in OPN, and IL-8, whereas PR/CR patients showed decreases in IL-6R, IL-4, and G-CSF. Conclusion: Longitudinal analyses in the present study revealed increased IL-6 and decreased IL-6R levels. These dynamics likely reflect a more active mode of IL-6R blockade and may have contributed to improved clinical outcomes. The next phase of the trial is a randomized comparison of INR +/- S, and biospecimens from this randomized comparison will be analyzed to build on our findings.

利益披露 Disclosure

T. Mizutani, None. A. Puranik, Bespoke MultiOmics Consultants Other, No relevant financial relationship with the presented research.. J. Goldberg, None.. M. Dimitrova, None.. P. Arriola, None.. S. Idga, None.. X. Li, None.. B. Levinson, None.. J. Cohen, None.. D. Lawrence, None.. A. Kalyan, None.. M. Simons, None. F. Hodi, Bristol-Myers Squibb (BMS) Independent Contractor, ). Merck,AstraZeneca,Compass Therapeutics,Apricity,Bicara Independent Contractor. Novartis Independent Contractor, ). Checkpoint Therapeutics, Bioentre, Gossamer, Iovance Independent Contractor. Catalym, Immunocore, Kairos, Solu Therapeutics Independent Contractor. Puretech, Corner Therapeutics, Curis, Pliant, Vir Biotechnology Independent Contractor. Pieris Pharmaceuticals Other, Other financial relationship. 92Bio, Rheos, Bayer, Zumutor,Blueprint Oncology Independent Contractor. Abalytics Other, Other financial relationship. O. Hamid, BMS Independent Contractor, ). M. Krogsgaard, Roche / Genentech ). Novartis ). Biogen ). Merck ). J. M. Mehnert, Pfizer Other Business Ownership. Medscape Gift. Merck Sharp & Dohme Independent Contractor. MP Global Gift. Sanofi / Regeneron Independent Contractor. Bristol-Myers Squibb Independent Contractor, ). Immunocore Independent Contractor. Sun Pharma Independent Contractor. Cugene Independent Contractor. Moderna Therapeutics Independent Contractor. GV20 Therapeutics ). Nested Therapeutics ). Amgen ). AstraZeneca ). Incyte ). Merck ). Novartis ). Regeneron ). Kinnate ). decipher ).

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