PO.CT01.04 · 临床试验

罕见肿瘤中联合抗肿瘤药物的快速分析与缓解评估（RARE CANCER）试验（RARE 3）：Tiragolumab + Atezolizumab

Rapid analysis and response evaluation of combination anti-neoplastic agents in rare tumors (RARE CANCER) trial (RARE 3): Tiragolumab + Atezolizumab

编号 CT259 展板 24 时间 4/21 02:00–05:00 区域 Section 50 主讲 Amanda Walker, MD

分会场 Phase II Clinical Trials

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作者与单位 Authors & Affiliations

Amanda Walker¹, Naoko Takebe², Murielle Hogu², Sarah J. Shin², Jared Foster³, Andre De Souza², Lamin Juwara⁴, Katherine V. Ferry-Galow⁵, Ralph E. Parchment⁵, Laura Kuhlmann², Helen X. Chen⁶, James H. Doroshow², Alice P. Chen², Jibran Ahmed²

¹National Heart, Lung & Blood Institute, National Institutes of Health, Bethesda, MD,²Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD,³Biometric Research Program, National Cancer Institute, National Institutes of Health, Bethesda, MD,⁴Clinical Research Directorate Frederick National Laboratory for Cancer Research, Frederick, MD,⁵Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD,⁶Cancer Therapy Evaluation Program Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD

摘要 Abstract

中文摘要

背景：罕见肿瘤（在美国的年发病率<6/100,000）的治疗选择有限。联合免疫检查点抑制（ICI）——抗PD-L1（atezolizumab）与抗TIGIT（tiragolumab）——在早期临床试验中显示出活性，并在临床前模型中增强了CD8⁺ T细胞介导的肿瘤排斥。本试验将评估该联合方案在罕见肿瘤中激活的瘤内CD8⁺ T细胞及临床活性。方法：RARE-3（NCT05715281）是一项II期药效动力学（PD）试验，主要目的是评估基线及第3周期第1天（±3天）前肿瘤活检中激活的CD8⁺ T细胞比例的增加。次要目的包括总体缓解率（RECIST v1.1）、无进展生存期（PFS）以及CD8⁺ T细胞浸润出现临床有意义增加的患者比例。合格患者须经组织学确诊的肿瘤，年龄≥18岁，ECOG≤2且器官功能充分。允许既往接受ICI治疗（抗TIGIT除外）。患者每21天接受atezolizumab（1200mg IV）加tiragolumab（600mg IV），直至疾病进展或不可接受的毒性。10对可评估活检样本可提供95%的概率和88%的把握度（alpha=0.05），以检测出相对基线>1.25个标准差的增加。结果：从2023年9月26日至2025年8月18日共入组12例患者。中位年龄为60.5岁（范围19-71）；患者人群中75%为女性，83.3%为白人，既往系统治疗的中位数为3（范围0-9）。截至2025年11月3日，9例患者报告了最高级别的治疗中出现的不良事件（AE），为3级。治疗相关AE包括淋巴细胞减少、吉兰-巴雷综合征、瘙痒、斑丘疹、肌炎及腹泻。9例患者接受了缓解评估，包括6例（50%）疾病稳定（SD）（其中3例SD≥6个周期；包括肾上腺皮质癌、嫌色细胞肾癌、血管周上皮样细胞肿瘤），以及3例疾病进展。1例患者因临床进展停止治疗；2例因未开始治疗及在1个周期后撤回知情同意而不可评估。中位PFS为4.29个月（四分位距，2.29-8.97）。目前正在评估8对配对活检样本。结论：本研究因申办方决定而提前关闭。未发生非预期毒性。正在进行的分析评估治疗对瘤内CD8⁺ T细胞及其他PD标志物的影响及其与临床活性的关联，以为未来研究提供依据。由NCI合同编号HHSN261201500003I资助。

查看英文原文 English abstract

Background: Rare tumors (incidence <6 per 100,000 per year in the US) have limited therapeutic options. Combined immune checkpoint inhibition (ICI) with anti-PD-L1 (atezolizumab) and anti-TIGIT (tiragolumab) demonstrated activity in early clinical trials and enhanced CD8⁺ T-cell-mediated tumor rejection in preclinical models. This trial will assess activated intratumoral CD8⁺ T cells and clinical activity of this combination in rare tumors. Methods: RARE-3 (NCT05715281) is a phase II pharmacodynamic (PD) trial with a primary objective of assessing the increase in proportion of activated CD8⁺ T cells in tumor biopsies at baseline and prior to cycle 3, day 1 (±3 days). Secondary objectives included overall response rate (RECIST v1.1), progression-free survival (PFS), and the proportion of patients (pts) with a clinically meaningful increase in CD8⁺ T-cell infiltration. Eligible pts had histologically confirmed tumors, age ≥18 years, ECOG ≤2 and adequate organ function. Prior ICI therapy (excluding anti-TIGIT) was permitted. Pts received atezolizumab (1200mg IV) plus tiragolumab (600mg IV) every 21 days until progression or unacceptable toxicity. Ten evaluable paired biopsies would provide 95% probability and 88% power (alpha=0.05) to detect a >1.25 standard deviation increase from baseline. Results: Twelve pts were enrolled from 9/26/23 to 8/18/25. Median age was 60.5 years (range 19-71); pt population was 75% female, 83.3% White, and median number of prior systemic therapies was 3 (range 0-9). As of 11/3/25, the highest treatment-emergent adverse events (AEs), reported in 9 pts, were grade 3. Treatment-related AEs included lymphopenia, Guillain-Barré syndrome, pruritus, maculopapular rash, myositis, and diarrhea. Nine pts were assessed for response including stable disease (SD) in 6 pts (50%) (3 with SD ≥6 cycles; including adrenocortical carcinoma, chromophobe renal carcinoma, perivascular epithelioid cell tumor), and progressive disease in 3 pts. One pt discontinued treatment for clinical progression; 2 were not evaluable due to not starting treatment and consent withdrawal after 1 cycle. Median PFS was 4.29 months (interquartile range, 2.29-8.97). Eight paired biopsies are currently being assessed. Conclusion: The study closed early due to sponsor decision. There was no unexpected toxicity. Ongoing analyses are assessing the impact of treatment on intratumoral CD8⁺ T cells and other PD markers, and their association with clinical activity to inform future studies. Funded by NCI Contract No. HHSN261201500003I.

利益披露 Disclosure

A. Walker, None.. N. Takebe, None.. M. Hogu, None.. S. J. Shin, None.. J. Foster, None.. A. De Souza, None.. L. Juwara, None.. K. V. Ferry-Galow, None.. R. E. Parchment, None.. L. Kuhlmann, None.. H. X. Chen, None.. J. H. Doroshow, None.. A. P. Chen, None.. J. Ahmed, None.

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