Sandip Pravin Patel, Jillian Fisher, Young Kwang Chae, Luisa Solis Soto, Anup Kasi, Bhavana Konda, Mark Walshauser, Edwin Parra, Jiexin Zhang, Caroline Duault, Edgar Gonzalez-Kozlova, Ganiraju Manyam, Jianhua Zhang, Hong Chen, Dzifa Yawa Duose, Caddie Laberiano Fernandez, Raja Luthra, Gheath Al-Atrash, Seunghee Kim-Schulze, Holden T Maecker, Ignacio I Wistuba, Sacha Gnjatic, J Jack Lee, Jianjun Zhang, Christine M Magner, Helen X Chen, Elad Sharon, Megan Othus, Christopher W Ryan, Charles Blanke, Cara L Haymaker, Razelle Kurzrock
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We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort.</p><p><strong>Experimental design: </strong>Treatment consisted of ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative studies were performed. The trial was conducted by the National Cancer Institute/Southwest Oncology Group Early Therapeutics and Rare Cancers Committee and opened at >1,000 sites.</p><p><strong>Results: </strong>19 patients with PNEN were enrolled. The median number of lines of prior therapy was 2 (range: 0-4). The ORR was 11% (2/19 patients); the clinical benefit rate (CBR; stable disease >6 months+partial response+complete response), 26% (5/19). The median PFS was 3 months; median OS, 24 months. The longest PFSs were 26 (intermediate grade PNEN), 31 (low grade) and 39+months (intermediate grade). The most common toxicities were fatigue (47% of patients) and aspartate aminotransferase (AST) elevation (32%); the most common grade 3/4 immune-related adverse event (AE) was AST (32%) and bilirubin elevation (26%), with no grade 5 events. Programmed death-ligand 1 expression by chromogenic immunohistochemistry (N=12 patients assessed) did not associate with ORR; tumor mutation burden (TMB) was high in three patients; one of the two patients with partial remission (PFS=26 months) had high TMB (150 mutations/mb). 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引用次数: 0
摘要
目的：SWOG S1609 Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare tumor （DART）研究ipilimumab联合nivolumab治疗多种罕见肿瘤类型的疗效。我们报告胰腺神经内分泌肿瘤（PNEN）队列的结果。实验设计：治疗包括伊匹单抗1 mg/kg每6周静脉注射，纳武单抗240 mg每2周静脉注射。主要终点是总体缓解率（ORR）（实体肿瘤反应评价标准recist V.1.1）。次要终点包括无进展生存期（PFS）、总生存期（OS）和毒性。观察6个月的临床获益率（包括ORR +病情稳定（SD））。进行相关研究。该试验由美国国家癌症研究所/西南肿瘤小组早期治疗和罕见癌症委员会进行，在1000个地点开展。结果：19例PNEN患者入组。既往治疗的中位数为2（范围：0-4）。ORR为11%（2/19例）；临床获益率（CBR）；病情稳定（6个月+部分缓解+完全缓解），26%（5/19）。中位PFS为3个月；中位生存期，24个月。最长PNEN时间为26个月（中度PNEN）、31个月（低度PNEN）和39个月以上（中度PNEN）。最常见的毒性是疲劳（47%）和天冬氨酸转氨酶（AST）升高（32%）；最常见的3/4级免疫相关不良事件（AE）是AST（32%）和胆红素升高（26%），无5级事件。通过显色免疫组化检测程序性死亡配体1的表达（N=12例评估患者）与ORR无关；3例患者肿瘤突变负荷（TMB）较高；2例部分缓解（PFS=26个月）患者中的1例TMB较高（150个突变/mb）。外周效应记忆t细胞激活（N=11例患者通过细胞术通过飞行时间评估，其中5例进行纵向分析）与反应相关，尽管评估的患者数量有限。结论：在难治性PNEN患者中，低剂量ipilimumab联合nivolumab显示出11%的ORR和26%的CBR（包括SD bbb6个月），在3例（16%）患者中具有持久的益处（>2年）。试验注册号：NCT02834013。
Phase II basket trial of Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609: pancreatic neuroendocrine neoplasm (PNEN) cohort.
Purpose: SWOG S1609 Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort.
Experimental design: Treatment consisted of ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative studies were performed. The trial was conducted by the National Cancer Institute/Southwest Oncology Group Early Therapeutics and Rare Cancers Committee and opened at >1,000 sites.
Results: 19 patients with PNEN were enrolled. The median number of lines of prior therapy was 2 (range: 0-4). The ORR was 11% (2/19 patients); the clinical benefit rate (CBR; stable disease >6 months+partial response+complete response), 26% (5/19). The median PFS was 3 months; median OS, 24 months. The longest PFSs were 26 (intermediate grade PNEN), 31 (low grade) and 39+months (intermediate grade). The most common toxicities were fatigue (47% of patients) and aspartate aminotransferase (AST) elevation (32%); the most common grade 3/4 immune-related adverse event (AE) was AST (32%) and bilirubin elevation (26%), with no grade 5 events. Programmed death-ligand 1 expression by chromogenic immunohistochemistry (N=12 patients assessed) did not associate with ORR; tumor mutation burden (TMB) was high in three patients; one of the two patients with partial remission (PFS=26 months) had high TMB (150 mutations/mb). Peripheral effector memory T-cell activation (N=11 patients assessed by cytometry by time-of-flight with 5 having longitudinal analysis) was associated with response, though the number of patients evaluated was limited.
Conclusions: Low-dose ipilimumab plus nivolumab demonstrated an 11% ORR and 26% CBR (includes SD>6 months) in patients with refractory PNEN, with durable benefit (>2 years) in 3 (16%) patients.
期刊介绍：
The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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