Patel Sandip Pravin, Fisher Jillian, Chae Young Kwang, Soto Luisa Solis, Kasi Anup, Konda Bhavana, Walshauser Mark, Parra Edwin, Zhang Jiexin, Duault Caroline, Gonzalez-Kozlova Edgar, Manyam Ganiraju, Zhang Jianhua, Chen Hong, Duose Dzifa Yawa, Laberiano Fernandez Caddie, Luthra Raja, Al-Atrash Gheath, Kim-Schulze Seunghee, Maecker Holden T, Wistuba Ignacio I, Gnjatic Sacha, Lee J Jack, Zhang Jianjun, Magner Christine M, Chen Helen X, Sharon Elad, Othus Megan, Ryan Christopher W, Blanke Charles, Haymaker Cara L, Kurzrock Razelle
UC San Diego Health Moores Cancer Center, La Jolla, California, USA
University of Washington, Seattle, Washington, USA.
J Immunother Cancer. 2025 Jun 30;13(6):e011760. doi: 10.1136/jitc-2025-011760.
SWOG S1609 ual nti-CTLA-4 and anti-PD-1 blockade in are umors (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.
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.
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.
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.
NCT02834013.
SWOG S1609 联合抗 CTLA-4 和抗 PD-1 阻断剂治疗罕见肿瘤（DART）研究了伊匹木单抗联合纳武利尤单抗在多种罕见肿瘤类型中的疗效。我们报告胰腺神经内分泌肿瘤（PNEN）队列的结果。
治疗方案为每 6 周静脉注射 1mg/kg 伊匹木单抗，每 2 周静脉注射 240mg 纳武利尤单抗。主要终点为总缓解率（ORR）（实体瘤疗效评价标准 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。检查临床获益率（包括 ORR 加疾病稳定（SD）>6 个月）。进行了相关性研究。该试验由美国国立癌症研究所/西南肿瘤学组早期治疗与罕见癌症委员会开展，在 1000 多个地点开放。
19 例 PNEN 患者入组。既往治疗的中位疗程数为 2（范围：0 - 4）。ORR 为 11%（2/19 例患者）；临床获益率（CBR；疾病稳定>6 个月+部分缓解+完全缓解）为 26%（5/19）。中位 PFS 为 3 个月；中位 OS 为 24 个月。最长 PFS 分别为 26 个月（中级别 PNEN）、31 个月（低级别）和 39 个月以上（中级别）。最常见的毒性反应为疲劳（47%的患者）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）为 AST（32%）和胆红素升高（26%），无 5 级事件。通过显色免疫组织化学检测程序性死亡配体 1 表达（评估了 12 例患者）与 ORR 无关；3 例患者肿瘤突变负荷（TMB）较高；2 例部分缓解患者（PFS = 26 个月）中有 1 例 TMB 较高（150 个突变/mb）。外周效应记忆 T 细胞活化（通过飞行时间流式细胞术评估了 11 例患者，其中 5 例进行了纵向分析）与反应相关，不过评估的患者数量有限。
低剂量伊匹木单抗加纳武利尤单抗在难治性 PNEN 患者中显示出 11%的 ORR 和 26%的 CBR（包括 SD>6 个月），3 例（16%）患者有持久获益（>2 年）。
NCT02834013。
