NCI 8628 试验：随机、二期研究比较 ziv-aflibercept 联合高剂量白细胞介素-2 与高剂量白细胞介素-2 单药治疗不可切除 III 或 IV 期黑色素瘤的疗效。
NCI 8628: A randomized phase 2 study of ziv-aflibercept and high-dose interleukin 2 or high-dose interleukin 2 alone for inoperable stage III or IV melanoma.
机构信息
University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center, Cleveland, Ohio.
出版信息
Cancer. 2018 Nov 15;124(22):4332-4341. doi: 10.1002/cncr.31734. Epub 2018 Oct 10.
BACKGROUND
Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2.
METHODS
NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS).
RESULTS
A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in favor of arm A, with a median of 6.9 months (95% confidence interval [95% CI], 4.1-8.7 months) versus 2.3 months (95% CI, 1.6-3.5 months) (P<.001). No significant difference was noted with regard to overall survival, with a median of 26.9 months (95% CI, 14.4-63.6 months) for arm A and 24.2 months (95% CI, 11.3-36.4 months) for arm B. The response rate (according to Response Evaluation Criteria In Solid Tumors [RECIST]) was 22% in arm A (4 complete responses [CRs] and 8 partial responses [PRs]) and 17% in arm B (1 CR and 4 PRs). Stable disease or PR or CR was noted in 65% of patients in arm A and 48% of patients in arm B. The combination was found to be superior to monotherapy in patients with high and low levels of serum VEGF and VEGF receptor 2. Adverse events were consistent with the expected profiles of monotherapy with IL-2 and ziv-aflibercept.
CONCLUSIONS
Ziv-aflibercept and IL-2 were found to significantly improve PFS compared with IL-2 alone, thereby meeting the primary endpoint of the current study. These findings support further study of immunotherapeutic combination strategies involving VEGF inhibitors.
背景
白细胞介素 2（IL-2）是 T 细胞和自然杀伤细胞的生长因子，可促进前炎症细胞因子的产生，并可使黑色素瘤患者产生持久的应答。血管内皮生长因子（VEGF）促进血管生成并调节宿主固有和适应性免疫。研究发现，高水平的 VEGF 与对 IL-2 无应答有关。Ziv-aflibercept 可能会耗尽 VEGF，从而增强抗肿瘤 T 细胞应答，因此支持与 IL-2 联合使用的免疫治疗联合策略。
方法
NCI 8628 是一项 Ziv-aflibercept 联合 IL-2（A 组）与单独 IL-2（B 组）的 2 期临床试验，分别以 2:1 的比例随机分组。入组患者为不可切除的美国癌症联合委员会（AJCC）分期 III 或 IV 期黑色素瘤。主要终点为无进展生存期（PFS）。
结果
共纳入 89 例患者，84 例患者接受治疗。中位随访时间为 41.4 个月。在接受治疗的患者（A 组 55 例，B 组 29 例）中，A 组的 PFS 显著改善，中位 PFS 为 6.9 个月（95%置信区间[95%CI]，4.1-8.7 个月），而 B 组为 2.3 个月（95%CI，1.6-3.5 个月）（P<.001）。两组总生存期无显著差异，A 组中位总生存期为 26.9 个月（95%CI，14.4-63.6 个月），B 组为 24.2 个月（95%CI，11.3-36.4 个月）。根据实体瘤反应评价标准（RECIST），A 组的缓解率（完全缓解[CR]和部分缓解[PR]）为 22%（4 例 CR 和 8 例 PR），B 组为 17%（1 例 CR 和 4 例 PR）。A 组 65%的患者疾病稳定或 PR 或 CR，B 组 48%的患者疾病稳定或 PR 或 CR。与单独使用 IL-2 相比，该联合疗法在血清 VEGF 和 VEGF 受体 2 水平较高和较低的患者中均显著改善了 PFS，从而达到了本研究的主要终点。这些发现支持进一步研究涉及 VEGF 抑制剂的免疫治疗联合策略。
结论
与单独使用 IL-2 相比，Ziv-aflibercept 联合 IL-2 显著改善了 PFS，从而达到了本研究的主要终点。这些发现支持进一步研究涉及 VEGF 抑制剂的免疫治疗联合策略。
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