在晚期实体瘤中联合使用激动型抗 CD27 抗体（varlilumab）和抗 PD-1（nivolumab）的安全性、耐受性和疗效。
Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors.
机构信息
Providence Cancer Institute, Earle A. Chiles Research Institute, Portland, Oregon, USA
Department of Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia, USA.
出版信息
J Immunother Cancer. 2022 Aug;10(8). doi: 10.1136/jitc-2022-005147.
BACKGROUND
Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors.
METHODS
Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures.
RESULTS
175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%).
CONCLUSION
Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes.
TRIAL REGISTRATION NUMBER
NCT02335918.
背景
一项评估 varlilumab（一种完全人源化的抗 CD27 mAb）联合 nivolumab 治疗抗 PD-1/L1 初治、难治性实体瘤的 1/2 期剂量递增和扩展研究。
方法
1 期评估 varlilumab（0.1-10mg/kg）联合 nivolumab（3mg/kg）每 2 周 1 次的安全性。2 期评估 varlilumab 方案（3mg/kg 每 2 周 1 次、3mg/kg 每 12 周 1 次和 0.3mg/kg 每 4 周 1 次）联合 nivolumab 240mg 每 2 周 1 次在肿瘤特异性队列中的疗效。主要终点为安全性；关键临床终点包括客观缓解率（ORR）和 12 个月总生存率（OS12）（仅用于胶质母细胞瘤（GBM））。探索性目标包括确定对外周血和肿瘤内免疫特征的影响。
结果
共纳入 175 例患者（1 期 36 例，2 期 139 例）。1 期剂量递增至最高 varlilumab 剂量水平，未确定最大耐受剂量。在 2 期，卵巢癌的 ORR 为 12.5%，头颈部鳞状细胞癌为 12.5%，结直肠癌为 5%，肾细胞癌为 0%；GBM 的 OS12 为 40.9%。卵巢癌患者观察到肿瘤 PD-L1 和肿瘤内 T 细胞浸润增加，增加≥5%与更好的无进展生存期相关。最常见的治疗相关不良事件为疲劳（18%）、瘙痒（16%）和皮疹（15%）。
结论
Varlilumab 和 nivolumab 耐受性良好，无明显毒性超过单独使用每种药物的预期。在对抗 PD-1 治疗通常耐药的患者中观察到临床活性，但总体上并不超过 nivolumab 单药治疗。治疗与肿瘤微环境中的促炎变化相关，特别是在卵巢癌中，这些变化与更好的临床结局相关。
试验注册
NCT02335918。
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