Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Eur Urol Oncol. 2024 Aug;7(4):804-811. doi: 10.1016/j.euo.2023.10.017. Epub 2023 Nov 7.
Although different kidney cancers represent a heterogeneous group of malignancies, multiple subtypes including Von Hippel-Lindau (VHL)-altered clear cell renal cell carcinoma (ccRCC), fumarate hydratase (FH)- and succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC), and renal medullary carcinoma (RMC) are affected by genomic instability. Synthetic lethality with poly ADP-ribose polymerase inhibitors (PARPis) has been suggested in preclinical models of these subtypes, and paired PARPis with immune checkpoint blockade (ICB) may achieve additive and/or synergistic effects in patients with previously treated advanced kidney cancers.
To evaluate combined PARPi + ICB in treatment-refractory metastatic kidney cancer.
DESIGN, SETTING, AND PARTICIPANTS: We conducted a single-center, investigator-initiated phase 2 trial in two genomically selected advanced kidney cancer cohorts: (1) VHL-altered RCC with at least one prior ICB agent and one vascular endothelial growth factor (VEGF) inhibitor, and (2) FH- or SDH-deficient RCC with at least one prior ICB agent or VEGF inhibitor and RMC with at least one prior line of chemotherapy.
Patients received talazoparib 1 mg daily plus avelumab 800 mg intravenously every 14 d in 28-d cycles.
The primary endpoint was objective response rate (ORR) by Immune Response Evaluation Criteria in Solid Tumors at 4 mo, and the secondary endpoints included progression-free survival (PFS), overall survival, and safety.
Cohort 1 consisted of ten patients with VHL-altered ccRCC. All patients had previously received ICB. The ORR was 0/9 patients; one patient was not evaluable due to missed doses. In this cohort, seven patients achieved stable disease (SD) as the best response. The median PFS was 3.5 mo (95% confidence interval [CI] 1.0, 3.9 mo). Cohort 2 consisted of eight patients; four had FH-deficient RCC, one had SDH-deficient RCC, and three had RMC. In this cohort, six patients had previously received ICB. The ORR was 0/8 patients; two patients achieved SD as the best response and the median PFS was 1.2 mo (95% CI 0.4, 2.9 mo). The most common treatment-related adverse events of all grades were fatigue (61%), anemia (28%), nausea (22%), and headache (22%). There were seven grade 3-4 and no grade 5 events.
The first clinical study of combination PARPi and ICB therapy in advanced kidney cancer did not show clinical benefit in multiple genomically defined metastatic RCC cohorts or RMC.
We conducted a study to look at the effect of two medications, talazoparib and avelumab, in patients with metastatic kidney cancer who had disease progression on standard treatment. Talazoparib blocks the normal activity of molecules called poly ADP-ribose polymerase, which then prevents tumor cells from repairing themselves and growing, while avelumab helps the immune system recognize and kill cancer cells. We found that the combination of these agents was safe but not effective in specific types of kidney cancer.
尽管不同的肾癌代表了一组异质性的恶性肿瘤，但多种亚型包括 Von Hippel-Lindau（VHL）改变的透明细胞肾细胞癌（ccRCC）、富马酸水合酶（FH）和琥珀酸脱氢酶（SDH）缺陷的肾细胞癌（RCC）和肾髓质癌（RMC）都受到基因组不稳定性的影响。在这些亚型的临床前模型中，已经提出了聚 ADP-核糖聚合酶抑制剂（PARPi）的合成致死性，并且在以前接受过治疗的晚期肾癌患者中，PARPi 与免疫检查点阻断（ICB）联合使用可能会产生附加和/或协同作用。
评估在治疗抵抗性转移性肾细胞癌中联合使用 PARPi 和 ICB。
设计、地点和参与者：我们在两个基因组选择的晚期肾细胞癌队列中进行了一项由研究者发起的单中心、2 期临床试验：（1）VHL 改变的 RCC，至少有一个既往 ICB 药物和一个血管内皮生长因子（VEGF）抑制剂，以及（2）FH 或 SDH 缺陷的 RCC，至少有一个既往 ICB 药物或 VEGF 抑制剂和 RMC，至少有一线化疗。
患者接受每日 1 毫克他拉唑帕尼联合每 14 天静脉注射 800 毫克avelumab，每 28 天为一个周期。
主要终点是 4 个月时固体肿瘤免疫反应评估标准的客观缓解率（ORR），次要终点包括无进展生存期（PFS）、总生存期和安全性。
队列 1 由 10 名 VHL 改变的 ccRCC 患者组成。所有患者均曾接受过 ICB 治疗。ORR 为 0/9 例患者；由于错过剂量，1 例患者无法评估。在这个队列中，7 例患者的最佳反应为稳定疾病（SD）。中位 PFS 为 3.5 个月（95%置信区间[CI]1.0，3.9 个月）。队列 2 由 8 名患者组成；其中 4 例为 FH 缺陷的 RCC，1 例为 SDH 缺陷的 RCC，3 例为 RMC。在这个队列中，6 例患者曾接受过 ICB 治疗。ORR 为 0/8 例患者；2 例患者的最佳反应为 SD，中位 PFS 为 1.2 个月（95%CI0.4，2.9 个月）。所有等级最常见的治疗相关不良事件是疲劳（61%）、贫血（28%）、恶心（22%）和头痛（22%）。有 7 例 3-4 级和无 5 级事件。
在多个基因组定义的转移性 RCC 队列或 RMC 中，晚期肾细胞癌中首次进行的 PARPi 和 ICB 联合治疗的临床研究并未显示出临床获益。
我们进行了一项研究，以观察两种药物，他拉唑帕尼和avelumab，在标准治疗后疾病进展的转移性肾细胞癌患者中的效果。他拉唑帕尼阻断了称为聚 ADP-核糖聚合酶的分子的正常活性，从而阻止肿瘤细胞自我修复和生长，而 avelumab 有助于免疫系统识别和杀死癌细胞。我们发现，这些药物联合使用是安全的，但对特定类型的肾癌无效。
