特瑞普利单抗联合阿昔替尼治疗局部进展期透明细胞肾细胞癌的单臂、Ⅱ期临床试验

Neoadjuvant toripalimab combined with axitinib in patients with locally advanced clear cell renal cell carcinoma: a single-arm, phase II trial.

机构信息

Department of Urology, RenJi Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

Department of Urology, RenJi Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.

出版信息

J Immunother Cancer. 2024 Jun 11;12(6):e008475. doi: 10.1136/jitc-2023-008475.

DOI:10.1136/jitc-2023-008475

PMID:38862251

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11168135/

Abstract

BACKGROUND

A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy, and biomarkers of neoadjuvant toripalimab plus axitinib in non-metastatic clear cell RCC.

METHODS

This is a single-institution, single-arm phase II clinical trial. Patients with non-metastatic biopsy-proven clear cell RCC (T2-T3N0-1M0) are enrolled. Patients will receive axitinib 5 mg twice daily combined with toripalimab 240 mg every 3 weeks (three cycles) for up to 12 weeks. Patients then will receive partial (PN) or radical nephrectomy (RN) after neoadjuvant therapy. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease-free survival, safety, and perioperative complication rate. Predictive biomarkers are involved in exploratory analysis.

RESULTS

A total of 20 patients were enrolled in the study, with 19 of them undergoing surgery. One patient declined surgery. The primary endpoint ORR was 45%. The posterior distribution of πORR had a mean of 0.44 (95% credible intervals: 0.24-0.64), meeting the predefined primary endpoint with an ORR of 32%. Tumor shrinkage was observed in 95% of patients prior to nephrectomy. Furthermore, four patients achieved a pathological complete response. Grade ≥3 adverse events occurred in 25% of patients, including hypertension, hyperglycemia, glutamic pyruvic transaminase/glutamic oxaloacetic transaminase (ALT/AST) increase, and proteinuria. Postoperatively, one grade 4a and eight grade 1-2 complications were noted. In comparison to patients with stable disease, responders exhibited significant differences in immune factors such as Arginase 1(ARG1), Melanoma antigen (MAGEs), Dendritic Cell (DC), TNF Superfamily Member 13 (TNFSF13), Apelin Receptor (APLNR), and C-C Motif Chemokine Ligand 3 Like 1 (CCL3-L1). The limitation of this trial was the small sample size.

CONCLUSION

Neoadjuvant toripalimab combined with axitinib shows encouraging activity and acceptable toxicity in locally advanced clear cell RCC and warrants further study.

TRIAL REGISTRATION NUMBER

clinicaltrials.gov, NCT04118855.

摘要

背景

阿昔替尼联合免疫检查点抑制剂（ICI）在治疗晚期肾细胞癌（RCC）方面显示出有前景的疗效。本研究旨在前瞻性评估新辅助特瑞普利单抗联合阿昔替尼在非转移性透明细胞 RCC 中的安全性、疗效和生物标志物。

方法

这是一项单中心、单臂 II 期临床研究。招募经活检证实的非转移性透明细胞 RCC（T2-T3N0-1M0）患者。患者接受阿昔替尼 5mg 每日两次联合特瑞普利单抗 240mg 每 3 周（3 个周期）治疗，最长 12 周。新辅助治疗后，患者接受部分（PN）或根治性肾切除术（RN）。主要终点为客观缓解率（ORR）。次要终点包括无病生存期、安全性和围手术期并发症发生率。预测性生物标志物纳入探索性分析。

结果

共有 20 名患者入组研究，其中 19 名患者接受了手术。1 名患者拒绝手术。主要终点 ORR 为 45%。πORR 的后分布平均值为 0.44（95%可信区间：0.24-0.64），达到了预设的主要终点 ORR 为 32%。在肾切除术之前，95%的患者观察到肿瘤缩小。此外，4 名患者达到了病理完全缓解。25%的患者发生≥3 级不良事件，包括高血压、高血糖、谷草转氨酶/谷丙转氨酶（ALT/AST）升高和蛋白尿。术后，有 1 例 4a 级和 8 例 1-2 级并发症。与疾病稳定的患者相比，应答者的免疫因子如精氨酸酶 1（ARG1）、黑色素瘤抗原（MAGEs）、树突状细胞（DC）、肿瘤坏死因子超家族成员 13（TNFSF13）、阿皮林受体（APLNR）和 C-C 基序趋化因子配体 3 样 1（CCL3-L1）有显著差异。本试验的局限性是样本量小。