Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
The Royal Marsden Hospital, London, United Kingdom.
J Clin Oncol. 2023 May 10;41(14):2493-2502. doi: 10.1200/JCO.22.01414. Epub 2023 Feb 21.
Metastatic papillary renal cancer (PRC) has poor outcomes, and new treatments are required. There is a strong rationale for investigating mesenchymal epithelial transition receptor (MET) and programmed cell death ligand-1 (PD-L1) inhibition in this disease. In this study, the combination of savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) is investigated.
This single-arm phase II trial explored durvalumab (1,500 mg once every four weeks) and savolitinib (600 mg once daily; ClinicalTrials.gov identifier: NCT02819596). Treatment-naïve or previously treated patients with metastatic PRC were included. A confirmed response rate (cRR) of > 50% was the primary end point. Progression-free survival, tolerability, and overall survival were secondary end points. Biomarkers were explored from archived tissue (MET-driven status).
Forty-one patients treated with advanced PRC were enrolled into this study and received at least one dose of study treatment. The majority of patients had Heng intermediate risk score (n = 26 [63%]). The cRR was 29% (n = 12; 95% CI, 16 to 46), and the trial therefore missed the primary end point. The cRR increased to 53% (95% CI, 28 to 77) in MET-driven patients (n/N = 9/27) and was 33% (95% CI, 17 to 54) in PD-L1-positive tumors (n/N = 9/27). The median progression-free survival was 4.9 months (95% CI, 2.5 to 10.0) in the treated population and 12.0 months (95% CI, 2.9 to 19.4) in MET-driven patients. The median overall survival was 14.1 months (95% CI, 7.3 to 30.7) in the treated population and 27.4 months (95% CI, 9.3 to not reached [NR]) in MET-driven patients. Grade 3 and above treatment related adverse events occurred in 17 (41%) patients. There was 1 grade 5 treatment-related adverse event (cerebral infarction).
The combination of savolitinib and durvalumab was tolerable and associated with high cRRs in the exploratory MET-driven subset.
转移性乳头状肾细胞癌（PRC）预后较差，需要新的治疗方法。在这种疾病中，研究间质上皮转化受体（MET）和程序性死亡配体-1（PD-L1）抑制具有很强的理论依据。在这项研究中，我们研究了索拉非尼（MET 抑制剂）和度伐鲁单抗（PD-L1 抑制剂）的联合应用。
这是一项单臂 II 期试验，探索了度伐鲁单抗（1500mg，每四周一次）和索拉非尼（600mg，每日一次；ClinicalTrials.gov 标识符：NCT02819596）在转移性 PRC 患者中的应用。纳入未经治疗或既往接受过治疗的转移性 PRC 患者。主要终点为确认缓解率（cRR）>50%。无进展生存期、耐受性和总生存期为次要终点。从存档组织中探索了生物标志物（MET 驱动状态）。
本研究共纳入 41 例接受晚期 PRC 治疗的患者，并接受了至少一剂研究药物治疗。大多数患者的 Heng 中间风险评分（n=26[63%]）。cRR 为 29%（n=12；95%CI，16 至 46），因此未能达到主要终点。在 MET 驱动的患者（n/N=9/27）中，cRR 增加至 53%（95%CI，28 至 77），而在 PD-L1 阳性肿瘤（n/N=9/27）中，cRR 为 33%（95%CI，17 至 54）。治疗人群的中位无进展生存期为 4.9 个月（95%CI，2.5 至 10.0），MET 驱动的患者为 12.0 个月（95%CI，2.9 至 19.4）。治疗人群的中位总生存期为 14.1 个月（95%CI，7.3 至 30.7），MET 驱动的患者为 27.4 个月（95%CI，9.3 至未达到[NR]）。17 例（41%）患者发生 3 级及以上与治疗相关的不良事件。1 例（5%）患者发生 5 级治疗相关不良事件（脑梗死）。
索拉非尼联合度伐鲁单抗在探索性的 MET 驱动亚组中具有良好的耐受性，并与高 cRR 相关。
