加州大学Rana R. McKay团队近日取得一项新成果。经过不懈努力，他们探明了Casdatifan在肾癌中展现出与HIF-2α生物学相关的持久缓解。2026年7月1日出版的《自然》杂志发表了这项成果。

本研究表明，卡达替芬（一种口服生物可利用的、有效的、选择性的HIF-2α抑制剂）单药治疗对难治性转移性ccRCC患者产生有意义的、持久的抗肿瘤活性，且安全性可控。介绍了ARC-20研究（NCT05536141）的剂量扩展数据，包括100mg每日一次（QD）队列(n=32)和总队列（n = 127）。因卡地芬相关不良事件而停止治疗的情况很少（3%），类效毒性包括贫血和缺氧。确诊客观缓解率（ORRs）为35%(95%置信区间(CI) = 19-55%；100年mg QD)和31% (95% CI = 23-40%; 总计)；中位无进展生存期（PFS）不可估计(95% CI = 5.7 -不可估计；100mg QD)和12.2月（9.4-20.6；总数）。

较大的血清促红细胞生成素最大降低与改善的临床结果相关，包括更高的ORR (P = 0.001)，更低的疾病进展率（P = 0.003）和更长的PFS （P = 0.006）。促红细胞生成素的表达仅限于癌细胞，而在临床获益的患者中，促红细胞生成素的mRNA水平显著升高。HIF-2α蛋白表达和HIF-2α表达特征与PFS延长相关。总的来说，他们的研究结果表明，casdatifan在可控的安全性下实现了有意义、持久的反应。这些数据建立了靶向HIF-2α通路调节、肿瘤生物学和临床疗效之间的联系。

据悉，透明细胞肾细胞癌（ccRCC）主要由转录因子缺氧诱导因子2α (HIF-2α)1驱动。

附：英文原文

Title: Casdatifan shows durable response linked to HIF-2α biology in kidney cancer

Author: Choueiri, Toni K., Merchan, Jamie, Patnaik, Amita, Drakaki, Alexandra, Rini, Brian I., Rha, Sun Young, Lee, Jae Lyun, Ornstein, Moshe C., Kumar, Rohit, Hwang, Clara, Shao, Yusra, Park, Se Hoon, Barata, Pedro C., McGregor, Bradley A., Foster, Paul, Chen, Jianfen, Eisen, Melissa, Cole, Hunter, Weeder, Ben, Guan, Yinghui, Singh, Jaskirat, Kaplan, Angelo, Cho, Soonweng, Markus, Richard, Kabbarah, Omar, McKay, Rana R.

Issue&Volume: 2026-07-01

Abstract: Clear cell renal cell carcinoma (ccRCC) is largely driven by the transcription factor hypoxia-inducible factor 2α (HIF-2α)1. Here we show that monotherapy with casdatifan—an orally bioavailable, potent and selective HIF-2α inhibitor2—produces meaningful, durable antitumour activity with manageable safety in individuals with refractory metastatic ccRCC. Dose-expansion data from the ARC-20 study (NCT05536141) are presented, including for the 100mg once daily (QD) cohort (n=32) and the total cohort (n=127). Treatment discontinuation from casdatifan-related adverse events was infrequent (3%), and class-effect toxicities included anaemia and hypoxia. The confirmed objective response rates (ORRs) were 35% (95% confidence intervals (CI) = 19–55%; 100mg QD) and 31% (95% CI = 23–40%; total); median progression-free survival (PFS) was not estimable (95% CI = 5.7–not estimable; 100mg QD) and 12.2months (9.4–20.6; total). Greater maximal reductions in serum erythropoietin were associated with improved clinical outcomes, including a higher ORR (P=0.001), lower rates of progressive disease (P=0.003) and longer PFS (P=0.006). Erythropoietin expression was restricted to cancer cells and was significantly higher at the mRNA level in patients with clinical benefit. Concordantly, HIF-2α protein expression and HIF-2α expression signature were associated with prolonged PFS. Overall, our findings show that casdatifan achieves meaningful, durable responses with manageable safety. These data establish a link between on-target HIF-2α pathway modulation, tumour biology and clinical efficacy.

DOI: 10.1038/s41586-026-10718-x

Source: https://www.nature.com/articles/s41586-026-10718-x