Srinivasan Ramaprasad, Iliopoulos Othon, Beckermann Kathryn E, Narayan Vivek, Maughan Benjamin L, Oudard Stephane, Else Tobias, Maranchie Jodi K, Iversen Ane B, Cornell Jerry, Perini Rodolfo F, Liu Yanfang, Linehan W Marston, Jonasch Eric
Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
Lancet Oncol. 2025 May;26(5):571-582. doi: 10.1016/S1470-2045(25)00099-3. Epub 2025 Apr 12.
Hypoxia-inducible factor-2α inhibitor belzutifan is approved for von Hippel-Lindau disease-associated renal cell carcinoma, CNS haemangioblastomas, and pancreatic neuroendocrine tumours, based on previously published initial results from the LITESPARK-004 study. Updated results are presented here after a median follow-up of nearly 50 months.
In this single-arm, phase 2 study, participants were enrolled at 11 centres in Denmark, France, the UK, and the USA. Oral belzutifan 120 mg once daily was given to eligible adults aged 18 years or older with a diagnosis of von Hippel-Lindau disease (based on germline VHL alterations), at least one measurable renal cell carcinoma tumour, no tumour larger than 3 cm that necessitated immediate surgery, no metastatic disease, no previous systemic anticancer treatment, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. The primary endpoint was the proportion of participants with an objective response in von Hippel-Lindau disease-associated renal cell carcinoma per Response Evaluation Criteria in Solid Tumours, version 1.1, determined by an independent review committee, and assessed in all participants who received at least one dose of belzutifan. This ongoing study is no longer recruiting and is registered at ClinicalTrials.gov, NCT03401788.
Between May 31, 2018, and Mar 29, 2019, 61 participants were enrolled; 36 (59%) were continuing treatment as of April 3, 2023. The median age of all enrolled participants was 41·0 years (IQR 29·0-51·0); 32 (52%) of 61 participants were male and 29 (48%) were female; most were White (n=55; 90%). Median study follow-up was 49·9 months (IQR 48·9-52·2). 41 (67%; 95% CI 54-79) of 61 participants with renal cell carcinoma had an objective response; seven (11%) had a complete response and 34 (56%) a partial response. 13 grade 3 treatment-related adverse events occurred in 11 (18%) participants (anaemia: seven [11%]; fatigue: three [5%]; urinary tract infection: one [2%]; hypoxia: one [2%]; and blister: one [2%]). None of the participants had a grade 4 or 5 treatment-related adverse event. Four (7%) participants had serious treatment-related adverse events (one participant each: anaemia, urinary tract infection, intracranial haemorrhage, and hypoxia).
Updated results support the use of belzutifan as systemic treatment for von Hippel-Lindau disease-associated renal cell carcinoma.
Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA; the Intramural Research Program of the National Institutes of Health, National Cancer Institute Center for Cancer Research; and a grant from the National Cancer Institute.
基于先前发表的LITESPARK - 004研究的初步结果，缺氧诱导因子-2α抑制剂贝佐蒂凡已被批准用于治疗与冯希佩尔-林道病相关的肾细胞癌、中枢神经系统血管母细胞瘤和胰腺神经内分泌肿瘤。本文呈现了近50个月中位随访期后的更新结果。
在这项单臂2期研究中，参与者在丹麦、法国、英国和美国的11个中心入组。符合条件的18岁及以上成年患者，诊断为冯希佩尔-林道病（基于种系VHL改变），至少有一个可测量的肾细胞癌肿瘤，没有大于3 cm且需要立即手术的肿瘤，没有转移性疾病，没有先前的全身抗癌治疗，东部肿瘤协作组体能状态评分为0或1，给予口服贝佐蒂凡120 mg，每日一次。主要终点是根据实体瘤疗效评价标准1.1版，由独立审查委员会确定的、在接受至少一剂贝佐蒂凡的所有参与者中评估的、与冯希佩尔-林道病相关的肾细胞癌客观缓解参与者的比例。这项正在进行的研究不再招募患者，已在ClinicalTrials.gov注册，编号为NCT03401788。
在2018年5月31日至2019年3月29日期间，61名参与者入组；截至2023年4月3日，36名（59%）仍在继续治疗。所有入组参与者的中位年龄为41.0岁（四分位间距29.0 - 51.0）；61名参与者中32名（52%）为男性，29名（48%）为女性；大多数为白人（n = 55；90%）。中位研究随访期为49.9个月（四分位间距48.9 - 52.2）。61名肾细胞癌参与者中有41名（67%；95%置信区间54 - 79）有客观缓解；7名（11%）完全缓解，34名（56%）部分缓解。11名（18%）参与者发生了13起3级治疗相关不良事件（贫血：7例[11%]；疲劳：3例[5%]；尿路感染：1例[2%]；缺氧：1例[2%]；水疱：1例[2%]）。没有参与者发生4级或5级治疗相关不良事件。4名（7%）参与者发生了严重治疗相关不良事件（各1例：贫血（1名参与者）、尿路感染（1名参与者）、颅内出血（1名参与者）和缺氧（1名参与者））。
更新后的结果支持将贝佐蒂凡用作与冯希佩尔-林道病相关的肾细胞癌的全身治疗。
美国新泽西州拉威市默克公司的子公司默克雪兰诺公司；美国国立卫生研究院国家癌症研究所癌症研究中心的内部研究项目；以及一项来自国家癌症研究所的资助。
