Novel pembrolizumab-based treatments as first-line therapy in advanced clear cell renal cell carcinoma: Substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial.

IF 65.4 1区医学 Q1 ONCOLOGY

Annals of Oncology Pub Date : 2025-10-18 DOI:10.1016/j.annonc.2025.10.010

C Suarez, C Rojas, S J Shin, P Yanez Weber, L Albiges, R Motzer, H Hammers, A Peer, J-L Lee, W H Miller, T Waddell, V Neiman, D Keizman, A Zwenger Kloster, A Weickhardt, R Dziadziuszko, L Suttner, M Sharma, J E Burgents, T Powles

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引用次数: 0

Abstract

Background: First-line triplet therapy may expand clinical benefit for advanced clear cell renal cell carcinoma (ccRCC). The phase Ib/II KEYMAKER-U03 Substudy 03A (NCT04626479) investigated novel pembrolizumab (pembro)-based regimens in this setting.

Methods: Participants with advanced ccRCC and no prior systemic therapy were randomized 2:1 to quavonlimab (qmab)/pembro plus lenvatinib (lenva), favezelimab (fave)/pembro plus lenva, pembro plus lenva plus belzutifan (bel), and vibostolimab (vibo)/pembro plus bel or a concurrent reference treatment (pembro plus lenva). A safety lead-in of ∼10 participants occurred for all investigative treatments before randomization. Primary endpoints were objective response rate (ORR) per RECIST v1.1 by blinded independent central review in all randomized participants (excluding safety lead-in), and safety in all treated participants. Secondary endpoints included progression-free survival (PFS) and overall survival (OS).

Results: As of March 31, 2025, 393 participants were enrolled. Median follow-up for randomized participants across the 5 cohorts ranged between 16 and 39 months. ORR (95% CI) was 80.6% (68.6-89.6) with pembro plus lenva, 71.3% (60.0-80.8) with qmab/pembro plus lenva, 62.7% (48.1-75.9) with fave/pembro plus lenva, 77.5% (66.8-86.1) with pembro plus lenva plus bel, and 42.5% (31.5-54.1) with vibo/pembro plus bel. Median PFS (95% CI) in months was 26.3 (15.3-39.8) with pembro plus lenva, 18.0 (11.6-34.3) with qmab/pembro plus lenva, 26.0 (8.2-31.8) with fave/pembro plus lenva, 31.8 (26.3-NR) with pembro plus lenva plus bel, and 15.2 (12.4-NR) with vibo/pembro plus bel. Median OS was not reached in any arm. Grade ≥3 treatment-related adverse events occurred in 71.0% (44/62) of participants treated with pembro plus lenva, 73.3% (66/90) with qmab/pembro plus lenva, 86.9% (53/61) with fave/pembro plus lenva, 70.0% (63/90) with pembro plus lenva plus bel, and 68.9% (62/90) with vibo/pembro plus bel.

Conclusions: Observed efficacy and safety of pembro plus lenva were confirmatory of prior observations for this combination. ORR was similar to reference for pembro plus lenva plus bel and qmab/pembro plus lenva, but not the other investigative arms. Further investigation of pembro plus lenva plus bel and qmab/pembro plus lenva versus pembro plus lenva is ongoing in the phase 3 LITESPARK-012 study.

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新型基于派姆单抗的治疗方法作为晚期透明细胞肾细胞癌的一线治疗：开放标签伞式平台I/II期KEYMAKER-U03试验的亚研究03A

背景：一线三联疗法可能扩大晚期透明细胞肾细胞癌（ccRCC）的临床获益。在这种情况下，Ib/II期KEYMAKER-U03亚研究03A （NCT04626479）研究了基于pembrolizumab （pembrolizumab）的新型方案。方法：未接受过全身治疗的晚期ccRCC患者按2:1随机分为quavonlimab (qmab)/ pembroo + lenvatinib (lenva), favezelimab (fave)/ pembroo + lenva, pembroo + lenva + belzutifan (bel), vibostolimab (vibo)/ pembroo + bel或同时进行参考治疗（pembroo + lenva）。在随机化之前，所有调查性治疗都有10名参与者的安全引入。主要终点是所有随机参与者（不包括安全性引入）的客观缓解率（ORR），以及所有治疗参与者的安全性。次要终点包括无进展生存期（PFS）和总生存期（OS）。结果：截至2025年3月31日，393名参与者入组。5个队列中随机参与者的中位随访时间为16至39个月。pembro + lenva组的ORR （95% CI）为80.6% (68.6-89.6)，qmab/pembro + lenva组为71.3% (60.0-80.8)，fave/pembro + lenva组为62.7% (48.1-75.9)，pembro + lenva + bel组为77.5% (66.8-86.1)，vibo/pembro + lenva组为42.5%（31.5-54.1）。pembro + lenva组的月平均PFS （95% CI）为26.3 (15.3-39.8)，qmab/pembro + lenva组为18.0 (11.6-34.3)，fave/pembro + lenva组为26.0 (8.2-31.8)，pembro + lenva组为31.8 （26.3- nr）。vibo/ pembroo + bel组为15.2 （12.4 nr）。任何组均未达到中位OS。pembro + lenva组的不良事件发生率为71.0% (44/62)，qmab/pembro + lenva组为73.3% (66/90)，fave/pembro + lenva组为86.9% (53/61)，pembro + lenva + bel组为70.0% (63/90)，vibo/pembro + bel组为68.9%（62/90）。结论：pembro + lenva的疗效和安全性与先前观察结果一致。ORR与pembro + lenva + bel和qmab/pembro + lenva的参考相似，但与其他研究臂不同。在LITESPARK-012三期研究中，正在进一步研究pembroplus lenva + bel和qmab/ pembroplus lenva与pembroplus lenva的对比。

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来源期刊

Annals of Oncology 医学-肿瘤学

CiteScore

63.90

自引率

1.00%

发文量

3712

审稿时长

2-3 weeks

期刊介绍： Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine. The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings. Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.