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.

The phase Ib/II KEYMAKER-U03 substudy 03A (NCT04626479) investigated novel pembrolizumab (pembro)-based regimens in this setting.

Ib/II期KEYMAKER-U03亚研究03A（NCT04626479）在这个背景下研究了新型的帕博利珠单抗（pembro）为基础的治疗方案。

patients_and_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).

未接受过全身治疗的晚期ccRCC患者按2:1的比例随机分配到quavonlimab (qmab)/pembro联合lenvatinib (lenva)、favezelimab (fave)/pembro联合lenvatinib、pembro联合lenvatinib联合belzutifan (bel)以及vibostolimab (vibo)/pembro联合bel，或同时进行的参考治疗（pembro联合lenvatinib）。

A safety lead-in of ∼10 participants occurred for all investigative treatments before randomization.

所有研究治疗在随机分组前进行了约10名参与者的安全引导期。

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.

主要终点是根据RECIST v1.1标准，通过双盲独立中央审查在所有随机参与者（排除安全引导期）中的客观缓解率（ORR），以及在所有治疗参与者中的安全性。

Secondary endpoints included progression-free survival(PFS) and overall survival(OS).

次要终点包括无进展生存期（PFS）和总生存期（OS）。

Results

As of 31 March 2025, 393 participants were enrolled.

截至2025年3月31日，共有393名参与者被纳入研究。

Median follow-up for randomized participants across the five cohorts ranged between 16 and 39 months.

五个队列中随机分配的参与者中位随访时间在16至39个月之间。

The ORR was 80.6% [95% confidence interval(CI) 68.6% to 89.6%] with pembro plus lenva, 71.3% (95% CI 60.0% to 80.8%) with qmab/pembro plus lenva, 62.7% (95% CI 48.1% to 75.9%) with fave/pembro plus lenva, 77.5% (95% CI 66.8% to 86.1%) with pembro plus lenva plus bel, and 42.5% (95% CI 31.5% to 54.1%) with vibo/pembro plus bel.

客观缓解率(ORR)为80.6% [95% 置信区间 (CI) 68.6% 至 89.6%]，使用 pembrolizumab 加 lenvatinib；71.3% (95% CI 60.0% 至 80.8%)，使用 qmab/pembrolizumab 加 lenvatinib；62.7% (95% CI 48.1% 至 75.9%)，使用 fave/pembrolizumab 加 lenvatinib；77.5% (95% CI 66.8% 至 86.1%)，使用 pembrolizumab 加 lenvatinib 加 belinostat；以及42.5% (95% CI 31.5% 至 54.1%)，使用 vibo/pembrolizumab 加 belinostat。

Median PFS was 26.3 months (95% CI 15.3-39.8 months) with pembro plus lenva, 18.0 months (95% CI 11.6-34.3 months) with qmab/pembro plus lenva, 26.0 months (95% CI 8.2-31.8 months) with fave/pembro plus lenva, 31.8 months [95% CI 26.3 months-not reached (NR)] with pembro plus lenva plus bel, and 15.2 months (95% CI 12.4 months-NR) with vibo/pembro plus bel.

无进展生存期(PFS)的中位数为26.3个月 (95% 置信区间 15.3-39.8个月)，使用 pembrolizumab 加 lenvatinib；18.0个月 (95% CI 11.6-34.3个月)，使用 qmab/pembrolizumab 加 lenvatinib；26.0个月 (95% CI 8.2-31.8个月)，使用 fave/pembrolizumab 加 lenvatinib；31.8个月 [95% CI 26.3个月-未达到(NR)]，使用 pembrolizumab 加 lenvatinib 加 belinostat；以及15.2个月 (95% CI 12.4个月-NR)，使用 vibo/pembrolizumab 加 belinostat。

Median OS was not reached in any arm.

任何治疗组的中位总生存期均未达到。

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.

接受pembro联合lenva治疗的参与者中有71.0%（44/62）出现了3级或以上的治疗相关不良事件，接受qmab/pembro联合lenva治疗的参与者中有73.3%（66/90），接受fave/pembro联合lenva治疗的参与者中有86.9%（53/61），接受pembro联合lenva联合bel治疗的参与者中有70.0%（63/90），以及接受vibo/pembro联合bel治疗的参与者中有68.9%（62/90）。

Conclusions

Observed efficacy and safety of pembro plus lenva were confirmatory of prior observations for this combination.

观察到的帕博利珠单抗加仑伐替尼的疗效和安全性与先前的观察结果一致。

ORR was similar to reference for pembro plus lenva plus bel and qmab/pembro plus lenva, but not the other investigative arms.

客观缓解率（ORR）与帕博利珠单抗加仑伐替尼加bel和qmab/帕博利珠单抗加仑伐替尼的参考值相似，但与其他研究组不同。

Further investigation of pembro plus lenva plus bel and qmab/pembro plus lenva versus pembro plus lenva is ongoing in the phase III LITESPARK-012 study.

III期LITESPARK-012研究正在继续进行，以进一步研究pembro联合lenva联合bel和qmab与pembro联合lenva的比较。