编者按：KEYNOTE-564是全球首个肾细胞癌辅助免疫治疗获得阳性结果的III期临床试验。在2025年ASCO大会上，来自宾夕法尼亚大学阿布拉姆森癌症中心的Naomi Balzer Haas教授汇报了该研究随访5年更新的DFS和OS结果。《肿瘤瞭望》在大会现场邀请Naomi Balzer Haas教授解读如下。

 

 

KEYNOTE-564研究确立了帕博利珠单抗单药作为术后ccRCC患者复发风险增加的首个显著改善无病生存期（DFS）和总生存期（OS）的辅助治疗方案。这项研究报告了第4次预设的中期分析结果。

 

 

KEYNOTE-564是一项、双盲、安慰剂对照的3期研究，纳入了中高危（pT2 Gr 4或肉瘤样，或pT3Gr，N0 M0）或高危（pT4任何Gr，N0 M0，或任何pT和Gr，N M0）或M1且无证据（NED）的成人ccRCC患者，并在肾切除术和/或转移切除术12周前随机（1:1）接受帕博利珠单抗200 mg或安慰剂IV Q3W治疗。治疗持续约1年（17个周期），或直到复发、无法忍受的AEs或医生停止治疗。

 

研究的主要终点是研究者评估的DFS；关键次要终点是OS。该研究在早期分析中达到了DFS和OS目标；因此，没有进行后续正式统计检验。根据严重程度，在治疗停止后30-90天内收集了AEs，无论时间如何，都收集了严重的治疗相关AEs。

 

 

 

共994例患者被随机分配接受帕博利珠单抗（n=496）或安慰剂（n=98）治疗。截至2024年9月25日的数据截止日期，中位随访时间为69.5个月。所有患者在3年前完成了或停止了研究治疗。帕博利珠单抗组和安慰剂组分别发生了188例和241例DFS事件。中位DFS未达到（NR），而安慰剂组为68.3个月（HR 0.71，95%CI：0.59-0.86）；5年时的估计DFS率分别为60.9%和52.2%。帕博利珠单抗组和安慰剂组分别发生了68例和99例OS事件。两组的中位OS均为NR（HR 0.66，95%CI：0.48-0.90）；5年时的估计OS率分别为87.7%和82.3%。DFS和OS结果在包括预先规定的风险和肉瘤样特征在内的关键亚组中是一致的。在3年内没有报告新的严重治疗相关不良反应。

 

 

 

经过5年的随访，与安慰剂相比，帕博利珠单抗辅助治疗获益与既往分析一致，包括在所有亚组。没有发生新的严重治疗相关安全信号。帕博利珠单抗辅助治疗仍然是RCC复发风险增加患者的一线治疗选择。

 

Naomi Balzer Haas教授：肾细胞癌的辅助治疗发展始于血管内皮生长因子受体（VGFR）抑制剂。在这一领域开展了多项研究，但唯一显示出获益的试验是S-TRAC试验，该试验评估了为期一年的辅助舒尼替尼治疗。然而，无疾病生存期（DFS）的获益仅在治疗后延长了一年，并且没有总生存期（OS）的获益。鉴于免疫检查点抑制剂（ICIs）在晚期疾病中展现的疗效，人们开始对探索ICIs早期治疗的作用产生了兴趣。因此，开发并研究了四五项围ICIs围术期治疗的试验。迄今为止，唯一显示出获益的是KEYNOTE-564试验，该试验比较了为期一年的帕博利珠单抗对比安慰剂辅助治疗。该研究纳入了高危患者，包括pT2高分级肾癌、pT3或pT4期疾病、淋巴结阳性疾病患者，以及少数在原发肿瘤切除后一年内进行了转移灶切除或转移灶切除术的患者。

 

KEYNOTE-564试验在几年前显示出DFS的改善，最近又显示出OS的改善。所有患者的随访时间至少为5年，许多患者的中位随访时间接近6年。DFS的Kaplan-Meier曲线仍然分离，表明持续的获益。OS的获益也持续存在。安全性分析显示，在超过3年的随访后没有新的安全性事件。重要的是，我们分析了帕博利珠单抗组和安慰剂组中复发患者的后续治疗情况。我们发现两组中约60%的患者接受了某种形式的系统治疗，无论是否联合局部治疗（如手术或放疗）。VEGF靶向治疗是最常见的后续治疗，其使用在帕博利珠单抗组和安慰剂组的患者中基本相当。

 

 

目前最大的挑战之一是确定哪些患者可能存在治疗不足。这可能包括接受转移灶切除术的患者，因为转移性疾病通常需要联合治疗。此外，安慰剂组中约50%未复发的患者可能根本不需要辅助治疗。这些是我们仍需解决的未满足需求，我们需要更多关于生物标志物的数据，以更好地了解哪些患者将从辅助治疗中获益最多。OS仍然保持稳定，风险比保持一致。观察到的最常见严重不良反应是高血压、肝酶升高（转氨酶升高）和腹泻，其持续时间和缓解情况也在报告中呈现。

 

Oncology Frontier:Before the approval of pembrolizumab，the only adjuvant treatment for renal cell carcinoma after surgery was TKI drugs.Based on clinical practice，can you please share what stages of adjuvant treatment this type of patient has gone through，and what unmet clinical needs still exist?

 

Dr.Naomi Balzer Haas:The development of adjuvant therapy for renal cell carcinoma began with vascular endothelial growth factor receptor inhibitors.Several studies were conducted in this area，but the only trial that showed a benefit was the S-TRAC trial，which evaluated adjuvant sunitinib for a year.However，the disease-free survival benefit was only observed for one year beyond that，and there was no overall survival benefit.This led to an interest in exploring the role of immune checkpoint inhibitor treatments，given their activity in advanced disease settings.Consequently，four or five perioperative immune checkpoint inhibitor trials were developed and studied.The only one that demonstrated a benefit so far was the KEYNOTE-564 trial，which compared adjuvant pembrolizumab for one year versus placebo.This study enrolled high-risk patients，including those intermediate-high(pT2 Gr 4 or sarcomatoid，or pT3 any Gr，N0 M0)or high(pT4 any Gr，N0 M0，or any pT and Gr，N+M0)risk of recurrence or M1 with no evidence of disease(NED)who had nephrectomy and/or metastasectomy≤12 wks.

 

The KEYNOTE-564 trial showed an improvement in disease-free survival several years ago，and more recently，an improvement in overall survival.With a follow-up of at least five years for all patients and a median follow-up of almost six years for many，the Kaplan-Meier curves for disease-free survival remain separated，indicating a continued benefit.The overall survival benefit also persists.The safety profile shows no new safety events after more than three years of follow-up.Importantly，we analyzed patients in both the pembrolizumab and placebo arms who had recurred and looked at their subsequent treatments.We found that around 60%of patients in both arms received some form of systemic therapy，with or without local therapy such as surgery or radiation.VEGF-targeted therapy was the most common subsequent treatment，and its use was similar between patients who received adjuvant pembrolizumab and those who received placebo.

 

One of the biggest challenges now is to determine which patients might be undertreated.This could include patients with metastectomy，as metastatic disease often requires combination therapy.Additionally，about 50%of patients in the placebo arm who did not recur may not have needed adjuvant therapy in the first place.These are areas where we still have unmet needs，and we need more data on biomarkers to better understand which patients will benefit most from adjuvant therapy.The overall survival continues to be stable，with hazard ratios remaining consistent.The most common serious side effects observed were hypertension，elevated liver enzymes(transaminitis)，and diarrhea，with data on their duration and resolution also presented.

 

Naomi Balzer Haas教授：在KEYNOTE-564研究中，OS保持相对稳定。风险比与我们之前观察到的情况相似，Kaplan-Meier曲线在辅助治疗结束后不久即开始分离，并持续保持分离状态。在长期随访中，我们没有观察到新的安全性信号。在我们的报告中，我们展示了严重不良事件的频率和持续时间。最常见的严重不良事件是高血压、肝酶升高（转氨酶升高）和腹泻。我们还展示了这些事件的持续时间，即严重不良事件完全缓解所需的时间。这些数据也在报告中进行了展示。

 

 

Oncology Frontier:KEYNOTE-564 is the first study on immunoadjuvant therapy for renal cell carcinoma to obtain positive results.Could you please share its 5-year follow-up OS results and the safety of long-term application?

 

Dr.Naomi Balzer Haas:The overall survival in the KEYNOTE-564 study remains pretty stable.The hazard ratio is consistent with what we have seen previously，and the Kaplan-Meier curves separate close to the completion of adjuvant therapy and remain separated.We have not observed any new safety signals over the long-term follow-up.In our presentation，we showed the frequency and duration of serious adverse events.The most common serious side effects were hypertension，transaminitis or elevation of liver enzymes，followed by diarrhea.We also demonstrated the duration of these events，showing the time it takes for serious adverse events to completely resolve.This data was also included in the presentation.

Naomi Balzer Haas教授：这是一个很好的问题。目前仍需回答的一个重要问题是：接受过帕博利珠单抗辅助治疗的患者，未来是否仍应接受免疫检查点抑制剂治疗？目前正在进行多项研究来探讨这一问题。也许那些只接受过非常短暂治疗的患者，可能尚未获得我们通常看到的完全疗效。此外，对于那些在完成治疗后数年复发的患者，是否仍应接受辅助治疗也值得考虑。

 

然而，我们知道为这些患者提供VEGF抑制剂治疗是很重要的。新的HIF-1α抑制剂也显示出潜力。当然，我们还需要在肾癌中寻找新的靶点。

 

Oncology Frontier:For patients whose disease progresses during immunotherapy，what follow-up treatment options are available?

 

Dr.Naomi Balzer Haas:That’s a very good question.One of the most important questions still to be answered is whether there are patients who received adjuvant pembrolizumab that should still receive an immune checkpoint inhibitor in the future.There are a number of studies ongoing to look at this.Perhaps patients who were only on treatment for a very short period of time may not have reached the full benefit we typically see.Additionally，for patients who relapse several years after completing treatment，it’s worth considering whether they should still receive adjuvant therapy.

 

However，we know that it’s important to offer VEGF inhibitor therapy for these patients.The newer HIF-1 alpha inhibitors are also showing promise.Certainly，we need to identify new targets in kidney cancer as well.

 

Naomi Balzer Haas教授：我认为像KEYNOTE-564研究中所展示的具有生存获益的辅助治疗能够被应用，对于患者和医生来说都是非常重要的。我们希望它能帮助治愈更多的肾癌患者。然而，我认为我们仍需在这个领域不断改进。这项研究成果可能会被长期应用，但我认为我们需要更好地了解哪些患者可能不需要这种治疗，或者哪些患者可能需要更多治疗，因为目前我们还没有治愈所有患者。

 

Oncology Frontier:What impact do you think the results of the KEYNOTE-564 study will have on existing kidney cancer treatment guidelines and clinical practice?

 

Dr.Naomi Balzer Haas:I think having an available adjuvant therapy that shows a survival benefit，like the one demonstrated in the KEYNOTE-564 study，is very important for both patients and physicians.We hope that it will lead to curing more kidney cancer patients.However，I believe we need to continue improving in this area.The study results will likely be here to stay，but I think we need to better understand which patients might not need this therapy or might need more，because we’re still not curing everyone.

 

▌参考文献

 

[1]Ravaud A，Motzer RJ，Pandha HS，et al.Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.N Engl J Med.2016;375(23):2246-2254.doi:10.1056/NEJMoa1611406

 

[2]Choueiri TK，Tomczak P，Park SH，et al.Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.N Engl J Med.2021;385(8):683-694.doi:10.1056/NEJMoa2106391

 

[3]Powles T，Tomczak P，Park SH，et al.Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma(KEYNOTE-564):30-month follow-up analysis of a multicentre，randomised，double-blind，placebo-controlled，phase 3 trial[published correction appears in Lancet Oncol.2023 Jan;24(1):e10.doi:10.1016/S1470-2045(22)00759-8.].Lancet Oncol.2022;23(9):1133-1144.doi:10.1016/S1470-2045(22)00487-9

 

[4]Naomi Balzer Haas，et al.Five-year follow-up results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab(pembro)for the treatment of clear cell renal cell carcinoma(ccRCC).ASCO 2025;Abstract#5414

 

Naomi Balzer Haas教授

美国宾夕法尼亚大学艾布拉姆森癌症中心

Naomi Haas医学博士是宾夕法尼亚大学医学院肾脏和前列腺癌临床研究主任，同时也是宾夕法尼亚大学医院的医学副教授，始终站在肾脏和前列腺癌临床研究的前沿。她作为肾癌辅助临床试验设计和执行方面的专家，享有国际盛誉，加之她在前列腺癌和肾脏癌治疗领域的全国性权威地位，为推动该领域发展做出了重大贡献。