2024年ESMO大会主席论坛（Presidential Symposium I）披露的KEYNOTE-A18研究数据显示，接受帕博利珠单抗和同步放化疗（CRT）的新诊断局部晚期宫颈癌患者总生存（OS）显著提高（摘要号709O）。帕博利珠单抗+同步CRT治疗的36个月OS率为82.6%，安慰剂+同步CRT治疗的36个月OS率为74.8%（风险比[HR]=0.67；95%置信区间[CI]:0.50–0.90；P=0.0040）。两个治疗组均未达到中位OS。生存获益在所有预先设定的亚组中均一致。中位随访29.9个月时，帕博利珠单抗组和安慰剂组的36个月无进展生存（PFS）率分别为69.3%和56.9%，中位PFS仍为NR（HR=0.68;95%CI:0.56-0.84）。两个治疗组的≥3级治疗相关不良事件发生率分别为69.1%和61.3%。生活质量（QOL）并未受到影响，第36周使用EORTC QLQ-C30生活质量指数问卷，没有报告具有临床意义的组间差异。

 

KEYNOTE-A18研究3年OS

 

意大利米兰Humanitas San Pio X医院的Domenica Lorusso教授在2024 ESMO汇报了KEYNOTE-A18第二项中期分析结果，并在《肿瘤瞭望》访谈中进一步解读了研究数据对临床实践的影响。

 

 

Dr.Lorusso：KEYNOTE-A18是一项随机、安慰剂对照的III期试验，评估帕博利珠单抗联合放化疗在局部晚期高风险宫颈癌中的作用。KEYNOTE-A18是一项全球性试验，招募了来自全球30个国家176个中心的1000多名患者。该试验报告显示，放化疗基础上加用帕博利珠单抗使3年无进展生存率显著增加，风险比为0.68，3年总生存率显著增加，风险比为0.67。

 

帕博利珠单抗联合放化疗的毒性特征确实易于控制。我们对帕博利珠单抗与现代高质量放射疗法的组合方案的毒性可控性感到惊讶。帕博利珠单抗+放化疗组和安慰剂+放化疗组之间的不良事件发生率、类型和严重程度非常相似。最常见的毒性反应是贫血、恶心和腹泻，但就强度而言，两个治疗组之间的不良事件非常相似。

 

接受帕博利珠单抗治疗的患者发生了免疫相关不良事件。约40%的病例报告有甲状腺功能减退症，但主要是1/2级，并通过激素替代疗法进行治疗。此外，当采用帕博利珠单抗联合放化疗治疗时，患者的生活质量不会受到损害。因此，基于所有这些信息，我们认为KEYNOTE-A18方案是局部晚期高风险宫颈癌患者的新标准治疗方法。

 

基于KEYNOTE-A18研究数据，我们可以将同步放化疗+免疫疗法视为局部晚期高风险宫颈癌的新标准治疗方法。在过去25年中，宫颈癌的标准治疗没有任何变化。唯一带来重大影响的疗法是现代放射疗法（可降低毒性，同时提高了局部控制率和总生存）。在这种标准现代放射疗法基础上加用帕博利珠单抗使3年OS率提高了约8%（82.6%vs.74.8%），我们确信这是新的标准治疗。

 

Dr.Lorusso:KEYNOTE-A18 is a randomized placebo-controlled phase III trial evaluating the role of pembrolizumab i combination with chemoradiation in locally advanced high-risk cervical cancer.The trial is a global trial and enrolled>1000 patients across the world from 30 countries and 176 centers.The trial reported a significant three-year increase in progression-free survival with a hazard ratio of 0.68 and a significant three-year increase in overall survival with a hazard ratio of 0.67.The toxicity profile of the combination was really manageable.We were surprised at how manageable this pembrolizumab combination with modern and high quality radiotherapy was.The incidence，type and severity of adverse events were very similar between the two treatment arms.The most frequently reported toxicities were anemia，nausea and diarrhea，but in terms of intensity，very similar between the two treatment arms.Patients treated with pembrolizumab had immune-related adverse events.Hypothyroidism was reported in about 40%of cases，but it was mainly grade 1/2 and managed with hormone replacement therapy.In addition，quality of life was not jeopardized when pembrolizumab was combined with chemoradiation.So based on all this information，we consider this to be a new standard-of-care in patients with locally advanced high-risk cervical cancer.

 

I think based on these data，we can consider concurrent chemoradiation plus immunotherapy as the new standard-of-care.In the last 25 years，we have not had any change in the standard-of-care in cervical cancer.The only great impact was related to the modern radiotherapy that reduced toxicity，while increasing local control and overall survival.On top of this modern standard of radiotherapy，the addition of pembrolizumab and the extra 8%overall survival at three years，we are really convinced this is the new standard-of-care.

 

参考文献：

1.Lorusso D，et al.Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer:Overall survival results from the randomized，double-blind，phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study.ESMO Congress 2024，Abstract 709O