手术后免疫疗法可帮助高危膀胱癌患者更长时间摆脱癌症困扰

一项大型临床试验的结果表明，免疫疗法药物治疗可使高危肌层浸润性膀胱癌患者在膀胱切除术后的无癌生存时间延长近一倍。研究人员发现，术后使用帕博利珠单抗（Keytruda）进行治疗的效果优于观察疗法。帕博利珠单抗已获美国食品药品监督管理局 (FDA) 批准用于治疗至少 18 种不同癌症。这项由美国国立卫生研究院 (NIH) 研究人员领导的研究于 2024 年 9 月 15 日发表在《新英格兰医学杂志》上。

辅助治疗帕博利珠单抗可帮助肌层浸润性膀胱癌患者比单独观察更长时间地保持无癌状态。

图片来源：Terese Winslow/国家癌症研究所

“这项研究表明，派姆单抗可以为患者提供另一种治疗选择，帮助他们防止疾病复发，”美国国立卫生研究院 (NIH) 国家癌症研究所 (NCI)癌症研究中心首席研究员 Andrea B. Apolo 医学博士说道。“延长这些患者的无癌生存期，对他们的生活质量有着巨大的改善。”

肌层浸润性膀胱癌的诊断意味着膀胱肿瘤已侵入并穿透包裹膀胱的肌层组织。此类膀胱癌的标准治疗方法是手术切除整个膀胱。为了提高手术成功率并清除可能已从肿瘤中逸出的癌细胞，患者需在术前（称为新辅助治疗）或术后（称为辅助治疗）接受以顺铂为基础的化疗。

然而，许多患有肌层浸润性膀胱癌的患者无法接受或拒绝接受顺铂新辅助化疗。其他患者无法耐受以顺铂为基础的辅助化疗。还有一些患者，尽管接受了顺铂新辅助化疗，但仍患有持续性肌层浸润性膀胱癌，无法再次接受以顺铂为基础的辅助化疗。以往，这类患者通常需要接受严密监测，以观察复发迹象。

作为观察的替代方法，研究人员一直在研究在手术后给患者提供免疫治疗药物，看看是否可以帮助他们延长生命并且避免癌症复发。

2021年，FDA批准纳武单抗（Opdivo）作为高危肌层浸润性膀胱癌患者的辅助治疗，此前一项临床试验表明，这种免疫检查点抑制剂（一种释放T细胞“刹车”使其能够识别和攻击肿瘤的免疫疗法）与安慰剂相比，使患者无癌生存时间中位数延长了一倍。纳武单抗辅助治疗现已成为此类患者的标准治疗方案。

在当前的试验中，研究人员调查了免疫检查点抑制剂帕博利珠单抗是否也能作为辅助治疗有效。他们随机分配了702例已接受膀胱切除手术的高危肌层浸润性膀胱癌患者，分别接受帕博利珠单抗辅助治疗（每三周一次，持续一年）或观察相同时间。试验中约三分之二的患者已完成顺铂新辅助治疗。

经过中位近四年的随访，派姆单抗组患者的无癌生存期中位数为29.6个月，而观察组患者为14.2个月。派姆单抗耐受性良好，最常见的副作用是疲劳、瘙痒、腹泻和甲状腺功能减退。

在某些癌症类型中，免疫检查点抑制剂（例如派姆单抗）对PD-L1阳性（即肿瘤细胞表面产生大量PD-L1蛋白）的肿瘤比对PD-L1阴性（即非PD-L1阳性）的肿瘤更有效。因此，阿波罗博士和她的同事评估了派姆单抗的疗效是否会因PD-L1状态而异。

在404例PD-L1阳性肿瘤患者中，接受帕博利珠单抗治疗的患者中位无癌生存期为36.9个月，而观察组患者中位无癌生存期为21个月。在298例PD-L1阴性肿瘤患者中，接受帕博利珠单抗治疗的患者中位无癌生存期为17.3个月，而观察组患者中位无癌生存期为9个月。研究人员得出结论，不应以PD-L1状态来选择接受帕博利珠单抗治疗的患者，因为两组患者均受益于帕博利珠单抗的辅助治疗。

在总体生存率的初步数据显示，三年后，派姆单抗组约61%的患者仍然存活，而观察组约62%的患者仍然存活。研究人员指出，观察组中许多患者在纳武单抗获批或退出研究后才开始服用该药物，这可能扭曲了研究结果，使总体生存率数据难以解释。

研究团队已在该研究成果的基础上，探索使用各种药物与免疫检查点抑制剂组合进行辅助治疗。研究人员还在测试生物标志物，以识别出高危肌层浸润性膀胱癌患者，这些患者最有可能从任何类型的辅助治疗中获益，并避免那些可能不需要辅助治疗的患者。

这项名为“AMBASSADOR”的研究由美国国家癌症研究所 (NCI) 赞助。该研究由 NCI 资助的肿瘤临床试验联盟 (Alliance for Clinical Trials in Oncology) 牵头和执行，NCI 的国家临床试验网络 (National Clinical Trials Network) 也参与其中，这是默克公司与 NCI 通过合作研发协议开展合作的一部分。

来自：https://www.cancer.gov/news-events/press-releases/2024/high-risk-bladder-cancer-pembrolizumab

Immunotherapy after surgery helps people with high-risk bladder cancer live cancer-free longer

Drawing of stage II bladder cancer, also known as muscle-invasive bladder cancer. An inset shows cancer in the inner lining of the bladder and in the layer of connective tissue and the muscle layers of the bladder.

Adjuvant pembrolizumab helps people with muscle-invasive bladder cancer remain cancer-free longer than observation alone.

Credit: Terese Winslow/National Cancer Institute

Results from a large clinical trial show that treatment with an immunotherapy drug may nearly double the length of time people with high-risk muscle-invasive bladder cancer are cancer-free following surgical removal of the bladder. Researchers found that postsurgical treatment with pembrolizumab (Keytruda), which is approved by the Food and Drug Administration (FDA) for treating at least 18 different cancers, was superior compared with observation. The study, led by researchers at the National Institutes of Health (NIH), was published Sept. 15, 2024, in the New England Journal of Medicine.

“This study shows that pembrolizumab can offer patients another treatment option to help keep their disease from coming back,” said lead investigator Andrea B. Apolo, M.D., of the Center for Cancer Research at NIH’s National Cancer Institute (NCI). “Extending the time that these patients are cancer-free makes a big difference in their quality of life.”

A diagnosis of muscle-invasive bladder cancer means the tumor in the bladder has invaded into and through the muscular layer of tissue that encases the bladder. The standard treatment for this form of bladder cancer is to surgically remove the entire bladder. To improve the chances of successful surgery and of eliminating any cancer cells that may have already escaped from the tumor, patients are given cisplatin-based chemotherapy for a period before surgery, known as neoadjuvant therapy, or after surgery, known as adjuvant therapy.

However, many people with muscle-invasive bladder cancer can’t take or refuse neoadjuvant chemotherapy with cisplatin. Others can’t tolerate adjuvant cisplatin-based chemotherapy. Still others, who despite having received neoadjuvant chemotherapy with cisplatin, have persistent muscle-invasive disease but can’t be treated again with adjuvant cisplatin-based chemotherapy. Historically, these groups of patients were instead carefully monitored to watch for signs of relapse.

As an alternative to observation, researchers have been investigating giving patients immunotherapy drugs after surgery to see if it can help them live longer without their cancer coming back.

In 2021, FDA approved nivolumab (Opdivo) as an adjuvant therapy for people with high-risk muscle-invasive bladder cancer after a clinical trial showed that this immune checkpoint inhibitor—a type of immunotherapy that releases the brakes of T cells so they can recognize and attack tumors—doubled the median length of time patients remained cancer-free compared with a placebo. Adjuvant nivolumab is now the standard of care in this setting.

In the current trial, researchers investigated whether the immune checkpoint inhibitor pembrolizumab would also be effective as an adjuvant treatment. They randomly assigned 702 patients with high-risk muscle-invasive bladder cancer who had undergone bladder-removal surgery to receive adjuvant therapy with pembrolizumab every three weeks for a year, or to observation for the same period of time. About two-thirds of the patients in the trial had completed neoadjuvant therapy with cisplatin.

After a median follow-up of almost four years, patients in the pembrolizumab group remained cancer-free for a median of 29.6 months, compared with 14.2 months for the observation group. Pembrolizumab was well tolerated, with the most common side effects being fatigue, itching, diarrhea, and an underactive thyroid.

In some cancer types, immune checkpoint inhibitors such as pembrolizumab are more effective against tumors that are PD-L1-positive—that is, the tumor cells produce a large amount of the PD-L1 protein on their surface, than those that don’t, or PD-L1-negative. So Dr. Apolo and her colleagues assessed whether the effect of pembrolizumab varied by PD-L1 status.

Among the 404 patients whose tumors were PD-L1-positive, those treated with pembrolizumab remained cancer-free for a median of 36.9 months, compared with 21 months for those in the observation group. Among the 298 patients whose tumors were PD-L1-negative, those treated with pembrolizumab remained cancer-free for a median of 17.3 months, compared with nine months for the observation group. The researchers concluded that PD-L1 status should not be used to select patients for treatment with pembrolizumab, as both groups benefited from adjuvant pembrolizumab.

In preliminary data on overall survival, at three years, about 61% of patients in the pembrolizumab group were still alive, compared with about 62% of patients in the observation group. The researchers pointed out that many patients in the observation group began taking nivolumab once it was approved or withdrew from the study, which may have skewed the results and made the overall survival data difficult to interpret.

Research teams are already building on the study’s findings by exploring adjuvant treatment using various combinations of drugs with immune checkpoint inhibitors. Researchers are also testing biomarkers to identify patients with high-risk muscle-invasive bladder cancer who could benefit most from adjuvant treatment of any kind and spare those who may not need it.

The study, known as AMBASSADOR, is sponsored by NCI. The study is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology, and it includes participation by NCI’s National Clinical Trials Network as part of Merck’s collaboration with NCI through a Cooperative Research and Development Agreement.