用Opdivo加Yervoy治疗的患者中有三分之一的患者肿瘤全部或部

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FDA Approves Immunotherapy Combination for Liver Cancer

A third of patients treated with Opdivo plus Yervoy experienced complete or partial tumor remission.

April 1, 2020 • By Liz Highleyman

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On March 10, the Food and Drug Administration (FDA) approved a combination of the checkpoint inhibitors Opdivo (nivolumab) and Yervoy (ipilimumab) for people with advanced hepatocellular carcinoma (HCC), the most common type of liver cancer.

The accelerated approval was based on results from the Phase I/II CheckMate 040 trial, which showed a response rate of 33% among HCC patients previously treated with Nexavar (sorafenib).

Over years or decades, chronic hepatitis B or C, heavy alcohol use, fatty liver disease and other causes can lead to development of cirrhosis and hepatocellular carcinoma. Liver cancer is often detected late and is difficult to treat, as it does not respond well to traditional chemotherapy. The tyrosine kinase inhibitor Nexavar is a standard first-line treatment for advanced liver cancer, but it doesn’t work for many patients and most experience disease progression.

Opdivo is a PD-1 checkpoint inhibitor that helps the immune system fight cancer. PD-1, a receptor on T cells, helps regulate immune function. Some tumors can hijack PD-1 to turn off immune responses against them. Drugs that block the interaction between PD-1 and its binding partner, known as PD-L1, can release the brakes and restore T-cell activity. Opdivo was approved as a stand-alone treatment for HCC in 2017. Yervoy is a different type of checkpoint inhibitor that blocks CTLA-4, which turns off immune responses by suppressing T-cell replication.

Approval of the combination was based on results from the Phase I/II CheckMate 040 trial, which evaluated Opdivo alone and in various combinations in people with advanced HCC who had previously taken or could not tolerate Nexavar.

Participants were randomly assigned to receive different doses of Opdivo plus Yervoy, continuing treatment until they experienced disease progression or unacceptable side effects. A total of 49 people received the regimen approved by the FDA: 1 milligram per kilogram of Opdivo plus 3 mg/kg of Yervoy given by IV infusion every three weeks for four cycles, followed by 240 mg of Opdivo every two weeks.

Among people receiving this regimen, the overall response rate—meaning complete or partial tumor shrinkage—was 33%. Four patients (8%) experienced complete remission and twelve (24%) had partial responses. Most responses (88%) lasted at least six months, 56% lasted at least 12 months and 31% lasted at least two years.

At last year’s Liver Meeting, researchers reported that people treated with this regimen had a median overall survival of 22.8 months. The 12-month overall survival rate was 61% and the 24-month survival rate was 48%.

Treatment with Opdivo and Yervoy was generally safe, though side effects were common. More than half (59%) experienced serious adverse reactions, and 29% stopped treatment for this reason, according to manufacturer Bristol-Myers Squibb. The most frequently reported adverse events were rash, itching, musculoskeletal pain, diarrhea, cough, decreased appetite, fatigue and fever.

The major concern with checkpoint inhibitors is immune-related adverse events, which are more common when these drugs are combined. Immunotherapy works by restoring immune responses against cancer cells, but it can also activate the immune system more broadly, harming healthy tissue. Liver inflammation was the most common severe immune-mediated side effect, followed by skin rash, endocrine problems, lung inflammation and colon inflammation. In most cases, these side effects could with a short course of corticosteroids.

The FDA granted accelerated approval based overall response rate and duration of response. Continued approval may be contingent upon verification of clinical benefit in later-stage trials.

A Phase III clinical trial, CheckMate 9DW, is now evaluating Opdivo plus Yervoy versus Nexavar or Lenvima (lenvatinib) as first-line treatment for advanced HCC. At the recent American Society of Clinical Oncology Gastrointestinal Cancers Symposium, researchers reported that a triple combination of Opdivo, Yervoy and the kinase inhibitor Cabometyx (cabozantinib) led to a higher response rate than the dual regimen.

"HCC is an aggressive disease in need of different treatment approaches," lead study investigator Anthony El-Khoueiry, MD, of the Keck School of Medicine at the University of Southern California said in a Bristol-Myers Squibb press release. "The overall response rate observed in the Opdivo plus Yervoy cohort of the CheckMate-040 trial underscores the potential of this dual immunotherapy as a possible treatment option for patients."

StephenW

DA批准用于肝癌的免疫疗法组合

用Opdivo加Yervoy治疗的患者中有三分之一的患者肿瘤全部或部分缓解。

2020年4月1日•作者：Liz Highleyman

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3月10日，美国食品药品监督管理局（FDA）批准了检查点抑制剂Opdivo（nivolumab）和Yervoy（ipilimumab）的组合用于晚期肝细胞癌（HCC），这是最常见的肝癌类型。

加速批准是基于I / II期CheckMate 040期试验的结果，该试验显示，以前接受过Nexavar（索拉非尼）治疗的HCC患者的缓解率为33％。

数年或数十年以来，慢性乙型或丙型肝炎，大量饮酒，脂肪肝疾病和其他原因可导致肝硬化和肝细胞癌的发展。肝癌通常发现较晚且难以治疗，因为它对传统化学疗法反应不佳。酪氨酸激酶抑制剂Nexavar是晚期肝癌的标准一线治疗药物，但不适用于许多患者，并且大多数患者会经历疾病进展。

Opdivo是一种PD-1检查点抑制剂，可帮助免疫系统抵抗癌症。 PD-1是T细胞的一种受体，有助于调节免疫功能。一些肿瘤可以劫持PD-1来关闭针对它们的免疫反应。阻断PD-1及其结合伴侣之间相互作用的药物PD-L1可以释放刹车并恢复T细胞活性。 Opdivo在2017年被批准作为肝癌的独立治疗药物。Yervoy是另一种类型的关卡抑制剂，可阻断CTLA-4，后者可通过抑制T细胞复制来关闭免疫反应。

组合的批准基于I / II期CheckMate 040试验的结果，该试验单独评估了Opdivo以及先前已服用或不能耐受耐克沙华的晚期HCC患者的各种组合。

参与者被随机分配接受不同剂量的Opdivo加Yervoy，继续治疗直至他们经历疾病进展或不可接受的副作用。共有49人接受了FDA批准的治疗方案：每三周静脉输注1毫克每千克Opdivo加上3 mg / kg的耶伏伊（Yervoy），每四个星期一次，随后每两周注射240毫克Opdivo。

在接受该方案的患者中，总体缓解率（即肿瘤完全缩小或部分缩小）为33％。四名患者（8％）完全缓解，十二名患者（24％）部分缓解。大部分回应（88％）持续至少六个月，56％持续至少12个月，31％持续至少两年。

在去年的肝脏会议上，研究人员报告说，接受这种方案治疗的人的平均总生存期为22.8个月。 12个月总生存率为61％，24个月生存率为48％。

尽管副作用很常见，但使用Opdivo和Yervoy进行治疗通常是安全的。据制造商百时美施贵宝公司（Bristol-Myers Squibb）称，超过一半的人（59％）经历了严重的不良反应，有29％的人因此而停止治疗。最常见的不良反应是皮疹，瘙痒，肌肉骨骼疼痛，腹泻，咳嗽，食欲下降，疲劳和发烧。

检查点抑制剂的主要关注点是免疫相关的不良事件，这些药物联合使用时更常见。免疫疗法通过恢复针对癌细胞的免疫反应而起作用，但它也可以更广泛地激活免疫系统，从而损害健康组织。肝炎症是最常见的严重的免疫介导的副作用，其次是皮疹，内分泌问题，肺部炎症和结肠炎症。在大多数情况下，短期服用皮质类固醇激素可能会产生这些副作用。

FDA批准了基于总体反应率和反应持续时间的加速批准。能否继续批准取决于在后期试验中验证临床获益。

III期临床试验CheckMate 9DW目前正在评估Opdivo加Yervoy与Nexavar或Lenvima（lenvatinib）作为晚期HCC的一线治疗。在最近的美国临床肿瘤学会胃肠道癌专题讨论会上，研究人员报告说，将Opdivo，Yervoy和激酶抑制剂Cabometyx（cabozantinib）的三联使用比双重方案的应答率更高。

南加州大学凯克医学院的首席研究研究员安东尼·艾尔·库埃里伊（Anthony El-Khoueiry，MD）在百时美施贵宝公司的一份新闻稿中说：“肝癌是一种需要不同治疗方法的侵袭性疾病。” “在CheckMate-040试验的Opdivo和Yervoy队列中观察到的总体缓解率突显了这种双重免疫疗法作为患者可能的治疗选择的潜力。”