阿斯利康 Imfinzi-Tremelimumab 组合在肝癌中“树立新标杆”

StephenW

阿斯利康 Imfinzi-Tremelimumab 组合在肝癌中“树立新标杆”

发布时间：2022 年 1 月 19 日 作者：马克·特里

AstraZeneca_Bodo Marks/图片联盟来自 Getty

Bodo Marks/图片联盟通过盖蒂

阿斯利康一直在努力寻找其抗 CTLA-4 抗体曲美木单抗的有效用途。它可能在非小细胞肺癌、膀胱癌和头颈癌失败后终于找到了它。

与拜耳的多吉美（索拉非尼）相比，该公司在 HIMALAYA III 期试验中报告了其所谓的“前所未有的生存率”，该试验使用单次启动剂量的曲美木单抗添加到抗 PD-L1 检查点抑制剂 Imfinzi（durvalumab）中，与拜耳的多吉美（索拉非尼）相比治疗无法切除的肝细胞癌 (HCC) 患者，这些患者之前未接受过全身治疗，因此不符合局部治疗的条件。

“史无前例”可能是夸张的，因为对现有疗法的改进虽然在临床上意义重大，但不一定是戏剧性的。尽管如此，对于一种生存记录不佳的疾病，即使是适度的改善也是值得欢迎的。大约 75% 的原发性肝癌是 HCC，所有 HCC 患者中有 80% 至 90% 患有肝硬化，主要由乙型或丙型肝炎感染引起。超过一半的 HCC 病例在疾病进展较晚时才被诊断出来。

“迄今为止，”范德比尔特-英格拉姆癌症中心外科和内科肿瘤学主任、医学博士 Cathy Eng 说，“HIMALAYA 研究是规模最大的 III 期研究之一，长期随访证明了免疫疗法在不能手术切除的 HCC 中的作用。 HIMALAYA 选择了一种新的启动方法，先是单剂量联合免疫疗法，然后是单药 durvalumab。虽然达到了主要终点，但根据目前的数据，PFS 的次要终点在任一研究组中均不优于对照组，需要进一步讨论。”

早在 2021 年 5 月，该公司就报告了 Imfinzi 加铂类化疗或 Imfinzi、tremelimumab 和化疗的 POSEIDON III 期试验，与单独化疗作为 Stave IV （转移性）非小细胞肺癌（ NSCLC ）的一线治疗相比）。这表明积极的高水平结果显示与单独化疗相比具有统计学意义和临床意义的总体生存 (OS) 益处。

当 HIMALAYA 试验开始时，拜耳的 Nexavar 是唯一获批的晚期 HCC 一线护理标准。此后，卫材的 Lenvima (Lenvatinib) 和 Genentech 的 Tecentriq (atezolizumab) 加 Avastin (bevacizumab) 也获得了批准。

HIMALAYA 使用一种称为 STRIDE 的方法，包括单剂量的 tremelimumab 和 Imfinzi 1,500 mg 作为引物剂量，然后每四周单独使用 Imfinzi。与单独使用多吉美相比，这似乎将死亡风险降低了 22%。患者在联合治疗中的中位存活时间为 16.4 个月，而拜耳药物为 13.8 个月。

“无法切除的肝癌患者面临着令人沮丧的预后，新的治疗选择对于提高长期生存率至关重要，”纪念斯隆凯特琳癌症中心的主治医师和 HIMALAYA 试验的首席研究员 Ghassan Abou-Alfa 博士说。 “ STRIDE 方案的三年总生存率和良好的安全性在这种情况下树立了新的基准，并强调了这种创新治疗方法的潜力。”

在这项研究中，与多吉美相比，STRIDE 患者的死亡风险降低了 22%。中位 OS 为 16.4 个月，而多吉美为 13.8 个月。大约 31% 的患者在治疗三年后仍然活着，而多吉美为 20%。与多吉美相比，STRIDE 的客观缓解率 (ORR) 为 20.1% 至 5.1%。 STRIDE 的中位反应持续时间 (DoR) 为 22.3 个月，而多吉美为 18.4 个月。没有观察到新的安全信号。

AstraZeneca 肿瘤学研发执行副总裁 Susan Galbraith 表示：“HIMALAYA 试验强化了我们对 Tremelimumab 的科学方法，利用 CTLA-4 抑制的潜力和独特的给药方案来启动免疫系统，帮助患者延长寿命和副作用最小。我们期待尽快为无法切除的肝癌患者带来潜在的新治疗选择，这是一个高度未满足的需求。”

StephenW

AstraZeneca Imfinzi-Tremelimumab Combo “Sets New Benchmark” in Liver Cancer

Published: Jan 19, 2022 By Mark Terry

AstraZeneca_Bodo Marks/picture alliance via Getty

Bodo Marks/picture alliance via Getty

AstraZeneca has been struggling to find an effective use for its anti-CTLA-4 antibody tremelimumab. It may have finally found it after failures in non-small cell lung cancer, bladder cancer and head and neck cancer.

The company is reporting what it called “unprecedented survival,” in the HIMALAYA Phase III trial using a single priming dose of tremelimumab added to anti-PD-L1 checkpoint inhibitor Imfinzi (durvalumab) compared to Bayer’s Nexavar (sorafenib) as a first-line treatment for unresectable hepatocellular carcinoma (HCC) patients who had not received previous systemic therapy and as a result, weren’t eligible for localized treatment.

“Unprecedented” might be hyperbole, in that the improvements over existing therapies, although clinically significant, are not necessarily dramatic. Still, for a disease with a dismal survival record, even modest improvements are welcome. Approximately 75% of primary liver cancers are HCC, with 80 to 90% of all HCC patients having cirrhosis, primarily caused by hepatitis B or C infections. More than half of HCC cases are diagnosed late when the disease is more advanced.

“To date,” said Dr. Cathy Eng, M.D., the David H. Johnson chair in surgical and medical oncology at Vanderbilt-Ingram Cancer Center, “the HIMALAYA study is one of the largest Phase III studies conducted with long-term follow-up demonstrating the role of immunotherapy in surgically unresectable HCC. HIMALAYA chose a novel approach of priming with a single dose of combination immunotherapy followed by the single-agent durvalumab. While the primary endpoint was met, based on the current data, the secondary endpoint of PFS was not superior in either investigational arm relative to the control arm, requiring further discussion.”

Back in May 2021, the company reported on the POSEIDON Phase III trial of Imfinzi plus platinum-based chemotherapy or Imfinzi, tremelimumab and chemotherapy compared to chemotherapy alone as first-line treatment in Stave IV (metastatic) non-small cell lung cancer (NSCLC). That demonstrated positive high-level result showing a statistically significant and clinically meaningful overall survival (OS) benefit compared to chemotherapy alone.

When the HIMALAYA trial began, Bayer’s Nexavar was the only approved frontline standard of care for advanced HCC. Since then, Eisai’s Lenvima (Lenvatinib) and Genentech’s Tecentriq (atezolizumab) plus Avastin (bevacizumab) have also been approved.

HIMALAYA uses an approach called STRIDE, involving a single dose of tremelimumab and Imfinzi at 1,500 mg as a primer dose, followed by Imfinzi by itself every four weeks. This appears to decrease the risk of death by 22% over Nexavar alone. Patients survived a median 16.4 months on the combination therapy compared to 13.8 months on the Bayer drug.

“Patients with unresectable liver cancer face a dismal prognosis, and new treatment options are critical to improving long-term survival,” said Dr. Ghassan Abou-Alfa, attending physician at Memorial Sloan Kettering Cancer Center and principal investigator for the HIMALAYA trial. “The three-year overall survival rate and favorable safety profile seen with the STRIDE regimen set a new benchmark in this setting and underscore the potential of this innovative treatment approach.”

In the study, patients with STRIDE had a 22% decrease in the risk of death compared to Nexavar. Median OS was 16.4 months compared to 13.8 months for Nexavar. About 31% of patients were still alive three years after therapy compared to 20% for Nexavar. The STRIDE demonstrated an objective response rate (ORR) compared to Nexavar of 20.1% to 5.1%. Median duration of response (DoR) was 22.3 months with STRIDE versus 18.4 with Nexavar. No new safety signals were observed.

Susan Galbraith, executive vice president, oncology R&D at AstraZeneca, stated, “The HIMALAYA trial reinforces our scientific approach for tremelimumab, tapping into the potential of CTLA-4 inhibition and a unique dosing regimen to prime the immune system to help patients live longer and with minimal side effects. We look forward to bringing potential new treatment options to patients with unresectable liver cancer, an area of high unmet need, as quickly as possible.”