不可切除的肝细胞癌的潜在新一线选择

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不可切除的肝细胞癌的潜在新一线选择
— Tremelimumab-durvalumab 改善 OS，单药 durvalumab 不劣于索拉非尼

作者：Charles Bankhead，MedPage Today 高级编辑，2022 年 1 月 22 日
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旧金山——一项大型随机试验显示，与索拉非尼 (Nexavar) 作为不可切除肝细胞癌 (HCC) 的初始疗法相比，免疫疗法组合显着提高了总生存期 (OS)。

接受单次初始剂量 tremelimumab 和 durvalumab (Imfinzi) 治疗的患者中位 OS 为 16.4 个月，而索拉非尼为 13.8 个月。生存曲线在大约 9 个月后开始分离，此后继续分离。纽约市纪念斯隆凯特琳癌症中心的医学博士、工商管理硕士 Ghassan K. Abou-Alfa 报告说，单药 durvalumab 的中位 OS 为 16.6 个月，与索拉非尼相比符合非劣效性但不优越性的统计标准，在胃肠道癌症研讨会上。

“[当前] HIMALAYA 研究是一项大型 III 期研究，其中包括全球异质人群，代表患有不可切除的 HCC 患者，”Abou-Alfa 说。 “STRIDE [单次 Tremelimumab 定期间隔 durvalumab] 似乎提供了长期生存益处，具有里程碑意义的 36 个月总生存率为 30.7%。”

“durvalumab 单药治疗的总体生存率不劣于索拉非尼，具有良好的效益风险特征。STRIDE 方案和 durvalumab 单药治疗可能代表不可切除 HCC 患者的新治疗选择，”他说。

不可切除的肝癌

IMbrave150 试验在不可切除 HCC 的 III 期试验中设定了当前的高水位线，阿特珠单抗 (Tecentriq) 和贝伐单抗 (Avastin) 的中位数为 19.2 个月，而索拉非尼为 13.4 个月，使其成为当前的护理标准，受邀的讨论者安东尼说B. El-Khoueiry，医学博士，洛杉矶南加州大学诺里斯综合癌症中心。然而，该组合导致 25% 的患者发生出血事件，6.4% 的患者发生严重出血。

STRIDE 方案避免了与 VEGF 抑制剂相关的出血风险，鉴于大多数后续方案针对 VEGF，这可能是一个优势。 El-Khoueiry 指出，STRIDE 方案导致更多的免疫介导的不良事件 (IMAE)，其中 20% 需要使用类固醇进行管理。相比之下，在先前接受索拉非尼治疗的 HCC 中的 nivolumab (Opdivo) 和 ipilimumab (Yervoy) 的 CheckMate 040 试验中，57% 接受大剂量 ipilimumab 治疗的患者需要类固醇来管理 IMAE。

“STRIDE ... 是晚期 HCC 患者的一种新的一线治疗选择，”El-Khoueiry 说。 “STRIDE 具有与含 VEGF 的组合不同的毒性特征，并且没有 VEGF 相关的毒性。”

El-Khoueiry 继续说，单药 durvalumab 的结果与 CheckMate 459 试验中使用 nivolumab 单药治疗与索拉非尼获得的结果相似。尽管该试验没有证明 nivolumab 的优越性，但 16.4 个月的中位 OS 与 HIMALAYA 的 16.6 个月的中位 OS 几乎相同。

“这些数据确实为可能不适合联合治疗或有 VEGF 禁忌症的选定患者提供了一线治疗选择，”他说。

研究人员假设 CTLA-4 抑制剂的单次初始剂量，然后是抗 PD1/L1 免疫治疗，将提高不可切除 HCC 的存活率，并避免与 CTLA-4 抑制相关的不良反应。这样的方案还将避免与 VEGF 抑制相关的出血风险。该假设在 Tremelimumab 和 Durvalumab 的 I/II 期试验中得到支持，该试验使用 STRIDE 方案产生的中位 OS 为 18.7 个月，为 III 期 HIMALAYA 试验奠定了基础。

喜马拉雅结果

HIMALAYA 纳入了 1,324 名未经治疗、不可切除的 HCC 患者，随机接受 STRIDE 方案、单药 durvalumab 或单药索拉非尼。主要终点是 STRIDE 方案与索拉非尼的 OS，关键的次要目标是单药 durvalumab 与索拉非尼的 OS。

患者的中位年龄为 64-65 岁，男性占患者总数的 83%-84%，约 40% 的患者来自亚洲（不包括日本），55%-60% 的患者患有肝炎-相关的肝癌。

该试验达到了主要目标，因为与索拉非尼相比，分配到 STRIDE 方案的患者的生存风险降低了 22%（95% CI 0.65-0.92，P=0.0035）。
“到 9 个月的风险比为 0.87，但在 9 个月后一直提高到 0.70，”Abou-Alfa 说。 “这种 T 细胞的启动 [用 tremelimumab] 需要时间，而且，如果有的话，在 18 个月、24 个月和 36 个月的里程碑式分析中继续传播。到 36 个月时，[STRIDE] 上 30% 的患者仍然与使用索拉非尼的 20% 相比，存活。”

亚组分析显示，对于几乎所有预设组，联合用药与索拉非尼相比具有一致的益处。

与单药 durvalumab 相关的 16.6 个月中位 OS 被证明不劣于索拉非尼 (HR 0.86, 95% CI 0.73-1.03)，但没有达到统计学上的优势。地标分析显示 18 个月 OS 值为 47.4% 对 41.5%，24 个月值为 39.6% 对 32.6%，36 个月值为 24.7% 对 20.2%，都支持 durvalumab。

STRIDE（3.78 个月）、单药 durvalumab（3.65 个月）和索拉非尼（4.07 个月）的中位无进展生存期相似。与索拉非尼对照组 (5.1%) 相比，STRIDE (20.1%) 和 durvalumab (17.0%) 组的反应率更受欢迎。

STRIDE (50.5%) 和索拉非尼 (52.4%) 的 3/4 级 AE 发生率高于单药 durvalumab (37.1%)。索拉非尼 (36.9%) 与 STRIDE (25.8%) 或 durvalumab 单药治疗 (12.9%) 相比，治疗相关 AE (TRAE) 更常见。联合用药组发生严重 TRAE 的频率更高（17.5%），而 durvalumab 组为 8.2%，索拉非尼组为 9.4%。索拉非尼组导致停药的 TRAE 率为 11.0%，STRIDE 组为 8.2%，durvalumab 单药组为 4.1%。

    作者['full_name']

    Charles Bankhead 是肿瘤学高级编辑，还涵盖泌尿科、皮肤科和眼科。他于 2007 年加入今天的 MedPage。

StephenW

Potential New First-Line Options for Unresectable Hepatocellular Carcinoma
— Tremelimumab-durvalumab improves OS, single-agent durvalumab non-inferior to sorafenib

by Charles Bankhead, Senior Editor, MedPage Today January 22, 2022
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SAN FRANCISCO -- An immunotherapy combination significantly improved overall survival (OS) versus sorafenib (Nexavar) as initial therapy for unresectable hepatocellular carcinoma (HCC), a large randomized trial showed.

Patients treated with a single priming dose of tremelimumab followed by durvalumab (Imfinzi) had a median OS of 16.4 months as compared with 13.8 months with sorafenib. Survival curves began to separate after about 9 months and continued to separate thereafter. Single-agent durvalumab led to a median OS of 16.6 months, which met statistical criteria for non-inferiority versus sorafenib but not superiority, reported Ghassan K. Abou-Alfa, MD, MBA, of Memorial Sloan Kettering Cancer Center in New York City, at the Gastrointestinal Cancers Symposium.

"The [current] HIMALAYA study was a large phase III study that included a global, heterogeneous population, represented of patients with unresectable HCC," Abou-Alfa said. "STRIDE [single tremelimumab regular-interval durvalumab] appeared to provide a long-term survival benefit, with a landmark 36-month overall survival of 30.7%."

"Overall survival with durvalumab monotherapy was non-inferior to sorafenib with a favorable benefit-risk profile. The STRIDE regimen and durvalumab monotherapy may represent new treatment options for patients with unresectable HCC," he stated.

Unresectable HCC

The IMbrave150 trial set the current high-water mark among phase III trials in unresectable HCC with a median of 19.2 months with atezolizumab (Tecentriq) and bevacizumab (Avastin) versus 13.4 with sorafenib, making it the current standard of care, said invited discussant Anthony B. El-Khoueiry, MD, of USC Norris Comprehensive Cancer Center in Los Angeles. However, the combination led to bleeding events in 25% of patients and severe bleeding in 6.4%.

The STRIDE regimen avoids the bleeding risks associated with VEGF inhibitors, which could be an advantage given that most subsequent regimens target VEGF. The STRIDE regimen led to more immune-mediated adverse events (IMAEs), 20% of which required management with steroids, El-Khoueiry noted. In contrast, in the CheckMate 040 trial of nivolumab (Opdivo) and ipilimumab (Yervoy) in HCC previously treated with sorafenib, 57% of patients treated with high-dose ipilimumab required steroids to manage IMAEs.

"STRIDE ... is a new first-line treatment option for advanced HCC patients," said El-Khoueiry. "STRIDE has a differentiated toxicity profile from VEGF-containing combinations and does not have VEGF-related toxicities."

The results with single-agent durvalumab are similar to those obtained with nivolumab monotherapy versus sorafenib in the CheckMate 459 trial, El-Khoueiry continued. Although the trial did not demonstrate nivolumab superiority, the median OS of 16.4 months was nearly identical to the 16.6 median OS in HIMALAYA.

"The constellation of data does offer a first-line treatment option for selected patients who may not be candidates for combination therapy or who have VEGF contraindications," he said.

Investigators hypothesized that a single priming dose of a CTLA-4 inhibitor, followed by anti-PD1/L1 immunotherapy, would improve survival in unresectable HCC and avoid adverse effects associated with CTLA-4 inhibition. Such a regimen would also avoid the bleeding risks associated with VEGF inhibition. The hypothesis was supported in a phase I/II trial of tremelimumab and durvalumab, which produced a median OS of 18.7 months with the STRIDE regimen, setting the stage for the phase III HIMALAYA trial.

HIMALAYA Results

HIMALAYA included 1,324 patients with untreated, unresectable HCC, randomized to the STRIDE regimen, single-agent durvalumab, or single-agent sorafenib. The primary endpoint was OS for the STRIDE regimen versus sorafenib, and the key secondary objective was OS for single-agent durvalumab versus sorafenib.

The patients had a median age of 64-65, men accounted for 83%-84% of the total patient population, about 40% of patients were from Asia (excluding Japan), and 55%-60% of the patients had hepatitis-associated HCC.

The trial met the primary objective, as patients assigned to the STRIDE regimen had a 22% reduction in the survival hazard as compared with sorafenib (95% CI 0.65-0.92, P=0.0035).
"The hazard ratio to 9 months was 0.87 but then improved all the way to 0.70 after 9 months," said Abou-Alfa. "This priming of the T cells [with tremelimumab] takes time and, if anything, continues to propagate at landmark analyses at 18 months, 24 months, and 36 months. By 36 months, 30% of the patients on [STRIDE] were still alive as compared to 20% with sorafenib."

Subgroup analysis showed a consistent benefit for the combination versus sorafenib for almost all of the prespecified groups.

The 16.6-month median OS associated with single-agent durvalumab proved to be noninferior to sorafenib (HR 0.86, 95% CI 0.73-1.03) but did not achieve statistical superiority. Landmark analyses showed 18-month OS values of 47.4% versus 41.5%, 24-month values of 39.6% vs 32.6%, and 36-month values of 24.7% versus 20.2%, all favoring durvalumab.

Median progression-free survival was similar with STRIDE (3.78 months), single-agent durvalumab (3.65 months), and sorafenib (4.07 months). Response rates favored the STRIDE (20.1%) and durvalumab (17.0%) groups over the sorafenib control group (5.1%).

Grade 3/4 AEs occurred more often with STRIDE (50.5%) and sorafenib (52.4%) than with single-agent durvalumab (37.1%). Treatment-related AEs (TRAEs) were more common with sorafenib (36.9%) than with STRIDE (25.8%) or durvalumab monotherapy (12.9%). Serious TRAEs occurred more often with the combination (17.5%), versus 8.2% with durvalumab and 9.4% with sorafenib. Rates of TRAEs leading to discontinuation were 11.0% with sorafenib, 8.2% with STRIDE, and 4.1% with single-agent durvalumab.

    author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow