晚期 HCC 一线组合的混合生存数据

StephenW

晚期 HCC 一线组合的混合生存数据
— 在 COSMIC-312 中期分析中，卡博替尼加阿特珠单抗达到 PFS 终点，未达到 OS

作者：Mike Bassett，特约撰稿人，MedPage Today 2021 年 11 月 23 日

一项 III 期研究的中期分析显示，卡博替尼 (Cabometyx) 加阿特珠单抗 (Tecentriq) 与单独使用索拉非尼 (Nexavar) 相比，显着改善了先前未经治疗的晚期肝细胞癌 (HCC) 患者的无进展生存期 (PFS)。

COSMIC-312 试验达到了其主要终点之一，与单药索拉非尼相比，一线酪氨酸激酶抑制剂 (TKI) 加 PD-L1 检查点抑制剂组合可将疾病进展或死亡的风险降低 37%（中位 PFS分别为 6.8 个月和 4.2 个月；HR 0.63，99% CI 0.44-0.91，P=0.0012），加州大学旧金山分校医学博士 Robin Kate Kelley 报道。

然而，作为试验的第二个主要终点的中期总生存期 (OS) 分析显示，阿特珠单抗-卡博替尼或索拉非尼治疗组之间没有显着差异（中位分别为 15.4 个月和 15.5 个月；HR 0.90，96% CI 0.69-1.18， P=0.438)，根据欧洲肿瘤内科学会 (ESMO) 在 2021 年 ESMO 亚洲虚拟肿瘤学周上的虚拟全体会议。

该研究的第三组显示，与索拉非尼相比，单独使用 TKI 卡博替尼在数值 PFS 上具有优势（5.8 个月 vs 4.3 个月；HR 0.70，99% CI 0.51-1.01），但“未满足显着性所需的严格 P 值暂时的，”凯利说。

ESMO 讨论者、英国癌症研究所和皇家马斯登医院的医学博士 Ian Chau 指出，目前美国临床肿瘤学会 (ASCO) 指南建议将阿特珠单抗和贝伐珠单抗 (Avastin) 联合作为大多数患者的一线治疗。根据 IMbrave150 试验的结果，将这种组合与索拉非尼进行了比较。

“我们如何在 atezolizumab 和 bevacizumab 与 atezolizumab 和 cabozantinib 之间进行选择，到目前为止，这两者都显示出非常显着的 PFS 改善？”周说。

虽然 IMbrave150 的最新结果显示，atezolizumab-bevacizumab 的 OS 持续改善，但“我们尚未在中期分析中观察到 atezolizumab 和 cabozantinib 的总生存率 [benefit]，”他说，并补充说响应率也更高阿特珠单抗-贝伐单抗组合。

在目前的研究中，卡博替尼-atezolizumab 的客观缓解率为 11%，索拉非尼为 3.7%，单独卡博替尼为 6.4%。

“如果采用 ESMO-临床获益量表，[atezolizumab-cabozantinib 组合] 目前为 3，”Chau 说。 “因此，目前还没有将其视为非常重要的干预措施，但我们当然正在等待最终的操作系统结果。”

卡博替尼于 2019 年获得 FDA 批准，用于先前接受过索拉非尼治疗的 HCC 患者。 2020 年，atezolizumab-bevacizumab 获得了 FDA 的批准，用于治疗初治不可切除或转移性 HCC 患者。

COSMIC-312 包括全球 281 个中心的 837 名患者。患者以 2:1:1 的比例随机接受卡博替尼-atezolizumab (n=432)、索拉非尼单药 (n=217) 或单药卡博替尼 (n=188)。

Kelley 分享了中期分析中两个主要终点的结果：在随机接受卡博替尼-阿特珠单抗或索拉非尼治疗的前 372 名患者中评估的 PFS，称为 PFS 意向治疗 (ITT) 人群（中位随访时间为 15.8 个月）和完整研究 ITT 人群中的 OS（中位随访时间为 13.6 个月）。卡博替尼和索拉非尼单药治疗比较中的 PFS 是次要终点。

卡博替尼-atezolizumab 的疾病控制率（缓解加上疾病稳定）为 78%，索拉非尼为 65%，卡博替尼单药为 84%。

“考虑到在一线 HCC 环境中缺乏单药卡博替尼数据，这些比较被包括在内以更好地描述卡博替尼在这个联合治疗组中的贡献，”Chau 指出。

至于安全性，Kelley 报告说，使用 cabozantinib-atezolizumab 的不良事件 (AE) 是可控的，其安全性与每种单一药物的安全性一致。

该组合最常见的 3 级或更高 AE 是掌跖红斑感觉障碍（索拉非尼和卡博替尼单药治疗分别为 7.9% 和 8.2% 和 8.5%）、高血压（7.0%、6.3%、11.0%）、天冬氨酸转氨酶升高(6.5%, 2.4%, 5.3%) 和增加的丙氨酸转氨酶 (6.3%, 1.9%, 5.9%)。
卡博替尼-atezolizumab 的 3/4 级治疗相关 AE 的发生率为 51%，索拉非尼为 30%，卡博替尼单药治疗为 52%。卡博替尼-atezolizumab 组的治疗相关死亡发生率为 1.9%，单药治疗组的死亡率为 0.5%。

   
    Mike Bassett 是一名专职作家，专注于肿瘤学和血液学。他住在马萨诸塞州。

披露

该研究由 Exelixis 资助。

Kelley 披露了与 Agios、阿斯利康、百时美施贵宝、基因泰克/罗氏、吉利德科学、默克、Adaptimmune、阿斯利康、拜耳、EMD Serono、Exelixis、礼来、MedImmune、默克夏普和多美、合作伙伴疗法、QED Therapeutics、Taiho Pharmaceutical 的关系和易普森。

合著者披露了与行业的多种关系。

主要资源

欧洲肿瘤内科学会

来源参考：Kelley RK 等人“卡博替尼 (C) 加阿特珠单抗 (A) 与索拉非尼 (S) 作为晚期肝细胞癌 (aHCC) 的一线全身治疗：随机 III 期 COSMIC-312 试验的结果” ESMO 2021 ; VP10-2021。

StephenW

Mixed Survival Data for First-Line Combo in Advanced HCC
— In COSMIC-312 interim analysis, cabozantinib plus atezolizumab hits PFS endpoint, misses on OS

by Mike Bassett, Staff Writer, MedPage Today November 23, 2021

Cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) significantly improved progression-free survival (PFS) versus sorafenib (Nexavar) alone for patients with previously untreated advanced hepatocellular carcinoma (HCC), an interim analysis of a phase III study showed.

The COSMIC-312 trial met one of its primary endpoints, with the first-line tyrosine kinase inhibitor (TKI) plus PD-L1 checkpoint inhibitor combination reducing the risk of disease progression or death by 37% compared with single-agent sorafenib (median PFS 6.8 vs 4.2 months, respectively; HR 0.63, 99% CI 0.44-0.91, P=0.0012), reported Robin Kate Kelley, MD, of the University of California San Francisco.

However, an interim overall survival (OS) analysis, the trial's second primary endpoint, showed no significant difference between the groups treated with atezolizumab-cabozantinib or sorafenib (median 15.4 vs 15.5 months, respectively; HR 0.90, 96% CI 0.69-1.18, P=0.438), according to a European Society for Medical Oncology (ESMO) virtual plenary presentation at ESMO Asia Virtual Oncology Week 2021.

A third arm of the study showed a numerical PFS advantage for the TKI cabozantinib alone compared with sorafenib (5.8 vs 4.3 months; HR 0.70, 99% CI 0.51-1.01), but "did not meet the stringent P-value required for significance in the interim," Kelley said.

ESMO discussant Ian Chau, MD, of the Institute of Cancer Research and Royal Marsden Hospital in England, noted that current American Society of Clinical Oncology (ASCO) guidelines recommend offering the combination of atezolizumab and bevacizumab (Avastin) as first-line treatment for most patients with advanced HCC, based on results from the IMbrave150 trial, which compared that combination with sorafenib.

"How do we choose between atezolizumab and bevacizumab versus atezolizumab and cabozantinib, both of which have shown a highly significant improvement in PFS so far?" Chau said.

While updated results from IMbrave150 have shown a continued OS improvement with atezolizumab-bevacizumab, "we have not yet observed an overall survival [benefit] with atezolizumab and cabozantinib in the interim analysis," he said, adding that response rates were also higher with the atezolizumab-bevacizumab combination.

In the current study, objective response rates were 11% for cabozantinib-atezolizumab, 3.7% for sorafenib, and 6.4% for cabozantinib alone.

"If you go with the ESMO-Magnitude of Clinical Benefit Scale, the [atezolizumab-cabozantinib combination] is currently at 3," Chau said. "So, it is not deemed to be a highly significant intervention yet, but we of course are waiting for the final OS results."

Cabozantinib received FDA approval in 2019 for patients with HCC who have been previously treated with sorafenib. In 2020, atezolizumab-bevacizumab got the agency's green light for use in patients with treatment-naive unresectable or metastatic HCC.

COSMIC-312 included 837 patients at 281 centers globally. Patients were randomized 2:1:1 to receive cabozantinib-atezolizumab (n=432), sorafenib alone (n=217), or single-agent cabozantinib (n=188).

Kelley shared results for two primary endpoints in the interim analysis: PFS as assessed in the first 372 patients randomized to cabozantinib-atezolizumab or sorafenib, known as the PFS intention-to-treat (ITT) population (median follow-up of 15.8 months), and OS in the full-study ITT population (median follow-up of 13.6 months). PFS in the monotherapy comparison between cabozantinib and sorafenib was a secondary endpoint.

Disease control rates (response plus stable disease) were 78% for cabozantinib-atezolizumab, 65% for sorafenib, and 84% for single-agent cabozantinib.

"These comparisons were included to better characterize the contribution of cabozantinib in this combination arm, given the lack of single-agent cabozantinib data in the first-line HCC setting," Chau pointed out.

As for safety, Kelley reported that adverse events (AEs) with cabozantinib-atezolizumab were manageable, with a safety profile that was consistent with that of each single agent.

The most common grade 3 or higher AEs for the combination were palmar-plantar erythrodysesthesia (7.9% vs 8.2% and 8.5% for the sorafenib and cabozantinib monotherapies, respectively), hypertension (7.0%, 6.3%, 11.0%), increased aspartate aminotransferase (6.5%, 2.4%, 5.3%), and increased alanine aminotransferase (6.3%, 1.9%, 5.9%).
Rates of grade 3/4 treatment-related AEs were 51% for cabozantinib-atezolizumab, 30% for sorafenib, and 52% for cabozantinib monotherapy. Treatment-related deaths occurred in 1.9% of those on the cabozantinib-atezolizumab arm, and in 0.5% of those on each of the monotherapy arms.

   
    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was funded by Exelixis.

Kelley disclosed relationships with Agios, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Gilead Science, Merck, Adaptimmune, AstraZeneca, Bayer, EMD Serono, Exelixis, Lilly, MedImmune, Merck Sharp & Dohme, Partner Therapeutics, QED Therapeutics, Taiho Pharmaceutical, and Ipsen.

Co-authors disclosed multiple relationships with industry.

Primary Source

European Society for Medical Oncology

Source Reference: Kelley RK, et al "Cabozantinib (C) plus atezolizumab (A) versus sorafenib (S) as first-line systemic treatment for advanced hepatocellular carcinoma (aHCC): Results from the randomized phase III COSMIC-312 trial" ESMO 2021; VP10-2021.