IMbrave152研究未达主要终点 TIGIT抗体未能给晚期肝癌的一线治疗

2025年欧洲肿瘤内科学会（ESMO 2025）大会已如期召开，作为全球肿瘤领域的顶级学术盛会，其公布的Late-breaking Abstract（LBA）研究往往对临床实践具有重要指引意义。本次大会上，加州大学洛杉矶分校大卫格芬医学院Richard S. Finn教授团队的IMbrave152研究入选LBA（摘要号：LBA50），该研究聚焦晚期肝癌一线治疗的方案优化，试图在“阿替利珠单抗+贝伐珠单抗”这一标准双药方案基础上，加入抗TIGIT药物tiragolumab形成三联疗法以提升疗效——这一探索方向曾因Ib/II期MORPHEUS-liver研究的积极结果备受期待。然而，IMbrave152全球III期研究的最终结果却带来了“阴性”答案。

《肿瘤瞭望消化时讯》记者在ESMO大会现场就该研究对Richard S. Finn教授进行了专访。在对话中，Richard S. Finn教授分享了研究的关键数据，同时进一步梳理了当前晚期肝癌的标准治疗格局，并分享了本次ESMO大会上值得关注的其他重磅研究。我们对专访关键内容进行了整理，以飨读者。

肿瘤瞭望消化时讯

✓恭喜您的研究入选本届ESMO大会LBA，能否请您简单介绍一下该研究？

Richard S. Finn教授 ：我是来自加州大学洛杉矶分校大卫格芬医学院的Richard S. Finn博士，担任医学系及血液肿瘤科的教授。我此次参加2025年ESMO大会，展示了IMbrave152研究的数据——该研究评估了tirugolamab联合阿替利珠单抗与贝伐珠单抗的三联疗法，对比阿替利珠单抗+贝伐珠单抗+安慰剂作为晚期肝癌一线治疗的疗效。

本研究的理论基础源于TIGIT是一种关键的抑制性免疫检查点，与多种癌症的发生发展密切相关。Tiragolumab是一种抗TIGIT单克隆抗体，可与阿替利珠单抗等免疫治疗药物协同作用，而IMbrave150研究方案阿替利珠单抗+贝伐珠单抗已确立为晚期肝癌的标准治疗方案。此前，我们已经开展了一项Ib/II期MORPHEUS-liver研究，将tiragolumab与阿替利珠单抗+贝伐珠单抗联用，旨在通过双重免疫检查点抑制联合血管内皮生长因子（VEGF）抗体来改善疗效。在MORPHEUS-liver研究中，我们观察到客观缓解率（ORR）较阿替利珠单抗+贝伐珠单抗的历史数据显著提升（约42%），无进展生存期（PFS）达11个月左右。

在本次全球大型双盲安慰剂对照的IMbrave152研究中，我们原本希望能验证并进一步改善无进展生存期（主要终点）和总生存期。然而，研究结果未能复现MORPHEUS-liver Ib/II期研究中tiragolumab所带来的获益。尽管如此，我们证实了阿替利珠单抗+贝伐珠单抗在本研究中的表现与五年前IMbrave150研究一样出色——在12.5个月的中位随访中，ORR约为26%~27%，PFS约8个月，与三联疗法组相近，且与IMbrave150的历史数据高度一致。安全性方面同样表现良好：免疫相关不良事件需激素治疗的比例低，高级别出血事件发生率低；不过tiragolumab的加入确实增加了输注反应、瘙痒和皮疹的发生率。

遗憾的是，本研究未达到无进展生存期这一主要终点。因此，目前晚期肝癌的标准治疗方案仍将维持为阿替利珠单抗+贝伐珠单抗。

Prof. Richard S. Finn：Thank you sincerely for the opportunity to speak. I am Dr. Richard Finn from the David Geffen School of Medicine at UCLA, serving as a professor in the Department of Medicine and the Division of Hematology-Oncology. We are gathered here at the ESMO 2025 Congress, where we presented findings from the IMbrave152 study—a randomized trial evaluating the triplet therapy of tiragolumab (an anti-TIGIT antibody) combined with atezolizumab and bevacizumab versus the standard combination of atezolizumab, Bevacizumab, and placebo for the first-line treatment of advanced hepatocellular carcinoma (HCC).

The scientific rationale for this study stems from the recognition that TIGIT represents another immunoregulatory checkpoint pathway. Building on the IMbrave150 trial, which established atezolizumab plus bevacizumab (Atezo+Bev) as the standard of care for advanced HCC, we previously conducted the Phase Ib/II MORPHEUS study to explore whether dual immune checkpoint inhibition (targeting PD-L1 and TIGIT) in tandem with VEGF inhibition could enhance clinical outcomes. In that trial, the addition of a TIGIT inhibitor to Atezo+Bev demonstrated encouraging improvements in objective response rate (ORR ≈42%) and progression-free survival (PFS ≈11 months) compared to historical Atezo+Bev data.

For IMbrave152—a large-scale, double-blind, placebo-controlled global trial—our primary objective was to validate these Phase Ib/II findings and demonstrate improvements in PFS (the primary endpoint) and overall survival (OS). Unfortunately, this trial did not replicate the efficacy benefits observed with tiragolumab in the MORPHEUS study. Nevertheless, we confirmed that Atezo+Bev maintains robust efficacy in this study, mirroring its performance in the original IMbrave150 trial from five years ago. With a median follow-up of 12.5 months, the ORR was approximately 26%-27%, and the median PFS was 8 months—comparable between the triplet and control arms, and consistent with IMbrave150 outcomes.

Safety profiles remained manageable across arms, with low rates of steroid-requiring immune-related adverse events and grade ≥3 bleeding. Notably, the triplet arm showed increased incidences of infusion reactions, pruritus, and rash.

Regrettably, IMbrave152 did not meet its primary endpoint of improving PFS. Consequently, Atezo+Bev continues to be the established standard of care for first-line advanced HCC, pending further advances in therapeutic strategies.

肿瘤瞭望消化时讯

✓当前晚期肝癌的标准治疗方案有哪些？IMbrave152研究给我们带来了哪些临床启示？

Richard S. Finn教授 ：当前晚期肝癌的标准治疗方案是免疫检查点双药联合疗法，包括阿替利珠单抗+贝伐珠单抗（Atezo+Bev）、替雷利珠单抗+贝伐珠单抗、伊匹木单抗+纳武利尤单抗、度伐利尤单抗+曲美木单抗，以及中国常用的瑞戈非尼+卡瑞利珠单抗等组合。根据IMbrave152研究结果，从双药升级为三药方案并未带来实质性改善，因此现有标准治疗格局并未因此改变。

但是，我们通过这项五年后开展的双盲安慰剂对照研究进一步证实了Atezo+Bev作为一线方案的可靠性——特别是在纳入高风险患者群体（如门静脉主干侵犯和VP4分期患者）的情况下，这类患者常被其他III期研究排除。研究显示，Atezo+Bev在此类患者中仍保持了高客观缓解率、持久缓解持续时间、长无进展生存期，与关键性IMbrave150研究数据高度一致，且毒性特征依然良好。因此，尽管我们仍需探索超越Atezo+Bev的更优方案，但目前它仍是不可动摇的一线标准治疗选择。

Prof. Richard S. Finn：As you know, the current standard of care for advanced hepatocellular carcinoma involves immune checkpoint inhibitor combinations. These include Atezolizumab + Bevacizumab (Atezo+Bev), Tislelizumab + Bevacizumab, Ipilimumab + Nivolumab, Durvalumab + Tremelimumab, and in China, Regorafenib + Camrelizumab. We now have multiple therapeutic options for these patients. However, the results from the IMbrave152 study do not fundamentally alter this landscape, as moving from doublet to triplet therapy did not yield significant improvements.

What this five-year follow-up, double-blind, placebo-controlled study did confirm—particularly for high-risk patients with main portal vein invasion or VP4 staging, who are often underrepresented in Phase 3 trials—is that Atezo+Bev maintains exceptional efficacy. It demonstrated high objective response rates, durable responses, and prolonged progression-free survival, mirroring the pivotal IMbrave150 findings. Importantly, it retained a favorable safety profile with manageable toxicity.

While we must continue to seek advancements beyond Atezo+Bev, this regimen remains the established standard of care for first-line treatment of advanced HCC.

肿瘤瞭望消化时讯

✓本次ESMO大会中，您比较关注的研究有哪些？

Richard S. Finn教授 ：2025年ESMO大会呈现了多项极具价值的研究成果。其中CARES研究探讨了可切除肝癌患者采用瑞戈非尼+卡瑞利珠单抗新辅助治疗后行根治性手术，对比单纯手术方案的疗效差异——结果显示联合方案显著延长了患者的无复发生存期（即肿瘤复发速度减缓）。

另一项TALENTOP研究聚焦于血管侵犯等高风险不可切除肝癌患者群体。该研究设计为：患者先接受4周期Atezo+Bev治疗，病情稳定或部分缓解者随后被随机分配至单纯手术组或手术联合Atezo+Bev维持治疗组。结果显示，手术联合维持治疗组患者的疾病进展事件显著延迟。这一创新模式提示：通过术前Atezo+Bev治疗，可能筛选出即使处于临床晚期阶段仍能通过手术获益的患者群体。

此外，ABC-HCC研究作为一项研究者发起的试验，比较了Atezo+Bev与肝动脉栓塞化疗（TACE）在中期肝癌患者中的疗效。该研究以至治疗方案失败时间（TTFS）为主要终点，结果发现Atezo+Bev组表现优于单纯TACE组。这一发现颇具颠覆性意义——长期作为中晚期肝癌治疗支柱的TACE，在系统治疗药物不断革新的背景下，其绝对优势地位正面临挑战，系统治疗在中期肝癌中的应用合理性日益凸显。

本次会议的亮点远不止于此。当前肝癌领域正处于快速迭代期，大量早期临床研究正在探索新药开发，而如何优化现有药物的临床应用策略，仍是亟待解决的关键课题。

Prof. Richard S. Finn：The ESMO 2025 Congress featured several compelling studies in hepatocellular carcinoma. The CARES trial evaluated neoadjuvant regorafenib + camrelizumab followed by resection versus resection alone in resectable HCC, demonstrating a significant improvement in recurrence-free survival，or I should say, an increase in recurrence free survival patients did not recur as fast.

The TALENTOP study investigated high-risk, vascular-invasive HCC patients deemed unsuitable for upfront resection. After four cycles of Atezo+Bev, patients with stable disease or partial response were randomized to surgery alone or surgery plus adjuvant Atezo+Bev. This approach showed a marked delay in disease progression events in the adjuvant therapy arm, suggesting that preoperative Atezo+Bev may help identify patients with advanced-stage disease who could still benefit from surgical intervention.

The ABC-HCC trial, an investigator-initiated study, compared Atezo+Bev versus transarterial chemoembolization (TACE) in intermediate-stage HCC. With time to treatment failure as the primary endpoint, Atezo+Bev demonstrated superior efficacy to TACE monotherapy. This finding challenges the traditional paradigm where TACE has long been the cornerstone for intermediate HCC, as advancing systemic therapies now support medical treatment as a viable option in this population.

These studies underscore the dynamic landscape of HCC management. The field is crowded with early-phase developments, yet optimizing the use of existing agents remains a critical unmet need. As we continue to refine therapeutic strategies, the balance between systemic therapies and locoregional treatments will shape the future of HCC care.