Diphtheria-tetanus vaccine(Finlay Institute)

编者按：III期EMERALD-1研究已经证实，对于不可切除的中晚期肝细胞癌患者，经度伐利尤单抗+贝伐珠单抗+TACE可相较于单独TACE显著改善患者无进展生存期（PFS）。在近日举行的2024年国际肝癌协会（ILCA）大会上我国香港中文大学医学院Stephen L. Chan（陈林）教授报告了EMERALD-1研究根据治疗时期和基线肝功能的安全性和疗效分析，并在接受《肿瘤瞭望》联合《国际肝病》的采访中分享这些最新分析数据如下。 研究简介 EMERALD-1研究根据治疗时期和基线肝功能的分析：一项关于度伐利尤单抗联合/不联合贝伐珠单抗与经导管动脉化疗栓塞术（TACE）治疗适合栓塞的不可切除肝细胞癌（uHCC）患者的III期随机、安慰剂对照研究（摘要号：O-13） 研究方法 III期EMERALD-1研究（NCT03778957）的主要终点已达到：与安慰剂（PBO）+经导管动脉化疗栓塞术（TACE）相比，度伐利尤单抗（D）+贝伐珠单抗（B）+TACE在不可切除肝细胞癌（uHCC）患者中显著改善了无进展生存期（PFS）（15.0个月vs 8.2个月；HR 0.77；95%CI，0.61-0.98；P=0.032[阈值0.0435]），且安全性可控。EMERALD-1方案分为两个阶段进行，即D-TACE（D-T）期和D-B期。在uHCC患者中，可发生肝功能损伤，并可能因TACE而恶化。因此，了解D与TACE以及B联合使用的安全性至关重要。本事后分析评估了D+B+TACE和PBO+TACE在两个研究治疗期间的安全性，并按肝功能评估了其疗效。 研究结果 IP（研究药物）治疗组中，按治疗周期划分的暴露持续时间（DoE）如表所示；在D-B期间，D+B+TACE组的度伐利尤单抗或其安慰剂的中位DoE最长。在IP治疗组的D+B+TACE和PBO+TACE组中，D-T期间分别有139例（72.0%）和148例（74.0%）患者、D-B期间分别有147例（76.2%）和132例（66.0%）患者报告了不良事件（AEs）（如表所示）。 在D-T期间，分别有56例（29.0%）和41例（20.5%）患者的AEs可能与研究治疗相关；在D-B期间，分别有114例（59.1%）和69例（34.5%）患者的AEs可能与研究治疗相关。在D-T期间，分别有90例（46.6%）和85例（42.5%）患者的AEs由TACE引发；在D-B期间，分别有18例（9.3%）和21例（10.5%）患者的AEs由TACE引发。 在两个治疗周期中，各治疗组导致死亡结局的AEs发生率均较低，且在D-B期间未报告D+B+TACE组有此类AEs（如表所示）。无论基线ALBI分级如何，各治疗组的基线特征大体一致。在意向治疗（ITT）人群中，无论基线ALBI分级如何，与PBO+TACE相比，D+B+TACE在PFS和TTP方面均有所数值上的改善（如表所示）。 研究结论 在D-T和D-B期间，D+B+TACE的安全性是可管理的，这与个别药物和基础疾病相一致。此外，无论基线ALBI分级如何，与PBO+TACE相比，D+B+TACE在疗效结果方面均观察到数值上的改善。这进一步支持了D+B+TACE作为uHCC的潜在治疗新标准。 研究者说 01 《肿瘤瞭望》：您在报告中提到了针对巴塞罗那肝癌临床分期（BCLC）B期肝癌患者，将免疫检查点抑制剂（ICIs）联合经动脉栓塞化疗术（TACE）的策略。这种联合策略是基于怎样的科学假设或先前的研究成果？ Stephen L. Chan教授：该假设是基于系统治疗（例如免疫治疗药物度伐利尤单抗和贝伐珠单抗）与TACE相联合，能够产生与局部区域治疗的协同效应，从而改善患者预后。这种联合疗法可能激活免疫系统，同时直接将局部治疗作用于肿瘤，有可能增强整体治疗效果。 Oncology Frontier: In your presentation, you mentioned the strategy of combining immune checkpoint inhibitors (ICIs) with transarterial treatments like TACE for BCLC Stage B liver cancer patients. What scientific hypothesis or prior research findings is this combination strategy based on? Dr. Chan: The hypothesis is that the use of systemic therapy—including durvalumab, which is an immunotherapy, and bevacizumab—when combined with TACE, could create a synergistic effect with locoregional therapy and improve patient outcomes. This combination may activate the immune system while also delivering localized treatment directly to the tumor, potentially enhancing the overall treatment effect. 02 《肿瘤瞭望》：与单一疗法相比，这种联合疗法在提高患者生存率和延长无进展生存期方面有哪些具体优势或改进？ Stephen L. Chan教授：这种联合疗法在生存率方面优于单一治疗。与安慰剂加TACE相比，试验组（度伐利尤单抗、贝伐珠单抗和TACE）在无进展生存期方面表现出显著改善。此外，该组合还与较高的应答率和合理的副作用谱相关，证实了基于免疫治疗的系统疗法可以与TACE协同作用，改善肝细胞癌（HCC）患者预后的假设。 Oncology Frontier: Compared to single therapies, what are the specific advantages or improvements of this combination approach in terms of improving patient survival rates and extending progression-free survival? Dr. Chan: This combination treatment is better than single treatments in terms of survival rate. When compared to placebo plus TACE, the experimental arm—durvalumab, bevacizumab, and TACE—demonstrated a significant improvement in progression-free survival. It was also associated with a higher response rate and a reasonable side effect profile, confirming the hypothesis that this IO-based systemic therapy can synergize with TACE to improve outcomes for patients with HCC. 03 《肿瘤瞭望》：在EMERALD-1研究中，度伐利尤单抗、贝伐珠单抗和TACE的治疗被分为两个阶段：D-TACE（D-T）阶段和D-B（度伐利尤单抗和贝伐珠单抗）阶段。您能否详细介绍一下这两个不同阶段中该方案的安全性特征？ Stephen L. Chan教授：在EMERALD-1研究中，第一阶段涉及16周的TACE联合度伐利尤单抗治疗。第二阶段，即维持治疗或系统治疗阶段，仅涉及度伐利尤单抗和贝伐珠单抗。我们评估了两个阶段的安全性和不良事件。在16周的TACE阶段，试验组和对照组在不良事件方面没有显著差异。然而，在系统治疗阶段，我们观察到试验组中3/4级不良事件的发生率略高，但没有发生与治疗相关的死亡。这种不良事件略有增加可能是由于度伐利尤单抗和贝伐珠单抗组的治疗持续时间比安慰剂组更长。总体而言，我们没有观察到任何显著的安全信号，且不良事件谱符合预期。 Oncology Frontier: In the EMERALD-1 study, the treatment with durvalumab, bevacizumab, and TACE was divided into two treatment phases: the D-TACE (D-T) phase and the D-B (durvalumab and bevacizumab) phase. Could you elaborate on the safety profile of this regimen during these two distinct phases? Dr. Chan: In the EMERALD-1 study, the first phase involves 16 weeks of TACE combined with durvalumab. The second phase, known as the maintenance or systemic therapy phase, involves only durvalumab and bevacizumab. We assessed safety and adverse events across both phases. During the 16-week TACE phase, there was no significant difference in adverse events between the experimental and control arms. In the systemic therapy phase, however, we observed a slightly higher rate of Grade 3/4 adverse events in the experimental arm, though there were no treatment-related deaths. This slight increase in adverse events may be attributed to the longer duration of treatment in the durvalumab and bevacizumab arm compared to the placebo arm. Overall, we did not observe any significant safety signals, and the side effect profile was consistent with expectations. 04 《肿瘤瞭望》：研究中提到，无论基线白蛋白-胆红素（ALBI）分级如何，D+B+TACE组与PBO+TACE组相比，在无进展生存期（PFS）和至疾病进展时间（TTP）方面均表现出数值上的改善。您认为基线肝功能状态如何具体影响度伐利尤单抗、贝伐珠单抗和TACE联合疗法的疗效？这一发现对临床实践中的患者选择和治疗调整有何指导意义？ Stephen L. Chan教授：在我们的探索性分析中，我们评估了不同基线肝功能状态（特别是ALBI 1级和2级）患者中度伐利尤单抗、贝伐珠单抗和TACE联合疗法的疗效。对于这两个亚组的患者，与安慰剂组相比，试验组在无进展生存期（PFS）和至疾病进展时间（TTP）方面均有所改善，且风险比获益相似。这表明，无论基线肝功能如何，患者都能从该联合疗法中获益。这一发现强调了该治疗的广泛适用性，支持其在不同肝功能状态下的使用，并帮助临床医生做出更具包容性的治疗决策。 Oncology Frontier: The study abstract mentions that, regardless of baseline ALBI (albumin-bilirubin) grade, the D+B+TACE group showed numerical improvements in both progression-free survival (PFS) and time-to-progression (TTP) compared to the PBO+TACE group. How do you think baseline liver function status specifically impacts the efficacy of the durvalumab, bevacizumab, and TACE combination therapy? What guidance does this finding offer for patient selection and treatment adjustments in clinical practice? Dr. Chan: In our exploratory analysis, we evaluated the performance of the combination therapy—durvalumab, bevacizumab, and TACE—in patients with different baseline liver function statuses, specifically ALBI Grades 1 and 2. For both groups, we saw improvements in PFS and TTP in the experimental arm compared to the placebo arm, with similar hazard ratios. This suggests that patients derive benefit from the combination therapy regardless of their baseline liver function. This finding underscores the broad applicability of this treatment, supporting its use across different liver function statuses and helping clinicians make more inclusive treatment decisions. 05 《肿瘤瞭望》：基于EMERALD-1研究的结果，您对度伐利尤单抗、贝伐珠单抗和TACE联合作为不可切除肝细胞癌潜在新标准疗法的长期应用前景有何看法？还需要哪些进一步研究来确认其疗效和安全性，并探索其在更广泛患者群体中的潜力？ Stephen L. Chan教授：我认为EMERALD-1研究带来了几个关键信息。首先，这是一项积极的研究，显示出无进展生存期、至疾病进展时间和应答率的改善，同时不良事件可控。这些结果支持了该联合疗法在临床实践中的应用。虽然系统治疗传统上用于晚期肝癌，但我们看到了其在中期肝细胞癌中应用的可能性，提供了一种更积极的治疗选择。这种方法甚至可能使一些患者在未来能够接受手术治疗。未来的研究应侧重于在更大的患者队列中进一步验证这些发现，并探索将该联合疗法纳入更早期肝细胞癌治疗的可能性。 Oncology Frontier: Based on the results of the EMERALD-1 study, what are your thoughts on the long-term application prospects of the durvalumab, bevacizumab, and TACE combination as a potential new standard treatment for unresectable HCC? What further research is needed to confirm its efficacy and safety, and to explore its potential for a broader patient population? Dr. Chan: I think the EMERALD-1 study brings several key messages. First of all, it’s a positive study, showing improvement in progression-free survival, time-to-progression, and response rates, all with a reasonable toxicity profile. These results support the use of this combination therapy in clinical practice. While systemic therapy is traditionally used in advanced settings, we see potential for its application in intermediate-stage HCC as well, offering a more aggressive treatment option. This approach could even make some patients eligible for surgical intervention down the line. Future research should focus on further validating these findings in larger patient cohorts and exploring the possibility of integrating this combination therapy into earlier stages of HCC treatment. （来源：《肿瘤瞭望》编辑部） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。