编者按：既往研究显示，在晚期肝癌靶免治疗中，近期疗效指标客观缓解率（ORR）与远期疗效指标总生存期（OS）相关^[1]。在近日举行的2024年国际肝癌协会（ILCA）大会上，日本近畿大学医学院附属医院的Masatoshi Kudo（工藤正俊）教授进一步对相关研究进行了探索性分析^[2]，讨论了DpR、DoR等疗效指标与OS生存获益的相关性，及其用于指导药物全身治疗联合局部治疗的价值。《肿瘤瞭望》联合《国际肝病》在大会现场采访了Kudo教授分享其研究成果如下。

 

 

Kudo教授：在评估应答时，有三个关键因素：ORR、DpR和DoR。ORR与OS的相关性已为人熟知。DpR衡量的是肿瘤退缩的程度，并被分为五个等级。A级代表退缩60%至100%，B级退缩30%至60%，C级退缩0%至30%，D级为无变化至增长20%，E级为增长超过20%，表示疾病进展（PD）。稳定疾病（SD）包括退缩低于30%至增长20%的情况。这种缓解深度的分类使我们能够评估肿瘤退缩的程度。

 

另一方面，DoR适用于缓解者——即肿瘤退缩超过30%的患者，并衡量这种缓解持续的时间。DpR和DoR共同构成了至关重要的指标，为我们提供了关于肿瘤退缩程度和肿瘤应答持久性的重要见解，这两者在评估治疗疗效时至关重要。

 

图1.DpR分层

 

Oncology Frontier:In your study，how were Depth of Response(DpR)and Duration of Response(DoR)specifically defined，and what is their significance in assessing the treatment efficacy for patients with unresectable HCC?

 

Dr.Kudo:There are three key factors in evaluating response:objective response，Depth of Response(DpR)，and Duration of Response(DoR).Objective response is well known for its correlation with OS.Depth of Response measures how much tumor shrinkage is achieved and is classified into five grades.Grade A represents shrinkage from 60%to 100%，Grade B from 30%to 60%，Grade C from 0%to 30%，Grade D ranges from no change to 20%growth，and Grade E includes growth beyond 20%，indicating progressive disease.Stable disease includes shrinkage below 30%up to 20%growth.This depth classification allows us to assess how significantly the tumor has shrunk.

 

Duration of Response，on the other hand，applies to responders—patients who experience over 30%tumor reduction—and measures how long this response is maintained.Together，DpR and DoR are crucial metrics，providing essential insights into both the degree of tumor shrinkage and the durability of the response，which are key in evaluating treatment efficacy.

 

Kudo教授：迄今为止，还没有确定的数据将DpR或DoR与OS联系起来。在这项研究中，我们专门针对靶免联合治疗的一线治疗分析了这些指标。鉴于一线和二线治疗中有多种药物可供选择，我们想要确定初始治疗的缓解深度和持续时间是否影响OS。

 

我们的研究结果显示，五个DpR等级与OS之间存在强烈的相关性，每个等级都提供了清晰的生存结局分层结果。这表明，使用一线药物实现显著的深度缓解对OS具有持久影响，即使患者接受后续治疗也是如此。此外，在稳定疾病中，那些肿瘤有所退缩的患者比那些没有退缩的患者表现出更好的生存率，这凸显了实现至少部分肿瘤退缩的重要性。如果无法获得显著退缩，增加局部治疗可能会改善生存结局。

 

图2.根据DpR分层的阶段性OS亚组分析

 

图3.根据DpR分层的阶段性PFS亚组分析

 

Oncology Frontier:Your findings indicate an association between DpR and DoR with Overall Survival(OS).Could you elaborate on the specific nature and strength of this association?

 

Dr.Kudo:Until now，there was no definitive data linking DpR or DoR with OS.In this study，we analyzed these metrics specifically for the first-line treatment.With many drugs available across first-and second-line therapies，we wanted to determine if depth and duration of response to the initial therapy impacted OS.

 

Our findings show a strong correlation between the five DpR grades and OS，with each grade providing a clear stratification of survival outcomes.This suggests that achieving significant depth with the first-line agent has a lasting influence on OS，even when patients receive subsequent therapies.Additionally，within stable disease，those with some tumor shrinkage showed better survival rates than those without any reduction，highlighting the importance of achieving at least partial shrinkage.If significant shrinkage is not obtained，adding local therapies could potentially improve survival outcomes.

 

Kudo教授：实现深度缓解似乎对生存率有积极影响。肿瘤显著退缩的患者通常预后更好，因此临床试验中深度缓解患者的比例可以指示治疗改善OS的潜力。对于未达到显著退缩的患者，策略可能需要包括局部区域治疗，以改变疾病的自然进程，从而可能同时提高生存率和生活质量。

 

这种方法也适用于肿瘤几乎无退缩或没有退缩的稳定疾病病例。在这种情况下，将局部治疗与系统治疗相结合可能有助于改善患者结局。根据肿瘤应答的质量（如深度和持续时间）来调整治疗，可能提供更个性化的方法，从而提高患者的生存率和生活质量。

 

Oncology Frontier:Based on your findings，how do you suggest future treatment strategies for patients with unresectable HCC to optimize their survival rates and quality of life?

 

Dr.Kudo:Achieving a deep response appears to have a favorable impact on survival.Patients with substantial tumor shrinkage often have better outcomes，so the percentage of deep responders in a clinical trial can indicate the potential of a treatment to improve OS.For patients who do not reach significant shrinkage，the strategy may need to include local regional therapies to alter the natural course of the disease，potentially enhancing both survival and quality of life.

 

This approach also applies to stable disease cases where there is minimal or no shrinkage.In such cases，combining local therapies with systemic treatments could help improve patient outcomes.Adapting treatment based on the quality of response，such as depth and duration，may provide a more personalized approach，leading to enhanced survival and quality of life.

 

Kudo教授：将DpR和DoR整合到临床试验中是一项挑战，因为这些指标代表的是达到的最佳应答，需要时间来充分评估。试验中的深度DpR率高通常表明该治疗药物具有改善OS的潜力。然而，评估应答的深度和持续时间需要时间，可能会延迟某些试验的结果。尽管如此，整合这些指标是值得的，因为它们有助于评估药物在实际临床实践中的有效性。

 

在患者层面，即使仅实现SD，也可以添加局部治疗来改善OS。这种根据肿瘤应答的深度和持续时间来调整治疗的个性化方法，使我们有可能改变不可切除HCC患者的疾病自然进程，并改善其生存结局。

 

Oncology Frontier:With the continuous advancement of immunotherapy and targeted therapies，how do you envision better integrating DpR and DoR as assessment metrics in future clinical trials to accelerate the development of new drugs and optimize personalized treatment plans for patients with unresectable HCC?

 

Dr.Kudo:Integrating DpR and DoR into clinical trials is challenging，as these metrics represent the best response achieved，which requires time to fully evaluate.A high rate of deep responses in a trial is usually indicative of a strong therapeutic agent with the potential to improve OS.However，assessing the depth and duration of response takes time and may delay certain trial outcomes.Despite this，integrating these metrics is worthwhile，as they help assess a drug’s effectiveness in real clinical settings.

 

At the patient level，even in cases where only stable disease is achieved，local therapy might be added to improve OS.This personalized approach of adjusting treatment based on depth and duration of response allows us to potentially change the natural course of the disease and improve survival outcomes for patients with unresectable HCC.

 

 

▌参考文献：

 

[1]Villejuif.IMbrave150:Exploratory analysis to examine the association between treatment response and overall survival(OS)in patients(pts)with unresectable hepatocellular carcinoma(HCC)treated with atezolizumab(atezo)+bevacizumab(bev)versus sorafenib(sor).2021 ASCO poster.

 

[2]Finn RS，Qin S，Ikeda M，et al.Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.N Engl J Med.2020;382(20):1894-1905.doi:10.1056/NEJMoa1915745

 

[3]Lim M，Muquith M，Miramontes B，et al.Surrogate and modified endpoints for immunotherapy in advanced hepatocellular carcinoma.Hepatology.2023;78(6):1755-1762.doi:10.1097/HEP.0000000000000494

 

Masatoshi Kudo（工藤正俊）教授

日本近畿大学医学院附属医院