编者按：尽管基因组学、蛋白质组学和分子肿瘤学取得了重大进展，但许多新型抗癌药物仍因疗效有限或毒性问题在研发阶段失败。在2025第九届药物性肝损伤国际论坛上，本刊特邀意大利罗马生物医学大学Bruno Vincenzi教授就转化医学中的瓶颈、新型药物的肝毒性，以及早期临床试验中改善安全性评估的策略进行了深入探讨。

《国际肝病》

近年来，尽管基因组学和蛋白质组学取得了进展，但许多抗癌药物仍因疗效不足或毒性问题失败。在您看来，当前转化医学中最关键的瓶颈是什么？类器官、人工智能或虚拟临床试验能否帮助改善安全性和疗效的早期预测？

Bruno Vincenzi教授：感谢您提出这个非常重要的问题。抗癌药物研发的主要瓶颈之一在于肿瘤的生物学异质性。即便我们自认为对肿瘤生物学已有深入了解，也仍难以完全捕捉患者间和患者体内的变异。例如，《新英格兰医学杂志》一篇关于肾细胞癌的重要论文显示，同一患者不同转移部位的肿瘤生物学特征可能存在显著差异。这意味着，当一处转移病灶对治疗产生应答时，另一器官的病灶可能因独特的生物学特性而进展。这种复杂性是新型抗癌药物失败率高的主要原因之一。

类器官和人工智能等新兴工具确实能通过加速临床前评估支持药物研发，但它们无法完全替代传统的人体临床试验。过度依赖这些技术可能会低估某些毒性风险，尤其是罕见或迟发性不良反应。对许多新型药物类别而言，毒性仍是重大障碍。例如，对于抗体偶联药物（ADCs），我们逐渐深入认识到监测肺毒性的重要性，如间质性肺病，这类毒性可能大大限制药物更广泛的临床应用。尽管 ADCs代表了肿瘤学领域的突破性进展，但其毒性特征仍带来了显著的临床挑战。

Q1: In recent years, despite advances in genomics and proteomics, many anticancer drugs still fail due to insufficient efficacy or toxicity concerns. In your view, what are the most critical bottlenecks in current translational medicine? Could organoids, AI, or virtual clinical trials help improve early prediction of safety and efficacy?

Prof. Bruno Vincenzi: Thank you for this very important question. One of the primary bottlenecks in anticancer drug development lies in the biological heterogeneity of tumors. Even when we believe we have substantial knowledge about tumor biology, we still struggle to fully capture interpatient and intrapatient variability. For example, we have data from a notable New England Journal of Medicine paper on renal cell carcinoma demonstrating that tumor biology can differ significantly across metastatic sites within the same patient. This means that while one metastatic lesion may respond to treatment, another lesion in a different organ may progress due to distinct biological characteristics. This complexity is a major factor behind the high failure rate of new anticancer drugs.

Emerging tools such as organoids and artificial intelligence can indeed support drug development by accelerating preclinical evaluation. However, they cannot fully substitute for conventional clinical trials in humans. Over-reliance on such technologies may risk underestimating certain toxicities, particularly rare or delayed-onset adverse events. For many novel drug classes, toxicity remains a significant barrier. For example, with antibody-drug conjugates (ADCs), we are increasingly recognizing the importance of monitoring for pulmonary toxicities, such as interstitial lung disease, which can substantially limit the broader clinical use of these agents. While ADCs represent a transformative advancement in oncology, their toxicity profiles still pose meaningful clinical challenges.

《国际肝病》

ADCs和双特异性抗体等新型抗癌药物的肝毒性特征与传统化疗差异显著，常表现为混合型肝损伤或迟发性胆汁淤积。在临床实践中，我们应如何平衡治疗获益与肝损伤风险？

Bruno Vincenzi教授：正如我之前提到的，ADCs代表了在多种肿瘤类型治疗上的重大进步。这类药物展现出的疗效是其得以迅速被临床应用的驱动因素。然而，新兴的不良反应，尤其是肝毒性，正日益受到关注，需要谨慎管理。

在权衡治疗获益与毒性风险时，“天平”仍然明显倾向于这些创新药物，因为它们具有显著的临床活性。以 HER2 阳性乳腺癌为例：过去，治疗选择主要局限于曲妥珠单抗、帕妥珠单抗等针对HER2 高表达患者的 HER2 靶向单克隆抗体。如今，得益于新型 ADCs，我们能够治疗更广泛的患者群体，包括HER2 低表达的患者。这种治疗范围的扩大显著改善了乳腺癌患者的预后，并有望在其他多种肿瘤类型中得到复制。

尽管如此，肝毒性的全貌仍未被完全明确。随着更多数据的涌现，特别是来自真实世界的数据，我们需要优化管理策略，在确保安全性的同时，最大限度地保留药物的治疗获益。

Q2: The hepatotoxicity profiles of novel anticancer agents such as ADCs and bispecific antibodies differ markedly from traditional chemotherapy, often presenting as mixed-pattern liver injury or delayed-onset cholestasis. In clinical practice, how should we balance therapeutic efficacy with the risk of liver injury?

Prof. Bruno Vincenzi: As I previously mentioned, ADCs represent a major therapeutic advancement across multiple tumor types. The demonstrated efficacy of these agents is the driving force behind their rapid adoption. However, emerging adverse events—particularly hepatotoxicity—are increasingly recognized and require careful management.

When weighing therapeutic benefit against toxicity, the balance remains strongly in favor of these innovative agents due to their profound clinical activity. Take HER2-positive breast cancer as an example: not long ago, treatment options were largely limited to trastuzumab, pertuzumab, and other HER2-targeted monoclonal antibodies in patients with high HER2 expression. Today, we are able to treat a broader patient population, including those with low HER2 expression ("HER2-low"), thanks to newer ADCs. This expansion has significantly improved outcomes for breast cancer patients and is likely to be replicated across multiple other tumor types.

Nonetheless, the full spectrum of hepatotoxicity remains incompletely characterized, and as more data emerge, particularly from real-world practice, we will need to refine our management strategies to optimize safety while preserving the therapeutic benefit of these drugs.

《国际肝病》

如何将肝损伤的临床数据更具体地整合到早期药物研发中，以改善安全性评估？

Bruno Vincenzi教授：遗憾的是，药物性肝损伤（DILI）在临床试验中仍然存在报告不足和重视不够的问题。大多数早期研究主要关注血液学毒性、胃肠道副作用、肺部并发症等更易观察到的不良反应。与此同时，肝酶升高的记录虽然常见，但往往分析不足或未给予足够优先考虑。

这是一个被忽视的机会。从历史上看，我们往往在药物上市后，随着真实世界数据的积累，才充分认识到肝毒性的全部临床影响。为解决这一问题，必须从药物研发的最早期阶段（尤其是 I 期和 II 期试验）开始，更加严格地整合肝脏安全性监测。

结合前瞻性临床试验数据与真实世界证据的综合方法，可能是提升我们对肝毒性风险的理解、加强早期监测，并制定有效的肝脏相关不良反应管理方案的最有效途径。

Q3: How can clinical data on liver injury be more specifically integrated into early drug development to improve safety evaluation?

Prof. Bruno Vincenzi: Unfortunately, drug-induced liver injury (DILI) remains underreported and underemphasized in clinical trials. Most early-phase studies primarily focus on hematologic toxicities, gastrointestinal side effects, pulmonary complications, and other more visible adverse events. Meanwhile, liver enzyme elevations are often documented but not sufficiently analyzed or prioritized.

This represents a missed opportunity. Historically, we have often recognized the full clinical impact of hepatotoxicity only after a drug reaches the market and real-world data begin to accumulate. To address this, it is essential to integrate liver safety monitoring more rigorously from the earliest stages of drug development—specifically during phase I and phase II trials.

A combined approach utilizing both prospective clinical trial data and real-world evidence is likely the most effective pathway for improving our understanding of hepatotoxicity risk, enhancing early detection, and developing effective management protocols for liver-related adverse events.

（来源：《国际肝病》编辑部）

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