编者按：CheckMate 274研究是首个尿路上皮癌辅助免疫治疗领域获得阳性结果的3期临床试验，既往报告纳武利尤单抗辅助治疗可显著改善肌层浸润尿路上皮癌（MIBC）患者的无病生存期（DFS）。在近日举行的2024年欧洲泌尿外科协会（EAU）年会上，一场题为“改变膀胱癌游戏规则”的主题会议引起参会者关注。来自美国纽约西奈山伊坎医学院、Tisch癌症研究所的Matthew Galsky教授首次报告了CheckMate 274研究的总生存期（OS）结果。《肿瘤瞭望》在现场采访了Matthew Galsky教授，解读CheckMate 274研究最新OS结果。

 

Matthew Galsky教授：尿路上皮癌尤其是肌层浸润性尿路上皮癌的辅助治疗，一直是该领域的重大挑战。这段研究旅程始于几十年来对辅助化疗的探索，尽管其很有希望，但却并未获得明确证据。随着免疫检查点抑制剂的问世，尿路上皮癌的辅助治疗发生了重要转变，目前已经有三项关键3期研究：IMvigor010、CheckMate 274和AMBASSADOR研究取得了一定成果。这些研究中，AMBASSADOR和CheckMate 274已经证实PD-1抑制剂辅助治疗在提高无病生存率方面的确切疗效，阐明了前进道路。目前我们正在整合这些研究并期望可以总结出新的治疗策略，这方面仍需继续努力。

Oncology Frontier：In recent years，research in the field of urothelial cancer has continued to make breakthroughs.Could you please introduce the progress of adjuvant treatment after UC surgery?

 

Dr.Matthew Galsky:Adjuvant treatment for urothelial cancer，specifically muscle-invasive urothelial cancer，has been a domain of significant challenges and extensive study.The journey began with decades of exploring adjuvant chemotherapy，which，despite its promise，left us without definitive data.A pivotal shift occurred with the advent of adjuvant immune checkpoint blockade，marked by three critical phase three studies:IMvigor010，CheckMate 274，and the AMBASSADOR study.These studies，particularly the AMBASSADOR and CheckMate 274，have illuminated the path forward by demonstrating the efficacy of adjuvant PD-1 blockade in enhancing disease-free survival.However，the journey of discovery continues as we strive to unify these findings into a coherent treatment paradigm.

 

Matthew Galsky教授：CheckMate 274研究深入探索了无病生存期（DFS），并将其作为研究的基石（主要终点），并发现高PD-L1表达患者的获益仅有细微增加。虽然总生存期（OS）是一个关键的次要终点，但其分析需要遵循分层设计，仍需等待最终结果。中期分析显示，尽管没有超过统计学显著性阈值，但展现了充满希望的前景，提示接受纳武利尤单抗辅助治疗的患者具有OS获益趋势。本次EAU大会进一步公布了该研究的OS结果，已表现出DFS转化为OS获益的潜力。

 

△本次EAU大会报道的CheckMate 274研究OS结果：中位随访36.1个月，无论是在ITT人群（69.5 vs.50.1个月；HR 0.76，95%CI 0.61-0.96）还是PD-L1表达≥1%人群（NR vs.NR；HR 0.56，95%CI 0.36-0.86），均提示纳武利尤单抗组具有获益趋势，预设的多个亚组也显示纳武利尤单抗组具有获益趋势。

 

Oncology Frontier：Previous results of the CheckMate 274 study showed that the DFS，NUTRFS，DMFS and PFS2 of patients with nivolumab adjuvant therapy were improved.So can this benefit be converted to OS?

Dr.Matthew Galsky:The CheckMate 274 study meticulously explored disease-free survival(DFS)as its cornerstone，encompassing a broad spectrum of patients and highlighting the nuanced benefits in those with high PD-L1 expression.While overall survival(OS)emerges as a critical secondary endpoint，its intricate analysis adheres to a hierarchical design，awaiting the fruition of event-driven outcomes.Interim analyses，despite not crossing the statistical significance threshold，have sketched a promising landscape，hinting at a favorable OS trend for patients undergoing adjuvant nivolumab therapy.This evolving narrative，first unveiled at the EAU meeting，offers a glimpse into the potential of converting DFS benefits into tangible OS advancements.

 

Matthew Galsky教授：在术后管理中，特别是对MIBC进行干预时，需要充分考虑疗效和生活质量之间的微妙平衡。由于可能存在既往的化疗和手术创伤等，因而需要仔细制定治疗计划。幸运的是，免疫检查点抑制剂的出现为辅助治疗的探索提供了一条有利的途径。但仍需保持警惕，特别是考虑到CheckMate 274研究中严重TRAE事件（≥3级TRAEs）发生率较高（18%）。同时，也需要积极进行患者教育、早期症状识别和及时报告等减轻免疫相关不良反应的策略。

 

△本次EAU大会报道的CheckMate 274研究：纳武利尤单抗组和安慰剂组分别有18%和7%的患者发生3级以上治疗相关不良事件（TRAEs），其中纳武利尤单抗组最常见的≥3级TRAEs为脂肪酶升高（5%）、淀粉酶升高（4%）

Oncology Frontier：How do you think the adverse events during immunotherapy such as PD-1/PD-L1 inhibitors should be managed to further improve patients’quality of life?

 

Dr.Matthew Galsky:The post-operative landscape，particularly after radical interventions for muscle-invasive urothelial cancer，presents a delicate balance between therapeutic efficacy and quality of life considerations.The intersection of prior chemotherapy and surgical trauma underscores the imperative of thoughtful treatment planning.Fortunately，the tolerability profile of immune checkpoint inhibitors offers a conducive avenue for exploration in the adjuvant setting.Nevertheless，vigilance is paramount，especially in light of the 18%incidence rate of significant adverse events in the CheckMate 274 study.Proactive patient education，early symptom identification，and prompt reporting emerge as pivotal strategies in mitigating immune-related adverse effects，ensuring a balanced approach to patient care.

 

Matthew Galsky教授：尿路上皮癌的治疗范围正在扩大，其中的两个重点是：开发细胞免疫治疗的潜力和深入研究癌症的内在生物学。对调节髓细胞、树突状细胞、巨噬细胞和NK细胞的探索有望释放新的抗肿瘤反应。与此同时，人们对将丰富的癌症生物学知识转化为靶向治疗的兴趣与日俱增。通过双管齐下，利用肿瘤微环境和癌症细胞特异性途径，有望开拓尿路上皮癌症精准医学的新时代，完善和丰富我们的治疗手段。

Oncology Frontier：You have been researching in the field of immunotherapy for many years.What other treatment strategies will improve the clinical practice in the field of urothelial cancer in the future?

 

Dr.Matthew Galsky:The horizon of urothelial cancer treatment is broadening，with a dual focus on exploiting the untapped potential of cellular immunity and delving deeper into the cancer’s intrinsic biology.The quest to modulate myeloid cells，dendritic cells，macrophages，and NK cells holds the promise of unlocking novel anti-tumor responses.Concurrently，there’s a burgeoning interest in translating the rich tapestry of bladder cancer biology into targeted therapies.This dual-pronged approach，leveraging both the tumor microenvironment and cancer cell-specific pathways，heralds a new era of precision medicine in urothelial cancer，promising to refine and enrich our therapeutic arsenal.