|
ASCO GU 2021: Uncertainties in the Timing and Sequencing of Therapies for Metastatic Disease 转移性疾病治疗时机和顺序的不确定性 In a plenary presentation in the Navigating Uncertain Times in Muscle-Invasive and Advanced Bladder Cancer session at the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Dr. Apolo discussed uncertainties in the timing and sequence of therapies for patients with metastatic bladder cancer, emphasizing recent data, new approvals, and ongoing studies of emerging approaches. 2021年美国临床肿瘤学会泌尿生殖系统肿瘤研讨会（ASCO GU）上，在探索肌层浸润性和晚期膀胱癌待解决问题的全体会议报告中，Dr. Apolo讨论了转移性膀胱癌患者治疗的时间和顺序的不确定性，强调了最近的数据、新批准的疗法和正在进行的新兴方法的研究。 Considering patients with metastatic urothelial carcinoma, Dr. Apolo described her initial dichotomization on the basis of cisplatin-eligibility in order to select first-line therapy. For those who are cisplatin-eligible, combination chemotherapy regimens are the preferred approach. However, for those who are ineligible, carboplatin-based chemotherapy has been the standard approach. 考虑到转移性尿路上皮癌患者，Dr. Apolo介绍了她最初根据患者是否适合顺铂治疗来选择一线疗法的方法。对于适合接受顺铂治疗的患者，联合化疗方案是首选方法。然而，对于不适合顺铂治疗的患者，以卡铂为基础的化疗一直是标准方法。 Second-line treatment, until 2016 comprised single-agent chemotherapy. However, since then there has been the approval of five different checkpoint inhibitors in this disease space. At the same time, atezolizumab and pembrolizumab were approved in the first-line setting for patients who were cisplatin-ineligible. 截至2016年，二线治疗还包括单药化疗。然而，从那时起就有5种不同的检查点抑制剂在这个疾病领域获得批准。与此同时，阿特珠单抗和派姆单抗获批用于不适合接受顺铂治疗患者的一线治疗。 However, only pembrolizumab has phase III data supporting full FDA approval. 然而，只有派姆单抗拥有支持FDA完全批准的III期数据。 The nature next step is to consider the use of checkpoint inhibitors in the cisplatin-eligible patient population, either alone or in combination with chemotherapy. A number of clinical trials are assessing this question using a variety of different checkpoint inhibitors. 那么，下一步就是要考虑检查点抑制剂在适合顺铂治疗的患者中的应用（单药或者联合化疗）。许多临床试验正在使用各种不同的检查点抑制剂来评估这个问题。
The first available data was from IMvigor-130. First reported at ESMO 2019, this trial demonstrated improved overall survival for patients receiving atezolizumab plus chemotherapy compared to chemotherapy alone. However, atezolizumab monotherapy did not demonstrate benefit though the hazards were non-proportional with better outcomes in chemotherapy treated patients initially, and better outcomes in the atezolizumab group after 12 months. This cross-over effect was most pronounced in patients with low PD-L1 status. 第一个可用数据来自IMvigor-130。2019年欧洲肿瘤内科学会（ESMO）首次报告了这个试验，该试验证明，与单独化疗相比，接受阿特珠单抗+化疗的患者的总生存期更长。然而，尽管风险不成比例，最初化疗患者的结局更好，而12个月后阿特珠单抗组的结局更好，但是阿特珠单抗单药治疗并没有表现出获益。这种交叉效应在PD-L1低表达的患者中最为明显。 Subsequently, at ESMO 2020, the DANUBE study was reported assessing durvalumab with or without tremelimumab compared to chemotherapy. Durvalumab was not associated with a significant survival benefit compared to chemotherapy, with a hazard ratio of 0.89 (95% confidence interval 0.71 to 1.11) in the PD-L1 high population. 随后，2020年ESMO报告了DANUBE研究，该研究比较了度伐单抗（联合或不联合替西利姆单抗）与化疗。在PD-L1高表达人群中，度伐单抗组的生存获益并没有显著优于化疗组，风险比为0.89（95%置信区间，0.71-1.11）。 As with IMvigor130, there was crossover observed with chemotherapy-treated patients initially doing better. In the overall population, the combination IO approach did not demonstrate statistically significant benefits in overall survival compared to standard of care chemotherapy. Again, there was cross-over, this time around 8 months. 与IMvigor130研究一样，DANUBE研究也发现了最初化疗患者结局更好的交叉效应。在总体人群中，与标准治疗化疗相比，肿瘤免疫（IO）联合治疗在总生存期方面未显示出统计学显著获益。同样，总体人群中也发现了交叉效应，大约8个月后肿瘤免疫联合治疗组的结局更好。 At the same meeting, KEYNOTE-361 was presented, comparing pembrolizumab monotherapy, pembrolizumab plus chemotherapy and standard of care chemotherapy. While there were apparent improvements in overall survival in the ITT population with the use of combined pembrolizumab + chemotherapy versus chemotherapy, the study failed to reach its predefined significance threshold. 2020年ESMO还介绍了KEYNOTE-361研究，该研究对派姆单抗单药治疗、派姆单抗联合化疗和标准治疗化疗进行了比较。虽然在意向治疗分析（ITT）人群中，与化疗组相比，派姆单抗联合化疗组的的总生存期明显更长，但该研究未达到其预定义的显著性阈值。 In the pembrolizumab monotherapy versus chemotherapy comparisons, again, we saw evidence of the cross-over effect with better initial outcomes in patients receiving chemotherapy followed by better outcomes in the pembrolizumab group, with the crossing of the curves at 12 months. 在派姆单抗单药治疗与化疗的比较中，这项研究再次观察到交叉效应的证据，即最初接受化疗的患者结局更好，随后派姆单抗组结局更好，曲线在12个月时出现交叉。 The two remaining studies, CheckMate-091 and NILE, have completed enrollment and are awaiting read out. Dr. Apolo then emphasized that the available data provide a large amount of data regarding outcomes for the use of immunotherapy alone or in combination with chemotherapy in the first-line setting. 其余两项研究CheckMate-091和NILE已完成入组，正在等待公开报告。Dr. Apolo随后强调，现有数据提供了大量关于在一线治疗时选择单独使用免疫治疗或与化疗联合使用的结局数据。 Moving from the upfront setting, Dr. Apolo then discussed data from JAVELIN Bladder 100, presented at ASCO 2020, regarding the role of avelumab maintenance therapy following initial induction chemotherapy. This study, as previously reported, demonstrated a survival benefit associated with avelumab maintenance, compared to best supportive care with a hazard ratio of0.68 (95% confidence interval 0.56 to 0.86). 然后，Dr. Apolo从前期背景出发，讨论了在2020年美国临床肿瘤学会年会（ASCO）上展示的来源于JAVELIN Bladder 100的数据，该数据与初始诱导化疗后阿维单抗（avelumab）维持治疗作用有关。如前所述，本研究证明了与最佳支持治疗相比，阿维单抗维持治疗与生存获益有关，风险比为0.68（95%置信区间0.56-0.86）。 As a result of these data, avelumab was approved by the FDA. Interestingly, Dr. Apolo noted that approximately 50% of patients in the best supportive care arm of the trial did not receive checkpoint inhibitors at the time of disease progression. 由于这些数据，阿维单抗获得了FDA的批准。有趣的是，Dr. Apolo指出，试验最佳支持治疗组中约50%的患者在疾病进展时未接受检查点抑制剂。 In the second line setting, Dr. Apolo highlighted new data regarding the use of targeted therapies, erdafitinib (in patients with FGFR2/3 mutations) and enfortumab. These agents were approved by the FDA in the platinum refractory setting as of April and December 2019, respectively. At ASCO-GU 2020, the EV-103 study was reported examining the combination of enfortunab vendotin plus pembrolizumab in the first line treatment of patients with cisplatin ineligible disease, demonstrating responses independent of PD-L1 status. 在二线治疗中，Dr. Apolo强调了关于靶向治疗药物厄达替尼（在FGFR2/3突变患者中）和恩诺单抗（Enfortunab vendotin）使用的最新数据。FDA分别于2019年4月和12月批准这些药物用于治疗铂类药物难治性疾病。2020年ASCO-GU报道了EV-103研究，该研究在不适合顺铂治疗的患者中调查了恩诺单抗联合派姆单抗一线疗法，证明缓解与PD-L1状态无关。 Yet another promising targeted therapy is Sacituzumab govitecan, another antibody-drug conjugate. The results of TROPHY-01 were reported at ESMO 2020 demonstrating favourable outcomes with its use among patients with prior platinum-based and checkpoint inhibitor therapy. These data led to accelerated approval as of April 2020 with a confirmatory phase III trial (TROPiCS-04) currently underway. 另一种有前景的靶向治疗药物是赛妥珠单抗（Sacituzumab govitecan），其也是抗体-药物偶联物。2020年ESMO报告了TROPHY-01的研究结果，证明了对于既往接受过铂类药物和检查点抑制剂治疗的患者，赛妥珠单抗治疗的结局有利。这些数据加速了试验的批准（截止至2020年4月），目前一项确证性III期试验（TROPiCS-04）正在进行。 Dr. Apolo then highlighted many ongoing studies ongoing in this space. 然后，Dr. Apolo对这个领域正在进行的许多研究进行了重点介绍。
Returning to the question of sequencing therapies in metastatic urothelial carcinoma, Dr. Apolo emphasized that platinum-based chemotherapy should be the standard first line approach with immunotherapy considered in select cisplatin-ineligible patients particularly with high PD-L1 tumors. Maintenance immunotherapy is, in her view, a reasonable approach for those who have a good initial response. 关于转移性尿路上皮癌的治疗顺序，Dr. Apolo强调，在某些不适合接受顺铂治疗的患者，特别是PD-L1高表达的患者中，含铂化疗应该是与免疫治疗进行联合的标准一线方法。在她看来，维持免疫治疗对于那些初始反应良好的患者是一种合理的方法。 Alternatively, immunotherapy is an appropriate second line treatment at the time of progression. Additionally, for patients with actionable mutations, targeted therapy with enfortumab or erdafitinib are alternatives in the second line setting. These treatments are also options in the third line setting while fourth line treatments are available. However, clinicians should always consider clinical trials. 或者，在疾病进展时，免疫治疗是合适的二线治疗。此外，对于携带可诉性突变的患者，恩诺单抗或厄达替尼靶向治疗是其他可选择的二线疗法。这些治疗方法也是三线治疗的选择，而四线治疗也可以使用。然而，临床医生还是应该始终考虑临床试验。
Presented by: Andrea B. Apolo, MD, Investigator Genitourinary Malignancies Branch NIH Lasker Clinical Research Scholar Head, Bladder Cancer Section, Center for Cancer Research National Cancer Institute, Bethesda, MD Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Contact: @WallisCJD on Twitter during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021 |
|
|
