ELCC现场直击丨Dr. Gentzler点评MARIPOSA-2：新数据进一步确认患者获益深度
美国弗吉尼亚大学医学院Ryan D. Gentzler教授在2024 ELCC会议上汇报了MARIPOSA-2试验疾病进展后结局（摘要3MO）。MARIPOSA-2试验在奥希替尼治疗进展的EGFR突变晚期NSCLC患者中开展，其研究数据对临床实践有何启示？《肿瘤瞭望》在布拉格现场邀请Dr. Gentzler予以解答。
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请简要介绍2024 ELCC发布的MARIPOSA-2试验的进展后分析结果。
Dr. Gentzler： 在MARIPOSA-2 III期临床试验中，与单独化疗相比，Amivantamab联合化疗显著改善了无进展生存期（PFS），该研究已在2023 ESMO会议上发表结果。2024 ELCC发布了其他次要终点的更新信息，包括TTD（至停止治疗的时间）、TTST（至后续治疗的时间）和PFS2（从随机开始至第二次疾病进展或死亡的时间）的探索性终点数据。
与单独化疗相比，化疗加用Amivantamab后，TTD（11.0 vs. 4.5个月；HR=0.37）、TTST（12.1 vs. 6.6个月；HR=0.42）和PFS2（13.9 vs. 11.3个月；HR=0.60）得到显著改善，并且进一步增加了患者在接受化疗+Amivantamab联合治疗时的临床获益深度。
我们研究了本试验中的安全性结局，并对血液学不良事件发生的时间进行了最新分析。我们确实注意到，Amivantamab联合化疗的血液学不良事件（中性粒细胞减少和血小板减少）发生率较高。这些血液学不良事件主要发生在化疗+Amivantamab的第一个周期。我们观察了在第2~4个周期、第5周期以及之后的血液学不良事件，单独化疗与化疗+Amivantamab方案的结果非常相似。
MARIPOSA-2试验的血液学毒性以及随时间发生的变化
Dr. Gentzler: The efficacy updates from the MARIPOSA-2 phase III clinical trial show that there was a significant improvement in progression-free survival with the amivantamab plus chemotherapy compared to chemotherapy alone. This was previously presented at ESMO 2023. The updates we have on other secondary endpoints included time to discontinuation, time to subsequent therapy, as well as an exploratory endpoint in PFS-2. These were all significantly improved with the addition of amivantamab to chemotherapy compared to chemotherapy alone, and further add to the depth of clinical benefit that patients experience when getting the combination of chemotherapy plus amivantamab. We also looked at safety outcomes in this trial, with an updated analysis looking at the timing of hematologic adverse events. We did note that with amivantamab and chemotherapy there are higher rates of hematologic adverse events - neutropenia and thrombocytopenia. These were mostly occurring in the first cycle of chemotherapy and amivantamab. We looked at cycle 2 through 4, as well as cycle 5 or later, and the results between chemotherapy alone versus chemotherapy plus amivantamab were very similar in terms of hematologic adverse events.
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MARIPOSA-2研究中的一些患者发生了严重不良事件（AE）。为了几个月的治疗获益而付出毒性增加的代价值得吗?
Dr. Gentzler： 我认为MARIPOSA-2所展示的数据表明，尽管盲法独立中央审查（BICR）评估的Amivantamab+化疗相比单用化疗仅改善了两个月的PFS（6.3 vs. 4.2个月；HR=0.48），但研究者评估的PFS在数值上更高（8.2 vs. 4.2个月；HR=0.41）。2024 ELCC发布的其他终点（TTD、TTST和PFS2）数据确实表明，根据RECIST标准评估的PFS长度可能不代表临床实践中的获益程度。患者能够在疾病进展后继续使用这些药物，并获得更长的潜在临床获益时间。当然，在使用Amivantamab联合方案时必须考虑到其不良事件。2024 ELCC发布的MARIPOSA-2安全性结果证明不良事件在治疗早期发生得更频繁。
MARIPOSA-2试验的PFS
PAPILLON研究（评估Amivantamab联合化疗vs单独化疗用于未经治疗的EGFR外显子20插入突变晚期或转移性NSCLC）的数据也在2024 ELCC发表，这项分析研究了血液学不良事件之外的其他不良事件，结果显示不良事件也有类似的模式，即主要在治疗的早期发生。我认为通过Amivantamab中断给药和减少给药，可以在不牺牲临床获益的情况下减轻副作用。当然，我们必须平衡疗效和不良事件，但如果对不良事件进行精细管理，我们可以既让患者获益，又适当地管理额外发生的不良事件。
Dr. Gentzler: I think the data we have shown demonstrate that although there is only two months improvement in progression-free survival by blinded independent review, investigator-assessed PFS was numerically higher. And these other endpoints of time to treatment discontinuation really demonstrate that our RECIST criteria for procession-free survival may not represent what is done in clinical practice. Patients are able to continue beyond progression and stay on these drugs for longer and get a much longer duration of potential clinical benefit. Certainly, that has to be balanced with the additional adverse events that occur. We were able to show that this occurs more frequently earlier on.
Data from the PAPILLON study that was also presented today looking at other adverse events besides hematological adverse events, showed a similar pattern where these are occurring early on. I think with dose interruptions and dose reductions, these side effects can be mitigated without sacrificing clinical benefits. Obviously, we have to balance the efficacy and adverse events, but I think if managed carefully, we can get both the benefit and appropriately manage the additional adverse events that occur.
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EGFR突变NSCLC的治疗模式正变得越来越复杂，例如，同一药物的不同联合方案可用于一线和二线治疗。我们如何更好地为患者选择一线和二线治疗方案？
Dr. Gentzler: EGFR突变肺癌患者的治疗排序正变得越来越复杂，有大量的治疗选择。如FLAURA2试验将化疗与奥希替尼联合用药；MARIPOSA试验采用Amivantamab联合拉泽替尼作为一线治疗药物；MARIPOSA-2试验获得Amivantamab联合化疗的二线治疗数据。
目前没有随机研究数据可提示哪种用药排序策略最好最合理。我认为可能未来会有进一步的研究数据可以帮助我们找到 生物标志物 来选择患者。对于那些可能不适合联合化疗治疗或EGFR高表达或发生血液学不良事件的患者，也许 疾病负荷 是衡量早期采用强化治疗还是降低强度的另一个因素。对于治疗方案的排序，需要针对个体患者进行定制，我们等待未来发布的数据来指导用药决策。
Dr. Gentzler: Sequencing of therapies for patients with EGFR-mutant lung cancer is becoming increasingly complex with a large number of options. We could combine chemotherapy with osimertinib as seen in the FLAURA2 trial; amivantamab plus lazertinib as an active frontline agent; and now we have data with second-line MARIPOSA-2 combining amivantamab with chemotherapy. We do not have randomized data to suggest which of these strategies is best in the appropriate sequences. I think there may be further data that can help with this in terms of biomarkers that could select for patients. Perhaps burden of disease is another factor where we think about intensifying therapy early compared to reduced intensity upfront for patients who may not be fit to handle chemotherapy combinations or more intense EGFR or hematologic adverse events. I think this really has to be customized on a patient-by-patient basis as we wait for further data to help guide us with these decisions.