ESMO ASIA 2024微专辑

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2024 ESMO ASIA年会的胸部肿瘤的优选口头报告专场主要针对胸腺肿瘤和非小细胞肺癌（NSCLC）这两种肿瘤，其中胸腺肿瘤方面包括阿替利珠单抗联合卡铂/紫杉醇用于转移性或复发性胸腺癌患者的II期MARBLE试验（摘要号LBA8）和Lucitanib（德立替尼，AL3810）用于晚期复发性或转移性胸腺癌二线或后续治疗的II期AL3810-202研究（摘要号625O）。

 

多中心、单组、开放标签II期MARBLE研究招募了48名患者，未接受化疗的转移性或复发性胸腺癌患者接受阿替利珠单抗联合卡铂/紫杉醇治疗，其中27名（56.3%）出现部分缓解（PR），中位无进展生存（mPFS）为9.6个月，中位总生存（mOS）未达到。77.1%的患者发生了≥3级不良事件。该方案与历史对照相比显示出更高的疗效，且安全性可控。II期AL3810-202研究纳入了迄今全球最大的病例组（n=68），而且是唯一一项随机对照设计的临床试验。研究者评估的mPFS在德立替尼组为6.6个月，而安慰剂组是1.9个月（P=0.0306，HR=0.53），达到统计学显著差异。独立委员会（IRC）评估的mPFS也显著延长（5.8个月和3.7个月；P=0.1050，HR=0.60）。加权log-rank检验、限制均值生存时间分析以及贝叶斯分析都显示德立替尼组具有统计学显著优势。《肿瘤瞭望》邀请法国Institut Gustave Roussy肿瘤研究所Jordi Remon Masip教授针对这两项研究发现予以点评。

 

Dr.Remon：MARBLE试验的结果公布了阿替利珠单抗、卡铂和紫杉醇联合治疗的结果。这是一项针对晚期胸腺癌患者的一线临床试验，结果显示客观缓解率（ORR）为56.3%，mPFS为9.6个月。我认为MARBLE的研究结果有意义，但目前的主要问题是如何找到“相比接受卡铂/紫杉醇化疗，起始治疗接受免疫联合化疗获益更多的患者”，关于这类患者的序贯治疗，可选择免疫治疗+抗血管生成治疗。MARBLE是一项重要的临床试验，但我认为应该找到最能从一线免疫联合化疗中受益的人群，并对潜在毒性保持警惕，因为MARBLE试验中≥3级免疫相关不良事件（irAE）的发生率为66.7%。

 

第二项试验评估了德立替尼在经治胸腺癌中的疗效和安全性。AL3810-202试验是阳性结果，因为与最佳支持治疗相比，德立替尼改善了无进展生存期，将进展风险降低了40%。然而，在胸腺癌二线治疗领域已有其他抗血管生成药物，如舒尼替尼和仑伐替尼，它们也报告了具有临床意义的结果，甚至在这类患者中相比德立替尼的缓解率更高，无进展生存期更长。德立替尼的活性数据是有意义的，但与其他已经上市的可用药物相比，其带来的获益并不突出。

 

Dr.Remon:Thank you for this question.Today，the results of the MARBLE trial were presented with the combination of atezolizumab，carboplatin and paclitaxel.This was a positive clinical trial in the first-line setting in patients with advanced thymic carcinoma，reporting an objective response rate of 56%，and a median progression-free survival of 9.6 months.I think it is a relevant result，however，the major issue to-date is how to find the patients who should receive this combination upfront compared to those patients who should start with carboplatin and paclitaxel chemotherapy，and then，in a sequential approach，receive immunotherapy plus antiangiogenics.It is an important clinical trial，but I think we should find the population that will most benefit from this first-line combination，and keep attention about the potential risk of toxicity.In the MARBLE trial the rate of grade 3 immune related adverse events was 67%.

 

The second trial was about the efficacy and safety of lucitanib in advanced and pre-treated thymic carcinoma.The trial was positive，because compared to best supportive care，lucitanib improved progression-free survival，reducing the risk of progression by 40%.However，today，in this scenario，we have other antiangiogenic agents such as sunitinib and lenvatinib.These agents have reported clinically meaningful results，with higher response rates and longer progression-free survival than lucitanib in this setting.It is relevant that the activity of lucitanib is there，but it seems modest compared to other potential drugs that are already available.

 

Dr.Remon：我认为化疗-免疫疗法对晚期或复发性胸腺癌来说是一种有趣的治疗方法，因为化疗和免疫疗法都有效。目前至少有三项化疗-免疫疗法治疗晚期胸腺肿瘤的单臂临床试验报告约为50%的缓解率，这与单用化疗的缓解率相似，所以化疗-免疫疗法也许是一种潜在的一线治疗策略，但并不适用于所有患者。我认为未来的一线治疗将是化疗、抗血管生成药物和免疫疗法相结合，以期实现比单用化疗更高的疗效。

 

Dr.Remon:I think chemoimmunotherapy is an interesting approach in this population，because chemotherapy works and immunotherapy works.Currently，there are at least three single arm phase 2 clinical trials，each of these trials assessing chemoimmunotherapy in advanced thymic carcinoma，that have reported a response rate of approximately 50%.This is a similar response rate to what we can achieve with chemotherapy alone，so perhaps this is a potential strategy，but not for all patients.I think the future in first-line will be the combination of chemotherapy plus antiangiogenics plus immunotherapy to try to increase the efficacy of the chemotherapy alone.

 

Dr.Remon：胸部肿瘤优选口头报告专场除了报告胸腺癌研究进展，还介绍了Beamion LUNG-1研究中Zongertinib用于HER2突变晚期/转移性NSCLC的Ib期结果（摘要号LBA5）。Zongertinib是一种新的HER2酪氨酸激酶抑制剂（TKI），在120 mg的剂量水平下，患者报告的缓解率为71%，目前没有中位无进展生存期数据，但我认为在这些患者中，这种新的TKI用于治疗HER2突变晚期NSCLC是有意义的。

 

Beamion LUNG-1研究中Zongertinib 120 mg剂量的肿瘤缓解率

 

未来，我们需要讨论HER2 TKI是否比目前获批为HER2突变型NSCLC标准二线治疗方案的抗体-药物偶联物（ADC）更好。另一个需要解决的挑战是，这种HER2 TKI与化疗联合能否前移到HER2突变NSCLC一线治疗。在未来一线选择变丰富的情况下，很难确定何为最佳一线治疗选择，可以开展几项临床试验进行对比，以期为HER2突变型NSCLC患者找到最合适的一线选择。

 

Dr.Remon:During the oral session，we also presented the updated results regarding the activity of zongertinib，a new HER2 tyrosine kinase inhibitor，for HER2 mutant lung cancers.At the dose of 120mg，the drug reported a response rate of 75%.We don’t have the median progression-free survival data yet，but I think in these patients，this new TKI could be relevant.

 

In the future，we need to discuss whether the TKIs are better than the antibody-drug conjugates that currently are already approved as the standard second-line treatment option.Indeed，another challenge to address is whether this new TKI could be moved to first-line in combination with chemotherapy.So in the future，it will be difficult to decide the best treatment options for these patients，and several clinical trials can be conducted to try to evaluate the most appropriate first-line option in patients with HER2-mutant non-small cell lung cancer.