抗体药物偶联物在转移性乳腺癌中的最佳序贯策略：评估疗效和交叉耐药性。
Optimal Sequential Strategies for Antibody-Drug Conjugate in Metastatic Breast Cancer: Evaluating Efficacy and Cross-Resistance.
机构信息
Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
Medical Oncology Department III, Central Hospital of Guangdong Nongken, Zhanjiang, People's Republic of China.
出版信息
Oncologist. 2024 Aug 5;29(8):e957-e966. doi: 10.1093/oncolo/oyae055.
BACKGROUND
The optimal sequential strategy for antibody-drug conjugates (ADCs) in breast cancer remains uncertain. This study aimed to evaluate the efficacy and potential resistance of second ADC (ADC2) following the first ADC (ADC1) in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low MBC.
METHODS
This retrospective, multicenter, real-world study enrolled patients with MBC who received at least 2 different types of ADCs in 3 hospitals in China between July 1, 2017 and May 1, 2023. Outcomes included the objective response rate (ORR) for ADC1 and ADC2, progression free survival 2 (PFS2), defined as the time from initiation of ADC2 to progression, and overall survival (OS).
RESULTS
Seventy-nine female patients were included, 64 of whom had HER2-positive disease. The ORR for ADC2 with similar payload of ADC1 was found to be 5.3%. When switching to a different payload, the ORR of ADC2 increased to 22.6%. The PFS2 for ADC2 remained similar regardless of whether the payload was similar or different. Switching to different payload showed a higher ORR in patients with rapid progression and a durable response longer than 6 months (41.2% vs 15.0%). Specifically, significantly longer PFS2 and OS were seen in patients treated with trastuzumab deruxtecan (T-Dxd) compared to those treated with disitamab vedotin (RC48) after progression from trastuzumab emtansine (T-DM1; median PFS2 5.37 months vs 3.30 months, HR = 0.40, 95% CI 0.17-0.93, P = .034; median OS 50.6 months vs 20.2 months, HR = 0.27, 95% CI 0.08-0.91, P = .034). For patients who progressed after T-Dxd, the median PFS2 was 6.05 months for those treated with RC48 versus 0.93 months for those treated with T-DM1 (HR = 0.03, 95% CI 0.002-0.353, P = .0093). Genomic analysis revealed that alternation of retinoblastoma1 was significantly associated with superior PFS.
CONCLUSION
The alternation of payload achieves different responses in different settings. T-Dxd followed by RC48 may be a potentially beneficial strategy in HER2-positive disease. Further research is needed to elucidate the mechanism of cross-resistance.
背景
抗体药物偶联物（ADC）在乳腺癌中的最佳序贯策略仍不确定。本研究旨在评估人表皮生长因子受体 2（HER2）阳性和 HER2-低转移性乳腺癌（MBC）患者中，在使用第一代 ADC（ADC1）后使用第二代 ADC（ADC2）的疗效和潜在耐药性。
方法
这是一项回顾性、多中心、真实世界的研究，纳入了 2017 年 7 月 1 日至 2023 年 5 月 1 日期间在中国 3 家医院接受至少 2 种不同类型 ADC 治疗的 MBC 患者。主要终点包括 ADC1 和 ADC2 的客观缓解率（ORR）、无进展生存期 2（PFS2），定义为从开始使用 ADC2 到进展的时间，以及总生存期（OS）。
结果
共纳入 79 例女性患者，其中 64 例为 HER2 阳性疾病。结果发现，与 ADC1 相似有效载荷的 ADC2 的 ORR 为 5.3%。当切换到不同的有效载荷时，ADC2 的 ORR 增加到 22.6%。无论有效载荷是否相似，ADC2 的 PFS2 均相似。在快速进展和缓解持续时间超过 6 个月的患者中，切换到不同的有效载荷显示出更高的 ORR（41.2%比 15.0%）。具体来说，与接受迪西妥单抗（RC48）治疗的患者相比，接受曲妥珠单抗-美坦新偶联物（T-Dxd）治疗的患者在曲妥珠单抗恩美曲妥珠单抗（T-DM1）进展后的 PFS2 和 OS 更长（中位 PFS2 5.37 个月比 3.30 个月，HR=0.40，95%CI 0.17-0.93，P=0.034；中位 OS 50.6 个月比 20.2 个月，HR=0.27，95%CI 0.08-0.91，P=0.034）。对于接受 T-Dxd 后进展的患者，接受 RC48 治疗的患者的中位 PFS2 为 6.05 个月，而接受 T-DM1 治疗的患者的中位 PFS2 为 0.93 个月（HR=0.03，95%CI 0.002-0.353，P=0.0093）。基因组分析显示，视网膜母细胞瘤 1 的改变与更好的 PFS 显著相关。
结论
有效载荷的改变在不同情况下会产生不同的反应。T-Dxd 序贯 RC48 可能是 HER2 阳性疾病的一种潜在有益策略。需要进一步研究来阐明交叉耐药的机制。
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