滋养层细胞表面抗原TROP2高表达于HER2阴性乳腺癌和非小细胞肺癌等肿瘤组织，较少或几乎不表达于正常组织。戈沙妥珠单抗是第一代TROP2抗体缀合药物，将靶向药物与化疗药物合二为一，既可提高靶向药物对肿瘤组织的杀伤力，又可降低化疗药物对正常组织的杀伤力。2019年《新英格兰医学杂志》首次发表IMMU-132-01研究证实戈沙妥珠单抗对晚期三阴性乳腺癌有效：客观缓解率达34.3%，中位无进展生存5.5个月、中位总生存13.0个月；2021年《新英格兰医学杂志》再次发表ASCENT研究证实戈沙妥珠单抗与医师选择化疗相比，晚期三阴性乳腺癌客观缓解率35%比5%、中位无进展生存5.6个月比1.7个月、中位总生存12.1个月比6.7个月。2022年《临床肿瘤学杂志》进一步发表TROPiCS-02研究证实戈沙妥珠单抗与医师选择化疗相比，晚期激素受体阳性HER2阴性乳腺癌客观缓解率21%比14%、中位无进展生存5.5个月比4.0个月、进展或死亡风险减少34%；2023年《柳叶刀》最终发表TROPiCS-02研究证实戈沙妥珠单抗与医师选择化疗相比，中位总生存14.4个月比11.2个月、总死亡风险减少11%。 自从第二代HER2抗体缀合药物德曲妥珠单抗的DESTINY系列研究问世，在HER2阳性或低表达肿瘤治疗领域获得势如破竹、所向披靡的成功，DESTINY-Breast03研究甚至头对头直接碾压第一代HER2抗体缀合药物恩美曲妥珠单抗。随后，第二代TROP2抗体缀合药物德达托泊单抗的TROPION系列研究启动，2023年《临床肿瘤学杂志》首次发表TROPION-PanTumor01研究证实德达托泊单抗对晚期非小细胞肺癌有效。那么，德达托泊单抗对晚期乳腺癌是否有效？TROPION-PanTumor01 (NCT03401385): First-in-human Study of DS-1062a for Advanced Solid Tumors (Phase 1, Two-part, Multicenter, Open-label, Multiple Dose, First-in-human Study of DS-1062a in Subjects With Advanced Solid Tumors) 2024年4月23日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表美国哈佛大学医学院、麻省总医院癌症中心、达纳法伯癌症研究院、耶鲁大学癌症中心、南德克萨斯治疗研究中心、圣安东尼奥肿瘤医院、德克萨斯肿瘤医院、莎拉坎农研究院、田纳西肿瘤医院、洛杉矶加利福尼亚大学大卫格芬医学院、弗吉尼亚癌症研究院、德克萨斯大学MD安德森癌症中心、南德克萨斯肿瘤医院、日本癌症研究基金会癌研有明医院、国立癌症中心东院、国立癌症中心医院、和歌山医科大学医院、东京昭和大学、第一三共的TROPION-PanTumor01研究乳腺癌报告，首次探讨了德达托泊单抗对晚期激素受体阳性HER2阴性或三阴性乳腺癌的有效性和安全性。 该国际多中心剂量递增和剂量扩展一期临床研究于2020年6月30日至2021年10月7日从日本和美国17家医院入组多线治疗失败后晚期激素受体阳性HER2阴性乳腺癌患者41例、晚期三阴性乳腺癌患者44例，给予德达托泊单抗，其中2例三阴性乳腺癌每3周8mg/kg，其余83例每3周6mg/kg。主要研究目标为德达托泊单抗的安全性和耐受性。次要目标包括抗肿瘤活性和药物代谢动力学。 结果，截至2022年7月22日，激素受体阳性HER2阴性乳腺癌与三阴性乳腺癌相比：- 客观缓解率：26.8%、31.8%（95%置信区间：14.2～42.9、18.6～47.6）
- 任何级别全因治疗期间不良事件发生率：100%、100%
- ≥3级全因治疗期间不良事件发生率：41.5%、52.3%
因此，该小样本非对照初步研究结果表明，对于多线治疗失败的晚期激素受体阳性HER2阴性乳腺癌和三阴性乳腺癌患者，德达托泊单抗的临床活性大有希望、安全性可控，但是似乎难以像德曲妥珠单抗碾压恩美曲妥珠单抗一样，对戈沙妥珠单抗形成碾压之势，尤其对于三阴性乳腺癌。 于是，德达托泊单抗首先选择晚期激素受体阳性HER2阴性乳腺癌，与研究者选择化疗而非与戈沙妥珠单抗进行头对头比较，开展了国际多中心非盲随机对照三期临床研究TROPION-Breast01，对标TROPiCS-02研究，初步结果已于2023年10月欧洲肿瘤内科学会第47届大会公布：中位无进展生存6.9个月比4.9个月、进展或死亡风险减少37%，总生存未达中位，最终结果值得期待。 据悉，TROPION-Breast02研究将选择晚期三阴性乳腺癌，与研究者选择化疗进行头对头比较，对标ASCENT研究；TROPION-Breast03研究将选择早期三阴性乳腺癌，联合度伐利尤单抗与研究者选择化疗进行头对头比较；TROPION-Breast04研究将选择早期三阴性乳腺癌或激素受体低表达HER2阴性乳腺癌，联合度伐利尤单抗与研究者选择化疗进行头对头比较；TROPION-Breast05研究将选择PD-L1阳性晚期三阴性乳腺癌，联合度伐利尤单抗与研究者选择化疗联合帕博利珠单抗进行头对头比较……可惜，像DESTINY-Breast03研究那样与同类药物进行捉对厮杀的惊天地泣鬼神之战应该是看不到了。J Clin Oncol. 2024 Apr 23. IF: 45.3 Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2- and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study. OPEN ACCESS Bardia A, Krop IE, Kogawa T, Juric D, Tolcher AW, Hamilton EP, Mukohara T, Lisberg A, Shimizu T, Spira AI, Tsurutani J, Damodaran S, Papadopoulos KP, Greenberg J, Kobayashi F, Zebger-Gong H, Wong R, Kawasaki Y, Nakamura T, Meric-Bernstam F. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Yale Cancer Center, New Haven, CT; Dana-Farber Cancer Institute, Boston, MA; South Texas Accelerated Research Therapeutics, San Antonio, TX; NEXT Oncology, San Antonio, TX; Texas Oncology, San Antonio, TX; Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN; David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA; Virginia Cancer Specialists (VCS) Research Institute, Fairfax, VA; The University of Texas MD Anderson Cancer Center, Houston, TX; START, San Antonio, TX; Daiichi Sankyo, Inc, Basking Ridge, NJ; Cancer Institute Hospital of JFCR, Tokyo, Japan; National Cancer Center Hospital East, Kashiwa, Japan; National Cancer Center Hospital, Tokyo, Japan; Wakayama Medical University Hospital, Wakayama, Japan; Showa University, Tokyo, Japan; Daiichi Sankyo, Co, Ltd, Tokyo, Japan; Daiichi Sankyo Europe GmbH, Munich, Germany. PURPOSE: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker. PATIENTS AND METHODS: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported. RESULTS: At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts. CONCLUSION: In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies. KEY OBJECTIVE: The phase I TROPION-PanTumor01 study evaluated Dato-DXd, a TROP2-directed antibody-drug conjugate (ADC), in solid tumors, including hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) and triple-negative BC (TNBC). KNOWLEDGE GENERATED: The confirmed objective response rate was 26.8% and 31.8%, and the median progression-free survival was 8.3 months and 4.4 months for patients with HR+/HER2- BC and TNBC, respectively. Stomatitis was the most common treatment-emergent adverse event, and one adjudicated drug-related interstitial lung disease case was reported. RELEVANCE: Data-DXd is a new ADC with significant activity in previously treated BC. Additional studies are needed to evaluate the mechanisms of resistance to ADCs and to determine the optimal sequence of therapies. PMID: 38652877 DOI: 10.1200/JCO.23.01909
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