SOLTI Cancer Research Group, Barcelona; Medical Oncology Department, Vall d'Hebron University Hospital, and Breast Cancer Group, Vall D'Hebron Institute of Oncology (VHIO), Barcelona. Electronic address: https://twitter.com/MOliveira_MD.
SOLTI Cancer Research Group, Barcelona; Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
Ann Oncol. 2023 Aug;34(8):670-680. doi: 10.1016/j.annonc.2023.05.004. Epub 2023 May 19.
Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor 3 (HER3)-directed antibody-drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score [= -0.8 × tumor cellularity (in %) + 1.3 × tumor-infiltrating lymphocytes (TILs) (in %)], and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer.
Patients with previously untreated hormone receptor-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 messenger RNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score.
Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, -3.8 to 12.7; P = 0.003). Among patients assessable for clinical response (n = 62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 versus +1.9). Change in CelTIL score was independent of baseline ERBB3 messenger RNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease.
A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in hormone receptor-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.
Patritumab deruxtecan（HER3-DXd）是一种人表皮生长因子受体 3（HER3）靶向抗体药物偶联物，由完全人源抗 HER3 单克隆抗体（patritumab）通过稳定的、肿瘤选择性的、基于四肽的可切割接头与拓扑异构酶 I 抑制剂有效载荷共价连接而成。TOT-HER3 是一项机会性窗口研究，旨在评估生物活性，通过 CelTIL 评分[=-0.8×肿瘤细胞密度（%）+1.3×肿瘤浸润淋巴细胞（TIL）（%）]来衡量，以及在未经治疗的激素受体阳性/HER2 阴性早期乳腺癌患者中接受短期（21 天）术前治疗时的临床活性。
根据基线 ERBB3 信使 RNA 表达情况，将未经治疗的激素受体阳性/HER2 阴性肿瘤患者分配到四个队列之一。所有患者均接受一次 6.4 mg/kg 的 HER3-DXd 治疗。主要目标是评估 CelTIL 评分从基线的变化。
77 例患者进行了疗效评估。观察到 CelTIL 评分有显著变化，中位数从基线增加了 3.5（四分位距，-3.8 至 12.7；P=0.003）。在可评估临床反应的患者（n=62）中，观察到总体缓解率为 45%（卡尺测量肿瘤），与无反应者相比，反应者的 CelTIL 评分呈上升趋势（平均差异，+11.9 与+1.9）。CelTIL 评分的变化与基线 ERBB3 信使 RNA 和 HER3 蛋白水平无关。发生了基因组变化，包括基于 PAM50 亚型向增殖性较低的肿瘤表型转变、细胞增殖基因的抑制以及与免疫相关基因的诱导。96%的患者出现治疗相关不良事件（14%为 3 级及以上）；最常见的是恶心、疲劳、脱发、腹泻、呕吐、腹痛和中性粒细胞计数下降。
单次剂量的 HER3-DXd 与临床反应、免疫浸润增加、激素受体阳性/HER2 阴性早期乳腺癌增殖抑制以及可耐受的安全性特征相关，与先前报道的结果一致。这些发现支持进一步研究 HER3-DXd 在早期乳腺癌中的应用。
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