NEXT Oncology, San Antonio, Texas, USA
HonorHealth Research Institute, Scottsdale, Arizona, USA.
J Immunother Cancer. 2023 Feb;11(2). doi: 10.1136/jitc-2022-005267.
Cluster of differentiation (CD)73-adenosine and transforming growth factor (TGF)-β pathways are involved in abrogated antitumor immune responses and can lead to protumor conditions. This Phase 1 study (NCT03954704) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of dalutrafusp alfa (also known as GS-1423 and AGEN1423), a bifunctional, humanized, aglycosylated immunoglobulin G1 kappa antibody that selectively inhibits CD73-adenosine production and neutralizes active TGF-β signaling in patients with advanced solid tumors.
Dose escalation started with an accelerated titration followed by a 3+3 design. Patients received dalutrafusp alfa (0.3, 1, 3, 10, 20, 30, or 45 mg/kg) intravenously every 2 weeks (Q2W) up to 1 year or until progressive disease (PD) or unacceptable toxicity.
In total, 21/22 patients received at least one dose of dalutrafusp alfa. The median number of dalutrafusp alfa doses administered was 3 (range 1-14). All patients had at least one adverse event (AE), most commonly fatigue (47.6%), nausea (33.3%), diarrhea (28.6%), and vomiting (28.6%). Nine (42.9%) patients had a Grade 3 or 4 AE; two had Grade 5 AEs of pulmonary embolism and PD, both unrelated to dalutrafusp alfa. Target-mediated drug disposition appears to be saturated at dalutrafusp alfa doses above 20 mg/kg. Complete CD73 target occupancy on B cells and CD8+ T cells was observed, and TGF-β 1/2/3 levels were undetectable at dalutrafusp alfa doses of 20 mg/kg and higher. Free soluble (s)CD73 levels and sCD73 activity increased with dalutrafusp alfa treatment. Seventeen patients reached the first response assessment, with complete response, partial response, stable disease, and PD in 0, 1 (4.8%), 7 (33.3%), and 9 (42.9%) patients, respectively.
Dalutrafusp alfa doses up to 45 mg/kg Q2W were well tolerated in patients with advanced solid tumors. Additional evaluation of dalutrafusp alfa could further elucidate the clinical utility of targeting CD73-adenosine and TGF-β pathways in oncology.
细胞分化（CD）73-腺苷和转化生长因子（TGF）-β途径参与肿瘤免疫反应的破坏，并可能导致促肿瘤状态。这项 1 期研究（NCT03954704）评估了 dalutrafusp alfa（也称为 GS-1423 和 AGEN1423）在晚期实体瘤患者中的安全性、药代动力学、药效学和疗效。dalutrafusp alfa 是一种具有双功能的、人源化的、去糖基化的免疫球蛋白 G1 kappa 抗体，可选择性抑制 CD73-腺苷的产生，并中和活性 TGF-β信号。
剂量递增从加速滴定开始，然后是 3+3 设计。患者每 2 周（Q2W）静脉注射 dalutrafusp alfa（0.3、1、3、10、20、30 或 45mg/kg），持续 1 年或直至疾病进展（PD）或无法耐受的毒性。
共有 21/22 名患者接受了至少一剂 dalutrafusp alfa。接受 dalutrafusp alfa 治疗的中位剂量数为 3（范围 1-14）。所有患者均至少发生 1 次不良事件（AE），最常见的是乏力（47.6%）、恶心（33.3%）、腹泻（28.6%）和呕吐（28.6%）。9 例（42.9%）患者出现 3 级或 4 级 AE；2 例出现 5 级 AE 为肺栓塞和 PD，均与 dalutrafusp alfa 无关。在 dalutrafusp alfa 剂量高于 20mg/kg 时，靶介导的药物处置似乎达到饱和。在 dalutrafusp alfa 剂量为 20mg/kg 及以上时，观察到完全的 CD73 靶点占有率在 B 细胞和 CD8+T 细胞上，并且 TGF-β1/2/3 水平无法检测到。游离可溶性（s）CD73 水平和 sCD73 活性随着 dalutrafusp alfa 治疗而增加。17 名患者达到首次反应评估，0、1（4.8%）、7（33.3%）和 9（42.9%）名患者的完全缓解、部分缓解、疾病稳定和 PD 分别为 0、1（4.8%）、7（33.3%）和 9（42.9%）。
在晚期实体瘤患者中，dalutrafusp alfa 高达 45mg/kg Q2W 的剂量耐受良好。进一步评估 dalutrafusp alfa 可以进一步阐明靶向 CD73-腺苷和 TGF-β途径在肿瘤学中的临床应用。
