Hansen Aaron R, Gomez-Roca Carlos A, Robbrecht Debbie G J, Verlingue Loic, Italiano Antoine, Bauman Julie E, Steeghs Neeltje, Prenen Hans, Fayette Jérôme, Spicer James, Niu Jiaxin, Habigt Christin, Schneider Meike, Evers Stefan, Sleiman Nassim, Dejardin David, Ardeshir Caroline, Schmid Daniela, Boetsch Christophe, Charo Jehad, Kraxner Anton, Teichgräber Volker, Keshelava Nino, Bonomi Marcelo R
Division of Medical Oncology, Princess Margaret Cancer Center, Toronto, Canada.
Medical Oncology and Clinical Research Department, Institut Universitaire du Cancer, Toulouse, France.
Clin Cancer Res. 2024 Dec 16;30(24):5540-5547. doi: 10.1158/1078-0432.CCR-24-1562.
This phase Ib trial evaluated fibroblast activation protein-α-targeted IL2 variant (FAP-IL2v), a novel immunocytokine engineered to minimize CD25-mediated toxicities, in combination with cetuximab, in patients with recurrent, unresectable, or metastatic head and neck squamous cell carcinoma (HNSCC).
Patients received FAP-IL2v either on a continuous weekly (QW) schedule or QW for 4 weeks and then every 2 weeks (Q2W). Cetuximab was dosed at QW or Q2W schedules. The primary objectives were to evaluate the safety and tolerability, maximum tolerated dose, pharmacokinetics, and clinical activity for the combination of FAP-IL2v with cetuximab. Exploratory objectives included pharmacodynamic analyses.
A total of 58 patients were enrolled, 19 patients into the dose-escalation part, and 39 patients into the expansion part. The maximum tolerated dose of FAP-IL2v was defined as 10 mg (QW/Q2W) in combination with cetuximab (500 mg/m2, Q2W), which was further tested in the expansion part. The most common FAP-IL2v-related adverse events with a grade 3 or 4 severity were hypophosphatemia (19%), lymphopenia (16%), and infusion-related reaction (14%). The pharmacokinetics of FAP-IL2v in combination with cetuximab was similar to that after administration as monotherapy. Consistent with the proposed mode of action, FAP-IL2v preferentially expanded intratumoral NK and CD8 T cells. Four patients achieved a partial response, and the objective response rate was 7% (95% confidence interval, 3.2-14.7).
The safety profile of FAP-IL2v in combination with cetuximab was acceptable, and pharmacodynamic markers support the proposed mode of action of this combination, but the overall low antitumor activity does not warrant further clinical exploration in HNSCC. [Part C of Study BP29842 (NCT02627274).].
本Ib期试验评估了成纤维细胞活化蛋白-α靶向IL2变体（FAP-IL2v），一种经工程改造以尽量减少CD25介导的毒性的新型免疫细胞因子，联合西妥昔单抗用于复发性、不可切除或转移性头颈部鳞状细胞癌（HNSCC）患者的疗效。
患者接受FAP-IL2v，采用持续每周（QW）给药方案，或QW给药4周，然后每2周（Q2W）给药一次。西妥昔单抗采用QW或Q2W给药方案。主要目标是评估FAP-IL2v与西妥昔单抗联合使用的安全性、耐受性、最大耐受剂量、药代动力学和临床活性。探索性目标包括药效学分析。
共入组58例患者，19例进入剂量递增部分，39例进入扩展部分。FAP-IL2v与西妥昔单抗（500mg/m2，Q2W）联合使用时的最大耐受剂量定义为10mg（QW/Q2W），并在扩展部分进行了进一步测试。3级或4级严重程度的最常见FAP-IL2v相关不良事件为低磷血症（19%）、淋巴细胞减少（16%）和输液相关反应（14%）。FAP-IL2v与西妥昔单抗联合使用时的药代动力学与单药给药后的药代动力学相似。与提议的作用模式一致，FAP-IL2v优先扩增肿瘤内NK细胞和CD8 T细胞。4例患者获得部分缓解，客观缓解率为7%（95%置信区间，3.2-14.7）。
FAP-IL2v与西妥昔单抗联合使用的安全性可接受，药效学标志物支持该联合用药的提议作用模式，但总体抗肿瘤活性较低，不支持在HNSCC中进行进一步的临床探索。[研究BP29842（NCT02627274）的C部分。]
