El-Khoueiry Anthony, Saavedra Omar, Thomas Jacob, Livings Claire, Garralda Elena, Hintzen Gabriele, Kohlhas Laura, Vanosmael Dessislava, Koch Joachim, Rajkovic Erich, Ravenstijn Paulien, Nuciforo Paolo, Fehniger Todd A, Foster Mark, Berrien-Elliott Melissa M, Wingert Susanne, Stäble Sina, Morales-Espinosa Daniela, Rivas Delcia, Emig Michael, Lopez Juanita
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.
Clin Cancer Res. 2025 Apr 1;31(7):1257-1267. doi: 10.1158/1078-0432.CCR-24-1991.
Innate immune cell-based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on NK cells/macrophages and EGFR on tumor cells, redirecting antitumor activity toward tumors. The safety and tolerability of AFM24 were evaluated in this phase I/IIa dose-escalation/dose-expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR.
The main objective in phase I was to determine the MTD and/or recommended phase II dose. The primary endpoint was the incidence of dose-limiting toxicities during the observation period. Secondary endpoints included the incidence of treatment-emergent adverse events and pharmacokinetics.
In the dose-escalation phase, 35 patients received AFM24 weekly across seven dose cohorts (14-720 mg). One patient experienced a dose-limiting toxicity of grade 3 infusion-related reaction. Infusion-related reactions were mainly reported after the first infusion; these were manageable with premedication and a gradual increase in infusion rate. Pharmacokinetics was dose-proportional, and CD16A receptor occupancy on NK cells approached saturation between 320 and 480 mg. Paired tumor biopsies demonstrated the activation of innate and adaptive immune responses within the tumor. The best objective response was stable disease in 10/35 patients; four patients had stable disease for 4.3 to 7.1 months.
AFM24 was well tolerated, with 480 mg established as the recommended phase II dose. AFM24 could be a novel therapy for patients with EGFR-expressing solid tumors, with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other immuno-oncology therapeutics.
基于先天免疫细胞的疗法已显示出对实体瘤和血液系统恶性肿瘤具有有前景的抗肿瘤活性。AFM24是一种双特异性先天细胞衔接器，可结合自然杀伤细胞/巨噬细胞上的CD16A和肿瘤细胞上的表皮生长因子受体（EGFR），将抗肿瘤活性重定向至肿瘤。在这项I/IIa期剂量递增/剂量扩展研究中，对复发或持续性晚期实体瘤且已知表达EGFR的患者评估了AFM24的安全性和耐受性。
I期的主要目标是确定最大耐受剂量（MTD）和/或推荐的II期剂量。主要终点是观察期内剂量限制性毒性的发生率。次要终点包括治疗中出现的不良事件的发生率和药代动力学。
在剂量递增阶段，35例患者每周接受AFM24治疗，分为7个剂量组（14 - 720毫克）。1例患者出现3级输液相关反应的剂量限制性毒性。输液相关反应主要在首次输液后报告；通过预处理和逐渐提高输液速度可控制这些反应。药代动力学呈剂量正比关系，自然杀伤细胞上的CD16A受体占有率在320至480毫克之间接近饱和。配对肿瘤活检显示肿瘤内先天和适应性免疫反应激活。最佳客观反应是35例患者中有10例病情稳定；4例患者病情稳定4.3至7.1个月。
AFM24耐受性良好，确定480毫克为推荐的II期剂量。AFM24可能是表达EGFR实体瘤患者的一种新型疗法，具有适合的耐受性和适当的药代动力学特性，可与其他免疫肿瘤学疗法联合进一步开发。
