Eigentler Thomas, Thomas Ioannis, Samoylenko Igor, Erdmann Michael, Heinzerling Lucie, Ochsenreither Sebastian, Krauss Jürgen, Oberoi Arjun, Robert Caroline, Lebbe Celeste, Martin-Liberal Juan, Koch Lukas, Richtig Erika, Terheyden Patrick, Weishaupt Carsten, Mohr Peter, Semiletova Yulia, Perez Casilda Llacer, Brossart Peter, Bauernfeind Franz Georg, Fluck Michael, Poltoratskiy Artem, Sekacheva Marina, Soria Ainara, Schmitt-Bormann Beate, Gonzalez Marina, Heß Jana, Wengenmayer Peter, Seibel Tobias, Koch Sven D, Quintini Gianluca, Codó Paula, Falk Martin, Schönborn-Kellenberger Oliver, Gnad-Vogt Ulrike
Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Berlin, Germany
Faculty of Medicine, University of Tübingen, Tubingen, Germany.
J Immunother Cancer. 2025 Feb 4;13(2):e009352. doi: 10.1136/jitc-2024-009352.
CV8102, a toll-like receptor 7/8 and RIG I agonist, has demonstrated antitumor immune responses in preclinical studies. We investigated intratumoral (IT) administration of CV8102 in patients with anti-programmed cell death protein-1 (PD-1) therapy-naïve or anti-PD-1 therapy-refractory cutaneous melanoma (cMEL) and in patients with advanced cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma and adenoid cystic carcinoma.
This open-label, cohort-based, phase I dose escalation study aimed to establish the maximum tolerated dose (MTD), recommended dose (RD), safety and preliminary efficacy of CV8102 as monotherapy or in combination with a PD-1 inhibitor. The preliminary efficacy of the RD was assessed in patients with cMEL in the expansion cohorts.
Between September 2017 and October 2022, 98 patients were enrolled in monotherapy and combination therapy dose escalation and dose expansion cohorts. Two patients in the CV8102 monotherapy dose escalation cohort experienced relevant toxicities at the 900 µg dose level. One patient had Grade 3 aspartate transaminase/alanine aminotransferase elevation which met dose-limiting toxicity (DLT) criteria. Another patient experienced Grade 3 immune-mediated pneumonitis. No DLTs occurred in the combination therapy dose escalation cohort. The MTD was not formally reached and the RD for expansion was 600 µg. Common treatment-emergent adverse events were fever (57%), chills (37%) and fatigue (25%). In the dose escalation part, objective responses occurred in 3/33 patients treated with CV8102 as monotherapy and in 2/25 patients treated with CV8102 plus a PD-1 inhibitor. In the expansion cohorts in patients with anti-PD-1 therapy-refractory melanoma, 0/10 patients treated with CV8102 as monotherapy and 5/30 patients (17%) treated in combination with a PD-1 inhibitor experienced objective responses.
IT CV8102 was generally well tolerated with preliminary signs of efficacy as monotherapy and in combination with a PD-1 inhibitor.
NCT03291002.
CV8102是一种Toll样受体7/8和视黄酸诱导基因I激动剂，在临床前研究中已显示出抗肿瘤免疫反应。我们研究了在未接受过抗程序性细胞死亡蛋白1（PD-1）治疗或抗PD-1治疗难治的皮肤黑色素瘤（cMEL）患者以及晚期皮肤鳞状细胞癌、头颈部鳞状细胞癌和腺样囊性癌患者中瘤内（IT）注射CV8102的情况。
这项开放标签、基于队列的I期剂量递增研究旨在确定CV8102作为单药治疗或与PD-1抑制剂联合使用时的最大耐受剂量（MTD）、推荐剂量（RD）、安全性和初步疗效。在扩展队列中评估了RD对cMEL患者的初步疗效。
2017年9月至2022年10月期间，98名患者入组了单药治疗和联合治疗剂量递增及剂量扩展队列。CV8102单药治疗剂量递增队列中的两名患者在900µg剂量水平出现了相关毒性。一名患者出现3级天冬氨酸转氨酶/丙氨酸转氨酶升高，符合剂量限制毒性（DLT）标准。另一名患者出现3级免疫介导的肺炎。联合治疗剂量递增队列中未发生DLT。未正式达到MTD，扩展的RD为600µg。常见的治疗中出现的不良事件为发热（57%）、寒战（37%）和疲劳（25%）。在剂量递增部分，33名单药接受CV8102治疗的患者中有3名出现客观反应，25名接受CV8102加PD-1抑制剂治疗的患者中有2名出现客观反应。在抗PD-1治疗难治性黑色素瘤患者的扩展队列中，10名单药接受CV8102治疗的患者中0名出现客观反应，30名联合PD-1抑制剂治疗的患者中有5名（17%）出现客观反应。
瘤内注射CV8102总体耐受性良好，作为单药治疗以及与PD-1抑制剂联合使用时有初步疗效迹象。
NCT03291002。
