Department of Dermatology, Tohoku University School of Medicine, Sendai, Japan.
Department of Dermato-Oncology/Dermatology, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, Tokyo,Japan.
Br J Dermatol. 2024 Oct 17;191(5):691-697. doi: 10.1093/bjd/ljae231.
Anti-programmed cell death 1 antibodies (PD-1 Abs) are widely used for advanced melanoma, but information on the efficacy of anti-PD-1 Abs is limited in the Asian population. There remains an unmet need to improve the therapeutic effects of anti-PD-1 Ab-treatment, particularly in patients with melanoma who are refractory to anti-PD-1 Abs. The aim of this study was to evaluate anti-PD-1 Ab-treatment in combination with TM5614 (a plasminogen activator inhibitor-1 inhibitor) in patients with unresectable melanoma.
The TM5614-MM study was a multicentre, open-label, single-arm, phase II clinical trial to evaluate the efficacy and safety of nivolumab in combination with TM5614 in patients with advanced, unresectable malignant melanoma recruited at seven Japanese institutes between 13 September 2021 and 31 March 2023. Patients with metastatic or unresectable melanoma previously treated with anti-PD-1 Abs were enrolled. Nivolumab 480 mg was administered intravenously every 4 weeks for 8 weeks, while TM5614 was administered orally at a dose of 120 mg (0-4 weeks) and 180 mg once daily (5-8 weeks). The primary endpoint was the overall response rate after 8 weeks of concomitant use of TM5614.
Thirty-nine patients were enrolled, and 34 patients were included in the anti-PD-1 Ab-refractory cohort. The overall response rate at 8 weeks was 25.9% (95% confidence interval 12.9-44.9%, P = 0.027) in 27 patients who were anti-PD-1 Ab-refractory based on investigator assessment in the protocol per set cohort. Seven patients discontinued treatment owing to progressive disease or adverse events. Treatment-related grade 3 or higher adverse events occurred in 3 of 39 patients (7.7%) in the intention-to-treat cohort.
TM5614 in combination with nivolumab is well tolerated and effective in anti-PD-1 Ab-refractory unresectable melanoma.
抗程序性细胞死亡 1 抗体（PD-1Abs）广泛用于晚期黑色素瘤，但亚洲人群中抗 PD-1Abs 的疗效信息有限。在抗 PD-1Ab 治疗中，特别是在对抗 PD-1Abs 耐药的黑色素瘤患者中，仍然存在提高治疗效果的未满足需求。本研究旨在评估不可切除黑色素瘤患者联合使用 TM5614（纤溶酶原激活物抑制剂-1 抑制剂）的抗 PD-1Ab 治疗效果。
TM5614-MM 研究是一项多中心、开放标签、单臂、II 期临床试验，评估了在 2021 年 9 月 13 日至 2023 年 3 月 31 日期间，在日本的七家机构招募的晚期不可切除的恶性黑色素瘤患者中，nivolumab 联合 TM5614 的疗效和安全性。纳入转移性或不可切除的黑色素瘤患者，这些患者之前接受过抗 PD-1Abs 治疗。nivolumab 480mg 静脉输注，每 4 周一次，连用 8 周；TM5614 口服，剂量为 120mg（0-4 周）和 180mg 每日一次（5-8 周）。主要终点是 TM5614 联合使用 8 周后的总体缓解率。
共纳入 39 例患者，34 例患者纳入抗 PD-1Ab 耐药队列。根据协议规定的队列中研究者评估，27 例抗 PD-1Ab 耐药患者的 8 周总缓解率为 25.9%（95%置信区间 12.9-44.9%，P=0.027）。7 例患者因疾病进展或不良事件而停止治疗。在意向治疗人群中，39 例患者中有 3 例（7.7%）发生了与治疗相关的 3 级或更高级别的不良事件。
TM5614 联合 nivolumab 对不可切除的抗 PD-1Ab 耐药黑色素瘤患者耐受良好，疗效显著。
