Dummer Reinhard, Robert Caroline, Scolyer Richard A, Taube Janis M, Tetzlaff Michael T, Menzies Alexander M, Hill Andrew, Grob Jean-Jacques, Portnoy David C, Lebbe Celeste, Khattak Muhammad A, Cohen Jonathan, Bar-Sela Gil, Mehmi Inderjit, Shapira-Frommer Ronnie, Meyer Nicolas, Webber Andrea L, Ren Yixin, Fukunaga-Kalabis Mizuho, Krepler Clemens, Long Georgina V
University Hospital Zurich, Zurich, Switzerland.
Gustave Roussy and Paris-Saclay University, Paris, France.
Nat Med. 2025 Jan;31(1):144-151. doi: 10.1038/s41591-024-03411-x. Epub 2025 Jan 7.
Neoadjuvant immunotherapies have shown antitumor activity in melanoma. Substudy 02C of the global, rolling-arm, phase 1/2, adaptive-design KEYMAKER-U02 trial is evaluating neoadjuvant pembrolizumab (anti-PD-1) alone or in combination, followed by adjuvant pembrolizumab, for stage IIIB-D melanoma. Here we report results from the first three arms: pembrolizumab plus vibostolimab (anti-TIGIT), pembrolizumab plus gebasaxturev (coxsackievirus A21) and pembrolizumab monotherapy. Pathologic complete responses occurred in 10 of 26 patients (38%) with pembrolizumab plus vibostolimab, 7 of 25 (28%) with pembrolizumab plus gebasaxturev and 6 of 15 (40%) with pembrolizumab monotherapy. Major pathologic responses occurred in 13 (50%), 10 (40%) and 7 (47%) patients, respectively. Safety was manageable. Treatment-related adverse events occurred in 24 of 26 patients (92%) with pembrolizumab plus vibostolimab, 21 of 25 (84%) with pembrolizumab plus gebasaxturev and 12 of 15 (80%) with pembrolizumab monotherapy; grade 3 or 4 treatment-related adverse events occurred in 2 (8%), 7 (28%) and 1 (7%) patient in each arm, respectively. No deaths due to adverse events occurred. Exploratory objective responses per RECIST v1.1 were observed in 13 (50%), 8 (32%) and 4 (27%) patients, in each arm, respectively. In a post hoc analysis, scores for tumor mutational burden and an 18-gene T cell-inflamed gene expression profile were generally higher in patients with major pathologic response. Longer follow-up will provide insight into the incremental benefit of combining neoadjuvant pembrolizumab with other therapies in stage IIIB-D melanoma. ClinicalTrials.gov registration: NCT04303169 .
新辅助免疫疗法已在黑色素瘤中显示出抗肿瘤活性。全球滚动臂1/2期适应性设计KEYMAKER-U02试验的02C子研究正在评估新辅助帕博利珠单抗（抗PD-1）单药治疗或联合治疗，随后进行辅助帕博利珠单抗治疗，用于IIIB-D期黑色素瘤。在此，我们报告前三个治疗组的结果：帕博利珠单抗联合维博利单抗（抗TIGIT）、帕博利珠单抗联合格巴萨克替韦（柯萨奇病毒A21）和帕博利珠单抗单药治疗。帕博利珠单抗联合维博利单抗治疗的26例患者中有10例（38%）出现病理完全缓解，帕博利珠单抗联合格巴萨克替韦治疗的25例患者中有7例（28%）出现病理完全缓解，帕博利珠单抗单药治疗的15例患者中有6例（40%）出现病理完全缓解。主要病理缓解分别发生在13例（50%）、10例（40%）和7例（47%）患者中。安全性可控。帕博利珠单抗联合维博利单抗治疗的26例患者中有24例（92%）发生治疗相关不良事件，帕博利珠单抗联合格巴萨克替韦治疗的25例患者中有21例（84%）发生治疗相关不良事件，帕博利珠单抗单药治疗的15例患者中有12例（80%）发生治疗相关不良事件；每个治疗组中3/4级治疗相关不良事件分别发生在2例（8%）、7例（28%）和1例（7%）患者中。未发生因不良事件导致的死亡。每个治疗组中分别有13例（50%）、8例（32%）和4例（27%）患者观察到根据RECIST v1.1标准的探索性客观缓解。在一项事后分析中，主要病理缓解患者的肿瘤突变负荷和18基因T细胞炎症基因表达谱评分通常更高。更长时间的随访将有助于深入了解在IIIB-D期黑色素瘤中联合新辅助帕博利珠单抗与其他疗法的额外获益。ClinicalTrials.gov注册号：NCT04303169 。
