开放标签、II 期研究：替莫唑胺联合帕博利珠单抗治疗先前抗 PD-1 治疗进展的晚期黑色素瘤：MASTERKEY-115。

Open-label, phase II study of talimogene laherparepvec plus pembrolizumab for the treatment of advanced melanoma that progressed on prior anti-PD-1 therapy: MASTERKEY-115.

机构信息

Gustave Roussy and Paris-Saclay University, Villejuif, France.

Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA.

出版信息

Eur J Cancer. 2024 Aug;207:114120. doi: 10.1016/j.ejca.2024.114120. Epub 2024 May 15.

DOI:10.1016/j.ejca.2024.114120

PMID:38870745

Abstract

BACKGROUND

Treatment options for immunotherapy-refractory melanoma are an unmet need. The MASTERKEY-115 phase II, open-label, multicenter trial evaluated talimogene laherparepvec (T-VEC) plus pembrolizumab in advanced melanoma that progressed on prior programmed cell death protein-1 (PD-1) inhibitors.

METHODS

Cohorts 1 and 2 comprised patients (unresectable/metastatic melanoma) who had primary or acquired resistance, respectively, and disease progression within 12 weeks of their last anti-PD-1 dose. Cohorts 3 and 4 comprised patients (resectable disease) who underwent complete surgery, received adjuvant anti-PD-1, and experienced recurrence. Cohort 3 were disease-free for < 6 months and cohort 4 for ≥ 6 months after starting the adjuvant anti-PD-1 therapy and before confirmed recurrence. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included complete response rate (CRR), disease control rate (DCR) and progression-free survival (PFS) per RECIST v1.1 and irRC-RECIST, and safety.

RESULTS

Of the 72 enrolled patients, 71 were treated. The ORR (95% CI) was 0%, 6.7% (0.2-32.0), 40.0% (16.3-67.7), and 46.7% (21.3-73.4) in cohorts 1-4, respectively; iORR was 3.8% (0.1-19.6), 6.7% (0.2-32.0), 53.3% (26.6-78.7), and 46.7% (21.3-73.4). iCRR was 0%, 0%, 13.3%, and 13.3%. Median iPFS (months) was 5.5, 8.2, not estimable [NE], and NE for cohorts 1-4, respectively; iDCR was 50.0%, 40.0%, 73.3%, and 86.7%. Treatment-related adverse events (TRAEs), grade ≥ 3 TRAEs, serious AEs, and fatal AEs occurred in 54 (76.1%), 9 (12.7%), 24 (33.8%), and 10 (14.1%) patients, respectively.

CONCLUSION

T-VEC-pembrolizumab demonstrated antitumor activity and tolerability in PD-1-refractory melanoma, specifically in patients with disease recurrence on or after adjuvant anti-PD-1.

TRIAL REGISTRATION

ClinicalTrials.gov identifier - NCT04068181.

摘要

背景

免疫治疗耐药性黑色素瘤的治疗选择是一个未满足的需求。MASTERKEY-115 是一项 II 期、开放标签、多中心试验，评估了替莫唑胺拉帕替尼（T-VEC）联合 pembrolizumab 治疗既往程序性死亡蛋白-1（PD-1）抑制剂治疗进展的晚期黑色素瘤。

方法

队列 1 和 2 包括分别具有原发性或获得性耐药性且在最后一次抗 PD-1 剂量后 12 周内疾病进展的不可切除/转移性黑色素瘤患者。队列 3 和 4 包括接受完全手术、辅助抗 PD-1 治疗且复发的可切除疾病患者。队列 3 在开始辅助抗 PD-1 治疗后且在确认复发前疾病无进展时间<6 个月，队列 4 疾病无进展时间≥6 个月。主要终点是根据 RECIST v1.1 评估的客观缓解率（ORR）。次要终点包括完全缓解率（CRR）、疾病控制率（DCR）和根据 RECIST v1.1 和 irRC-RECIST 评估的无进展生存期（PFS）以及安全性。

结果

在 72 名入组患者中，71 名接受了治疗。在队列 1-4 中，ORR（95%CI）分别为 0%、6.7%（0.2-32.0）、40.0%（16.3-67.7）和 46.7%（21.3-73.4）；iORR 分别为 3.8%、6.7%、53.3%和 46.7%。iCRR 分别为 0%、0%、13.3%和 13.3%。队列 1-4 的中位 iPFS（月）分别为 5.5、8.2、不可估计（NE）和 NE。iDCR 分别为 50.0%、40.0%、73.3%和 86.7%。54 名（76.1%）、9 名（12.7%）、24 名（33.8%）和 10 名（14.1%）患者分别发生治疗相关不良事件（TRAEs）、≥3 级 TRAEs、严重不良事件和致命不良事件。