Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study
Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study
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DOI：
10.1200/jco.20.02923
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发表时间：
2021-08-01
影响因子：
45.3
通讯作者：
Schilsky, Richard L.
中科院分区：
文献类型：
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作者：
Alva, Ajjai S.;Mangat, Pam K.;Schilsky, Richard L.
TAPUR研究是一项II期篮式试验，旨在鉴定市售靶向药物在晚期癌症患者中的抗肿瘤活性信号，这些晚期癌症患者的基因组改变已知是药物靶点。报告了接受派姆单抗治疗的高肿瘤突变负荷（HTMB）转移性乳腺癌（mBC）患者队列的结果。方法晚期mBC患者接受标准剂量的帕博利珠单抗2 mg/kg或200 mg输注，每3周1次。采用Simon的两阶段设计，疾病控制（DC）的主要研究终点定义为至少持续16周的客观缓解或疾病稳定。如果I期有2名或更多患者达到DC，则该队列将在II期招募另外18名患者。次要终点包括无进展生存期（PFS）、总生存期和安全性。结果2016年10月至2018年7月入组了28例患者。所有患者的肿瘤具有HTMB，范围为9至37个突变/兆碱基。分别在37%（95% CI，21 - 50）和21%（95% CI，8 - 41）的患者中观察到DC和客观缓解。中位PFS为10.6周（95% CI，7.7 - 21.1）;中位总生存期为30.6周（95% CI，18.3 - 103.3）。未观察到PFS与肿瘤突变负荷之间的关系。5例患者发生≥ 1起严重不良事件或至少可能与帕博利珠单抗相关的3级不良事件，与产品标签一致。结论Pembrolizumab单药治疗在以HTMB为特征的mBC患者中具有抗肿瘤活性。我们的研究结果支持最近美国食品和药物管理局批准派姆单抗用于治疗患有不可切除或转移性实体瘤的HTMB患者，而无需替代治疗方案。
PURPOSE The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported. METHODS Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety. RESULTS Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced >= 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label. CONCLUSION Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.