METHODS: This open-label, multi-cohort, phase II study examines the efficacy of olaparib in patients with an HR gene mutation in their tumor and disease progression on standard of care. Patients with a somatic or germline mutation in the same gene define a cohort. For each cohort, a Simon minimax two-stage design was used. If a response was observed in the first 13 patients, 14 additional patients were included. Here, we report the results on four completed cohorts: patients with a BRCA1, BRCA2, CHEK2 or ATM mutation.
RESULTS: The overall objective response rate across different tumor types was 11% in the BRCA1-mutated (n = 27) and 21% in the BRCA2-mutated (n = 27) cohorts. Partial responses were seen in pancreatic cancer, gallbladder cancer, endocrine carcinoma of the pancreas and parathyroid cancer. One patient with a BRCA2 germline-mutated colon cancer has an ongoing complete response with 19+ months on treatment. Median progression-free survival in responding patients was 14+ months (5-34+ months). The clinical benefit rate was 63% in the BRCA1-mutated and 46% in the BRCA2-mutated cohorts. No clinical activity was observed in the ATM (n = 13) and CHEK2 (n = 14) cohorts.
CONCLUSIONS: Olaparib showed efficacy in different cancer types harboring somatic or germline mutations in the BRCA1/2 genes but not in ATM and CHEK2. Patients with any cancer type harboring BRCA1/2 mutations should have access to olaparib.
方法:这个开放标签,多队列,II期研究检查了奥拉帕尼在肿瘤中具有HR基因突变和疾病进展的患者的疗效。具有相同基因中的体细胞或种系突变的患者定义了一个队列。对于每个队列,使用了Simonminimax两阶段设计。如果在前13名患者中观察到反应,包括另外14名患者。这里,我们报告了4个完整队列的结果:BRCA1,BRCA2,CHEK2或ATM突变患者.
结果:不同肿瘤类型的总体客观缓解率在BRCA1突变组(n=27)中为11%,在BRCA2突变组(n=27)中为21%。部分反应见于胰腺癌,胆囊癌,胰腺内分泌癌和甲状旁腺癌。一名BRCA2种系突变的结肠癌患者在治疗19个月后具有持续的完全反应。响应患者的中位无进展生存期为14个月(5-34个月)。BRCA1突变队列的临床获益率为63%,BRCA2突变队列的获益率为46%。在ATM(n=13)和CHEK2(n=14)组群中未观察到临床活性。
结论:Olaparib在BRCA1/2基因中具有体细胞或种系突变的不同癌症类型中显示出疗效,但在ATM和CHEK2中未显示。携带BRCA1/2突变的任何癌症类型的患者都应该可以使用奥拉帕尼。