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Abstract：
BACKGROUND: The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic next-generation sequencing in patients with advanced cancer and enhance access to molecularly guided treatment options. Academic tumor-agnostic basket phase II studies are part of this initiative. The current investigator-driven trial aimed to investigate the efficacy of olaparib in advanced cancers with a (likely) pathogenic mutation (germline or somatic) in a gene that plays a role in homologous recombination (HR).
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.
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.
摘要：
背景：比利时Precision计划旨在最大程度地在晚期癌症患者中实施与肿瘤无关的下一代测序，并增强对分子指导治疗方案的获取。学术肿瘤无关篮II期研究是该计划的一部分。目前由研究者驱动的试验旨在研究奥拉帕尼在具有（可能的）致病突变（种系或体细胞）的晚期癌症中的疗效，该基因在同源重组（HR）中起作用。
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。
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。
