CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Pembrolizumab and Olaparib (POLAR) Maintenance Therapy in Metastatic Pancreatic Cancer With or Without Homologous Repair Deficiency: A Biomarker Selected Phase II Trial.
Pembrolizumab and Olaparib (POLAR) Maintenance Therapy in Metastatic Pancreatic Cancer With or Without Homologous Repair Deficiency: A Biomarker Selected Phase II Trial.
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II期POLAR试验评估了维持治疗pembrolizumab联合olaparib，用于63例铂类化疗后疾病得到控制的转移性胰腺癌患者。根据同源重组缺陷（HRD）类型，前瞻性分为3个队列：A组（BRCA1/2或PALB2突变导致HRD，N=33）、B组（非核心HRD突变，N=15）及C组（铂类敏感但无HRD突变，N=15）。A组采用两阶段设计，共同主要终点为客观缓解率（ORR）43%和按实体瘤疗效评价标准（RECIST）1.1计算的6个月无进展生存率77%。A组ORR为35%（95% CI：15–59），6个月PFS率为64%（95% CI：49–82），未达到主要终点。
存活患者中（N=17），中位随访时间为26.0个月（范围：1.4–52.5），2年总生存率为56%（95% CI：41–76）。A组中位PFS为8.3个月（95% CI：5.3–未达到），B组为4.8个月（95% CI：4–12），C组为3.3个月（95% CI：1.9–4.8）。预先计划的转化研究分析显示，循环游离DNA（cfDNA）分子应答、TIL密度高，以及移码插入/缺失和新抗原丰度增加，均与持久获益相关，尤其是在HRD肿瘤中。这些发现支持对胰腺癌生物标志物定义亚组采用精准免疫治疗策略。ClinicalTrials.gov注册号：NCT04666740。
The phase 2 POLAR trial evaluated maintenance pembrolizumab plus olaparib in 63 participants with metastatic pancreatic cancer with disease control on platinum-based chemotherapy. Participants were prospectively stratified into three cohorts by type of HRD: Cohort A (homologous recombination deficient [HRD] by BRCA1/2 or PALB2 mutations, N=33), Cohort B (non-core HRD mutations, N=15), and Cohort C (platinum-sensitive without HRD mutations, N=15). Cohort A used a two-stage design with co-primary endpoints of objective response rate (ORR) 43% and 6-month progression-free survival 77% per Response Evaluation Criteria in Solid Tumors (RECIST) version 1. 1.
For Cohort A, ORR was 35% (95% CI: 15-59) and 6-month-PFS rate was 64% (95% CI: 49-82), not meeting the primary endpoint. Among surviving participants (N=17), the median follow-up was 26. 0 months (range: 1. 4-52. 5), and the 2-year overall survival rate was 56% (95% CI: 41-76). Median PFS for Cohort A was 8. 3 months (95% CI: 5. 3-not reached), 4.
8 months (95% CI: 4-12) for Cohort B, and 3. 3 months (95% CI: 1. 9-4. 8) for Cohort C. Pre-planned translational profiling demonstrated that molecular response by circulating cell-free DNA (cfDNA), high tumor-infiltrating lymphocyte (TIL) density, and increased abundance of frameshift indels and neoantigens were associated with durable benefit, particularly in HRD tumors.
These findings support a precision immunotherapy approach for biomarker-defined subsets of pancreatic cancer. ClinicalTrials. gov identifier: NCT04666740.
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