Jeffrey A How, Minghao Dang, Sanghoon Lee, Bryan Fellman, Shannon N Westin, Anil K Sood, Nicole D Fleming, Aaron Shafer, Ying Yuan, Jinsong Liu, Li Zhao, Joseph Celestino, Richard Hajek, Margaret B Morgan, Edwin R Parra, Caddie D Laberiano Fernandez, Claudio A Arrechedera, Luisa Maren Solis Soto, Kathleen M Schmeler, Alpa Nick, Karen H Lu, Robert Coleman, Linghua Wang, Amir A Jazaeri
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Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood.</p><p><strong>Methods: </strong>In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples.</p><p><strong>Findings: </strong>Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling.</p><p><strong>Conclusions: </strong>Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. 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引用次数: 0
摘要
背景：pembrolizumab联合化疗在晚期高级别上皮性卵巢癌（EOC）一线治疗中的疗效和可行性尚不清楚。此外，对新辅助治疗后肿瘤微环境的改变也不甚了解：在这项单臂2期试验中（该研究已在ClinicalTrials.gov上注册：NCT02520154），符合条件的患者接受最多4个周期的新辅助化疗，然后进行间歇性细胞减灭术、3个周期的辅助静脉注射卡铂/每周紫杉醇/pembrolizumab，最后维持pembrolizumab直到病情进展或出现毒性反应（最多20个周期）。主要终点是无进展生存期（PFS）。次要终点包括可行性、毒性和总生存期（OS）。对化疗前后的样本进行了PD-L1染色、多重免疫荧光染色、RNA测序和反相蛋白质阵列分析：31名符合条件的患者入组。中位PFS和OS分别为14.88个月（95% CI 12.39-23.00）和57.43个月（95% CI 30.88-未达到）。在PD-L1联合阳性评分（CPS）≥10分的患者中，与CPS评分≥10分的患者相比，中位PFS和OS均未达到结论：Pembrolizumab 联合化疗是可行的，其 PFS 在该 EOC 群体的历史范围内。CPS≥10的患者可能从这一方案中获益更多，未来的研究应调查这一潜在的生物标志物：这项由研究者发起的试验由默克公司资助。
Pembrolizumab plus chemotherapy in frontline treatment of advanced ovarian cancer: Clinical and translational results from a phase 2 trial.
Background: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood.
Methods: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples.
Findings: Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling.
Conclusions: Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker.
Funding: This investigator-initiated trial was funded by Merck.
期刊介绍：
Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically.
Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.
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