美国约翰霍普金斯大学医学院Patrick M. Forde、Valsamo Anagnostou等研究人员合作完成durvalumab联合顺铂-培美曲塞治疗不可切除型胸膜间皮瘤的临床试验。相关论文于2021年11月8日在线发表在《自然—医学》杂志上。

研究人员报告了抗PD-L1抗体durvalumab加顺铂-培美曲塞化疗治疗55名先前未治疗、不可切除型胸膜间皮瘤患者的PrE0505期试验（NCT02899195）的结果。主要终点是与顺铂和培美曲塞化疗的历史对照相比的总生存期；次要和探索性终点包括安全性、无进展生存期和反应的生物标志物。durvalumab与化疗的组合达到了预先指定的主要终点，达到了20.4个月的中位生存期，而历史对照组为12.1个月。治疗引起的不良事件与化疗的已知副作用一致，所有因免疫疗法引起的不良事件都是2级或更低。综合基因组和免疫细胞类群分析显示，较高的免疫原性突变负担加上更多样化的T细胞汇演与有利的临床结果有关。

全基因组结构分析显示，上皮性组织学的反应性肿瘤的基因组不稳定性程度较高。癌症易感基因的种系改变，特别是那些参与DNA修复的基因，患者更有可能获得长期生存。这些研究结果表明，durvalumab与铂类化疗同时进行具有良好的临床活性，而且反应是由恶性胸膜间皮瘤的复杂基因组背景驱动的。

据介绍，间皮瘤是一种罕见的致命性癌症，在最近批准联合免疫检查点阻断疗法之前，其治疗选择有限。

附：英文原文

Title: Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial

Author: Forde, Patrick M., Anagnostou, Valsamo, Sun, Zhuoxin, Dahlberg, Suzanne E., Kindler, Hedy L., Niknafs, Noushin, Purcell, Thomas, Santana-Davila, Rafael, Dudek, Arkadiusz Z., Borghaei, Hossein, Lanis, Mara, Belcaid, Zineb, Smith, Kellie N., Balan, Archana, White, James R., Cherry, Christopher, Ashok Sivakumar, I. K., Shao, Xiaoshan M., Chan, Hok Yee, Singh, Dipika, Thapa, Sampriti, Illei, Peter B., Pardoll, Drew M., Karchin, Rachel, Velculescu, Victor E., Brahmer, Julie R., Ramalingam, Suresh S.

Issue&Volume: 2021-11-08

Abstract: Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. Here we report the results of the phase 2 PrE0505 trial (NCT02899195) of the anti-PD-L1 antibody durvalumab plus platinum-pemetrexed chemotherapy for 55 patients with previously untreated, unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historical control with cisplatin and pemetrexed chemotherapy; secondary and exploratory endpoints included safety, progression-free survival and biomarkers of response. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint, reaching a median survival of 20.4 months versus 12.1 months with historical control. Treatment-emergent adverse events were consistent with known side effects of chemotherapy, and all adverse events due to immunotherapy were grade 2 or lower. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire was linked to favorable clinical outcome. Structural genome-wide analyses showed a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to achieve long-term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma.

DOI: 10.1038/s41591-021-01541-0

Source: https://www.nature.com/articles/s41591-021-01541-0