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循环肿瘤DNA指导转移性结直肠癌帕尼单抗再激发的2期CHRONOS试验
作者:小柯机器人 发布时间:2022/8/5 15:58:15

意大利都灵大学Alberto Bardelli团队近期取得重要工作进展,他们完成了循环肿瘤DNA(ctDNA)指导转移性结直肠癌帕尼单抗再激发治疗的2期CHRONOS试验。该项研究成果2022年8月1日在线发表于《自然—医学》杂志上。

课题组研究人员之前的研究表明,在EGFR阻断期间出现在循环肿瘤DNA(ctDNA)中的RAS BRAFEGFR突变等位基因在停止治疗后会下降。研究人员假设监测血液中的耐药突变可以合理地指导随后的抗EGFR抗体治疗。他们在这里报告了CHRONOS的结果,这是一项开放单臂2期临床试验,利用基于血液的RAS/BRAF/EGFR突变水平鉴定来定制帕尼单抗的无化疗抗EGFR再激发。主要终点是客观反应率。次要终点是无进展生存期、总生存期、安全性和耐受性。

在CHRONOS中,组织RAS野生型肿瘤患者在先前使用基于抗EGFR的方案治疗后接受了基于ctDNA的介入性筛查。在52名患者中,16名(31%)携带至少一种突变导致对抗EGFR治疗产生耐药性并被排除在外。达到了试验的主要终点;并且,在27名入组患者中,8名(30%)实现了部分缓解和17名(63%)达到疾病控制,其中包括2名未经证实的缓解。这些临床结果优于标准三线治疗,表明介入性液体活检可以及时有效、安全地用于指导mCRC患者使用帕尼单抗进行抗EGFR再激发治疗。有必要进行更大规模的随机试验,以正式比较帕尼单抗再激发治疗与该患者环境中的标准护理疗法。

据介绍,抗表皮生长因子受体(EGFR)单克隆抗体已被批准用于RAS野生型转移性结直肠癌(mCRC)的治疗,但耐药突变的出现限制了其疗效。

附:英文原文

Title: Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial

Author: Sartore-Bianchi, Andrea, Pietrantonio, Filippo, Lonardi, Sara, Mussolin, Benedetta, Rua, Francesco, Crisafulli, Giovanni, Bartolini, Alice, Fenocchio, Elisabetta, Amatu, Alessio, Manca, Paolo, Bergamo, Francesca, Tosi, Federica, Mauri, Gianluca, Ambrosini, Margherita, Daniel, Francesca, Torri, Valter, Vanzulli, Angelo, Regge, Daniele, Cappello, Giovanni, Marchi, Caterina, Berrino, Enrico, Sapino, Anna, Marsoni, Silvia, Siena, Salvatore, Bardelli, Alberto

Issue&Volume: 2022-08-01

Abstract: Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.

DOI: 10.1038/s41591-022-01886-0

Source: https://www.nature.com/articles/s41591-022-01886-0

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex