日本国家癌症中心Takayuki Yoshino研究团队完成循环肿瘤DNA指导下的帕妥珠单抗加曲妥珠单抗治疗HER2扩增型转移性结直肠癌的临床试验。该项研究成果于2021年11月11日在线发表在《自然—医学》杂志上。

研究人员进行了一项2期试验，评估帕妥珠单抗加曲妥珠单抗治疗转移性结直肠癌（mCRC）的疗效，通过肿瘤组织或循环肿瘤DNA（ctDNA）分析前瞻性地确认人类表皮生长因子受体2（HER2）扩增（UMIN000027887）。30名mCRC患者的组织和/或ctDNA中确认了HER2扩增。该研究达到了主要终点，27名组织阳性患者的确认客观反应率为30%，25名ctDNA阳性患者的确认客观反应率为28%，而在匹配的真实世界参考人群中，接受标准护理挽救治疗的客观反应率为0%。

事后探索性分析显示，HER2拷贝数的基线ctDNA基因分型和同时发生的致癌性改变经肿瘤分型调整后，根据疗效对患者进行分层，其准确性与组织基因分型相似。治疗开始后3周ctDNA分数的减少与治疗反应有关。帕妥珠单抗加曲妥珠单抗对组织或ctDNA中HER2扩增型mCRC患者显示出相似的疗效，表明ctDNA基因分型可以识别从双HER2阻断中获益的患者，并监测治疗反应。这些发现证明了ctDNA基因分型在HER2扩增型mCRC临床试验中的进一步应用，这可能特别有利于一线治疗的患者。

据了解，ctDNA的基因分型是否适用于在临床试验中为癌症患者的入组提供信息尚未确定。

附：英文原文

Title: Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial

Author: Nakamura, Yoshiaki, Okamoto, Wataru, Kato, Takeshi, Esaki, Taito, Kato, Ken, Komatsu, Yoshito, Yuki, Satoshi, Masuishi, Toshiki, Nishina, Tomohiro, Ebi, Hiromichi, Sawada, Kentaro, Taniguchi, Hiroya, Fuse, Nozomu, Nomura, Shogo, Fukui, Makoto, Matsuda, Seiko, Sakamoto, Yasutoshi, Uchigata, Hiroshi, Kitajima, Kana, Kuramoto, Naomi, Asakawa, Takashi, Olsen, Steve, Odegaard, Justin I., Sato, Akihiro, Fujii, Satoshi, Ohtsu, Atsushi, Yoshino, Takayuki

Issue&Volume: 2021-11-11

Abstract: The applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. We conducted a phase 2 trial to evaluate the efficacy of pertuzumab plus trastuzumab for metastatic colorectal cancer (mCRC), with human epidermal growth factor receptor 2 (HER2) amplification prospectively confirmed by tumor tissue or ctDNA analysis (UMIN000027887). HER2 amplification was confirmed in tissue and/or ctDNA in 30 patients with mCRC. The study met the primary endpoint with a confirmed objective response rate of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an objective response rate of 0% in a matched real-world reference population treated with standard-of-care salvage therapy. Post hoc exploratory analyses revealed that baseline ctDNA genotyping of HER2 copy number and concurrent oncogenic alterations adjusted for tumor fraction stratified patients according to efficacy with similar accuracy to tissue genotyping. Decreased ctDNA fraction 3 weeks after treatment initiation associated with therapeutic response. Pertuzumab plus trastuzumab showed similar efficacy in patients with mCRC with HER2 amplification in tissue or ctDNA, showing that ctDNA genotyping can identify patients who benefit from dual-HER2 blockade as well as monitor treatment response. These findings warrant further use of ctDNA genotyping in clinical trials for HER2-amplified mCRC, which might especially benefit patients in first-line treatment.

DOI: 10.1038/s41591-021-01553-w

Source: https://www.nature.com/articles/s41591-021-01553-w