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

被引：160

作者：

Nakamura, Yoshiaki ^{[1
,2
]}

Okamoto, Wataru ^{[1
,2
,3
]}

Kato, Takeshi ^{[4
]}

Esaki, Taito ^{[5
]}

Kato, Ken ^{[6
]}

Komatsu, Yoshito ^{[7
]}

Yuki, Satoshi ^{[8
]}

Masuishi, Toshiki ^{[9
]}

Nishina, Tomohiro ^{[10
]}

Ebi, Hiromichi ^{[11
]}

Sawada, Kentaro ^{[1
,12
]}

Taniguchi, Hiroya ^{[1
,2
,9
]}

Fuse, Nozomu ^{[13
]}

Nomura, Shogo ^{[13
]}

Fukui, Makoto ^{[13
]}

Matsuda, Seiko ^{[13
]}

Sakamoto, Yasutoshi ^{[2
]}

Uchigata, Hiroshi ^{[2
]}

Kitajima, Kana ^{[2
]}

Kuramoto, Naomi ^{[2
]}

Asakawa, Takashi ^{[14
]}

Olsen, Steve ^{[15
]}

Odegaard, Justin, I ^{[16
]}

Sato, Akihiro ^{[13
]}

Fujii, Satoshi ^{[17
,18
]}

Ohtsu, Atsushi ^{[1
]}

Yoshino, Takayuki ^{[1
]}

机构：

[1] Natl Canc Ctr Hosp East, Dept Gastroenterol & Gastrointestinal Oncol, Kashiwa, Chiba, Japan

[2] Natl Canc Ctr Hosp East, Translat Res Support Sect, Kashiwa, Chiba, Japan

[3] Hiroshima Univ Hosp, Canc Treatment Ctr, Hiroshima, Japan

[4] Natl Hosp Org Osaka Natl Hosp, Dept Surg, Osaka, Japan

[5] Natl Hosp Org Kyushu Canc Ctr, Dept Gastrointestinal & Med Oncol, Fukuoka, Japan

[6] Natl Canc Ctr, Dept Head & Neck, Esophageal Med Oncol, Tokyo, Japan

[7] Hokkaido Univ Hosp, Dept Canc Ctr, Sapporo, Hokkaido, Japan

[8] Hokkaido Univ Hosp, Dept Gastroenterol & Hepatol, Sapporo, Hokkaido, Japan

[9] Aichi Canc Ctr Hosp, Dept Clin Oncol, Nagoya, Aichi, Japan

[10] Natl Hosp Org Shikoku Canc Ctr, Gastrointestinal Med Oncol, Matsuyama, Ehime, Japan

[11] Aichi Canc Ctr Res Inst, Div Mol Therapeut, Nagoya, Aichi, Japan

[12] Kushiro Rosai Hosp, Dept Med Oncol, Kushiro, Hokkaido, Japan

[13] Natl Canc Ctr Hosp East, Clin Res Support Off, Kashiwa, Chiba, Japan

[14] Chugai Pharmaceut Co Ltd, Tokyo, Japan

[15] Guardant Hlth AMEA, Clin & Med Affairs, Redwood City, CA USA

[16] Guardant Hlth, Clin Dev, Redwood City, CA USA

[17] Natl Canc Ctr, Div Pathol, Exploratory Oncol Res & Clin Trial Ctr, Kashiwa, Chiba, Japan

[18] Yokohama City Univ, Dept Mol Pathol, Grad Sch Med, Yokohama, Kanagawa, Japan

来源：

NATURE MEDICINE | 2021年 / 27卷 / 11期

关键词：

RESISTANCE; MULTICENTER; THERAPY;

D O I：

10.1038/s41591-021-01553-w

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1899 / +

页数：20

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