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

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

doi:10.1038/s41591-021-01553-w

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.

Highlights

The applicability of circulating tumor DNA genotyping to inform enrollment of patients with cancer in clinical trials has not been established
Based on a large-scale nationwide screening platform—the SCRUM-Japan GI-SCREEN and the GOZILA networks—we designed TRIUMPH, a phase 2 trial to evaluate the efficacy of pertuzumab plus trastuzumab in patients with metastatic colorectal cancer (mCRC) with RAS wild-type and human epidermal growth factor receptor 2 (HER2) amplification prospectively confirmed by tumor tissue or circulating tumor DNA (ctDNA) analysis
HER2 amplification was lost in four patients. This phase 2 trial met its primary endpoint, showing anti-tumor activity of pertuzumab plus trastuzumab with a confirmed objective response rate (ORR) of 30% and 28% in patients with mCRC harboring HER2 amplification prospectively confirmed by tumor tissue or ctDNA analysis, respectively

Summary

Introduction

The applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. Based on a large-scale nationwide screening platform—the SCRUM-Japan GI-SCREEN and the GOZILA networks—we designed TRIUMPH, a phase 2 trial to evaluate the efficacy of pertuzumab plus trastuzumab in patients with mCRC with RAS wild-type and HER2 amplification prospectively confirmed by tumor tissue or ctDNA analysis.

Results

Conclusion