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

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.

Human Epidermal Growth Factor Receptor 2 Overexpression and Amplification in Patients With Colorectal Cancer: A Large-Scale Retrospective Study in Chinese Population

“…Additionally, we did not perform NGS analysis in the matching peripheral blood to verify the consistency of HER2 amplification with tissue. A recent clinical trial showed that identification of the HER2 status by circulating tumor DNA (ctDNA) showed similar accuracy to conventional tissue genotyping ( 23 ). Although this suggests that ctDNA has good application value in identifying patients who benefit from the dual-HER2 blockade and monitor treatment response, it is still necessary to conduct a large number and detailed comparative analyses on the expression profile of HER2 in tissues and ctDNA and to comprehensively judge the clinical applicability of ctDNA genotyping on HER2 amplification.…”

Human Epidermal Growth Factor Receptor 2–Targeting Approaches for Colorectal Cancer: Clinical Implications of Novel Treatments and Future Therapeutic Avenues

“…The concordance of HER2 amplification results between tissue-based testing and blood-based ctDNA testing was noted to be 83%. 41 The confirmed ORR was 30% in patients with tissue-based confirmatory testing with positive HER2 amplification and 28% among patients with HER2 amplification determined by ctDNA. For patients with positive tissue confirmation, the median PFS was 4.0 months, the median OS was 10.1 months, and the median PFS and OS were 3.1 months and 8.8 months for patients with ctDNA testing, respectively.…”

The current state of molecular profiling in gastrointestinal malignancies

“…Another good example of ctDNA application is in HER2 amplified disease. Recent prospective trials have suggested that plasma HER2 amplifications predict response to HER2-directed therapies such as lapatinib, trastuzumab, pertuzumab, and fam-trastuzumab deruxtecan-nxki (T-DXd) [ 136 – 139 ]. For example, better responses to T-DXd in gastric cancers were seen when plasma HER2 and higher copy number amplifications were detected [ 138 ].…”

“…For example, better responses to T-DXd in gastric cancers were seen when plasma HER2 and higher copy number amplifications were detected [ 138 ]. Also, changes in plasma copy number during HER2-directed therapy were associated with therapeutic response and survival in upper GI cancers and CRCs [ 122 , 136 , 137 , 139 ]. Baseline and emerging resistance mutations detected in the plasma at the time of progression, such as MYC , EGFR , FGFR2 , and MET amplification, have also been reported along with promising therapeutic strategies to overcome resistance, including combining anti-HER2 and other targeted or immune therapies [ 136 , 139 ].…”