ctDNA-Guided Therapy with Pertuzumab plus Trastuzumab for HER2-Amplified mCRC

Based on the results from the TRIUMPH, a multicenter, open-label, single-arm, phase II study, a group of Japanese researchers led by Dr Takayuki Yoshino of the Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East in Kashiwa, Japan recommend the implementation of both circulating tumour DNA (ctDNA) genotyping and tissue HER2 testing in clinical practice for patients with metastatic colorectal cancer (mCRC) to identify candidates for dual-HER2 blockade treatment with pertuzumab plus trastuzumab. TRIUMPH evaluated the efficacy of pertuzumab plus trastuzumab in patients with mCRC with RAS wild-type and HER2 amplification prospectively confirmed by tumour tissue or ctDNA analysis. The findings are published on 11 November 2021 in the Nature Medicine.

In total, 30 patients with HER2 amplification were enroled in TRIUMPH; most patients were overlapped in both tissue-positive and ctDNA-positive groups. HER2 amplification was confirmed in both tissue and ctDNA for 22 of 30 patients (in tissue alone for 5 and in ctDNA alone for 3); therefore, 27 and 25 patients were assigned to tissue-positive and ctDNA-positive groups. One patient with HER2 amplification confirmed in HER2-Screening but for whom a baseline ctDNA result was unavailable was assigned only to the tissue-positive group. The median follow-up was 9.2 months in patients with tissue-positive and 7.6 months in patients with ctDNA-positive.

The study met the primary endpoint with a confirmed objective response rate (ORR) of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an ORR 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 tumour 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 studies for HER2-amplified mCRC, which might especially benefit patients in first-line treatment.

The authors wrote that the limitations of their study are relatively small sample size and use of a registry control arm. Despite this, the observed efficacy data are consistent with those from the similar phase II studies that explored dual-HER2 blockade for mCRC. Moreover, the markedly improved ORR observed in TRIUMPH relative to the real-world reference population strongly supports the activity of pertuzumab plus trastuzumab in patients with RAS wild-type and HER2-amplified mCRC confirmed by tissue or ctDNA analysis.

Findings from the TRIUMPH study show the utility of ctDNA genotyping as a screening platform to select patients with HER2-amplified mCRC who benefit from dual-HER2 blockade with trastuzumab and pertuzumab.

Reference

Nakamura Y, Okamoto W, Kato T, et al. Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial. Nature Medicine 2021;27:1899-1903.

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