HER2-targeted therapy should be shifted towards an earlier line for patients with anti-EGFR-therapy naïve, HER2-amplified metastatic colorectal cancer.

Bregni and colleagues suggested potential clinical utility for anti-epidermal growth factor receptor (EGFR) therapy in HER2-amplified metastatic colorectal cancer (mCRC), based on re-evaluation of the HERACLES study in which 14/26 patients with HER2-amplified mCRC had stable disease ≥6 months with that treatment.1 However, it is difficult to prove the presence of a survival benefit from anti-EGFR therapy due to the lack of a control. We previously reported progression-free survival (PFS) with anti-EGFR therapy was significantly shorter in patients with HER2-amplified mCRC versus those with wild-type RAS/BRAF (median PFS 2.6 vs 6.0 months; HR 3.89; 95% CI 1.49 to 10.18) and similar to those with mutant RAS (median PFS 2.6 vs 2.2 months; HR 1.05; 95% CI 0.38 to 2.92).2 Also, Korean investigators showed HER2-amplified patients treated with cetuximab±irinotecan had significantly shorter PFS vs those with non-amplified HER2 (median 3.1 vs 5.6 months; HR 2.73; 95% CI 1.18 to 6.31), among patients with refractory mCRC with wild-type RAS/BRAF.3 Consistent clinical Japanese and Korean efficacy data, plus preclinical results,4 suggest HER2-amplified mCRC will demonstrate primary resistance to anti-EGFR therapy.

The authors also indicated liquid biopsy was clinically useful in assessing HER2 amplification as an acquired anti-EGFR therapy resistance mechanism. However, it remains unclear whether acquired HER2 amplification is targetable. To address this issue, we evaluated emerging genomic alterations in circulating tumour DNA (ctDNA) after anti-EGFR therapy in 55 patients with RAS wild-type and HER2-non-amplified mCRC. HER2 amplifications were newly identified after therapy only in three patients (5.5%), with a low median copy number (adjusted value=4.0), suggesting it could not be targeted (UMIN000029315). Moreover, the MyPathway trial showed that patients with mCRC who were naïve to anti-EGFR therapy had better outcomes with dual-targeted HER2-directed therapy (trastuzumab plus pertuzumab) versus those receiving prior anti-EGFR treatment.5

Given the primary resistance to anti-EGFR therapy, the low prevalence of targetable acquired HER2 amplification after anti-EGFR therapy and promising clinical activity with HER2-directed dual-targeted therapy (particularly for patients with mCRC who are naïve to anti-EGFR agents), we recommend anti-EGFR-therapy naïve patients with a distinct subtype of HER2-amplified mCRC should have HER2-targeted treatment investigated in an earlier line. Note, in a situation that requires immediate determination of HER2 status, such as first-line treatment, ctDNA analysis, with its rapid turnaround time, can potentially take the place of tissue-based biomarker tests.