RAS wild-type + HER-2 positive

While dual-HER2 inhibition has shown promising clinical activity in patients with RAS wild-type HER2-positive metastatic colorectal cancer, predictive biomarkers of response/resistance are less well characterized. Activating HER2/RTK/MAPK genomic alterations appear to blunt the clinical benefit of dual anti-HER2 therapy and may hold a potential albeit partial role in patient selection.

PRESSING-HER2 panel and HER2 non-amplified status by NGS warrant validation as potential predictive markers in this setting.

On January 29, 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab for the treatment of patients with unresectable or metastatic RAS wild-type, HER2-positive colorectal cancer who have received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan. This is the first approval for the subset of patients with HER2-positive colorectal cancer. This article summarizes the FDA's thought process and review of data supporting this accelerated approval.

P2, N=25, Not yet recruiting, University of Wisconsin, Madison

Tucatinib plus trastuzumab had clinically meaningful anti-tumour activity and favourable tolerability. This treatment is the first US Food and Drug Administration-approved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer.

" We conducted a multicentric case-control study to evaluate the negative predictive impact of a panel of candidate genomic alterations of primary resistance (PRESSING-HER panel) in pts with HER2-positive, RAS wt mCRC treated with trastuzumab-based dual HER2 blockade... The combined assessment of HER2 on/off-target alterations and HER2 GCN stratifies patient outcomes to HER2 dual blockade."

P2, N=37, Recruiting, Memorial Sloan Kettering Cancer Center