Unlocking HER2 as a target in KRAS-mutated rectal cancer: a case of significant response to zanidatamab-based regimen

Colorectal cancer (CRC) with human epidermal growth factor receptor 2 (HER2) overexpression and RAS mutations is often associated with poor response to conventional treatments, presenting substantial therapeutic challenges. This report describes a remarkable response in a patient with HER2-amplified, KRAS-mutated metastatic rectal cancer, who was treated with a zanidatamab-based combination regimen.

A 54-year-old male was admitted to our hospital complaining of hematochezia and was diagnosed with rectal adenocarcinoma via biopsy. Baseline imaging revealed extensive, unresectable liver metastases. Next-generation sequencing identified a KRAS G12D mutation alongside HER2 amplification. Although the combination of chemotherapy and bevacizumab yielded promising efficacy, but tumor markers still remained high. When the anti-HER2 bispecific antibody zanidatamab was added, after three cycles of this triplet therapy, the liver metastases exhibited radiographic regression, and tumor markers showed substantial decline. The patient achieved sufficient downstaging and subsequently underwent successful hepatic resection. Pathological examination confirmed negative surgical margins.

This case underscores the potential of HER2 inhibition as an effective therapeutic strategy in KRAS-mutated CRC. It also highlights zanidatamab's promise as part of a conversion therapy approach in patients with historically refractory disease.