Targeted therapeutics have made notable inroads in treating colorectal cancer, including for patients with metastatic colorectal cancer (mCRC) with amplification of the human epidermal growth factor receptor 2 (HER2) gene, a proto-oncogene located on the long arm of chromosome 17. Experts theorize that research will eventually produce even more effective treatments down the road.

A team of researchers reviewed clinical studies involving a number of therapeutic approaches to HER2-amplified mCRC. Their analysis was published in JCO Oncology Practice.

The researchers reviewed the following recent trials that evaluated the efficacy of therapies targeting HER2 in combination with another agent:

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  • HERACLES trial evaluated the efficacy of the monoclonal antibody trastuzumab and the tyrosine kinase inhibitor (TKI) lapatinib in certain patients with HER2-amplified mCRC.
  • HERACLES B trial investigated the safety and efficacy of a combination of pertuzumab and ado-trastuzumab emtansine (T-DM1) in patients with metastatic RAS/RAF wild-type HER2-amplified CRC.
  • MyPathway and TAPUR trials, both phase 2 multiple basket trials, assessed the efficacy of trastuzumab in combination with pertuzumab in patients with chemotherapy-refractory HER2-amplified mCRC.
  • TRIUMPH trial also examined the efficacy of the trastuzumab/pertuzumab combination in patients with HER2-amplified RAS wild-type mCRC.
  • MOUNTAINEER trial investigated the clinical activity of tucatinib, a potent HER2-specific TKI, in combination with trastuzumab in patients with chemotherapy-refractory HER2-amplified RAS wild-type mCRC.
  • DESTINY-CRC01 trial examined the safety and efficacy of trastuzumab-deruxtecan (T-DXd) in chemotherapy-refractory, HER2-expressing RAS/RAF wild-type mCRC.

These clinical trials demonstrated the actionability of HER2 amplification in mCRC using the combination of a monoclonal antibody with TKIs or antibody-drug conjugates. “This progress will continue to evolve and change the treatment paradigm for HER2-amplified mCRC,” the researchers said in their report.

The research team also pointed to the potential of several novel approaches that are under investigation for the treatment of HER2-amplified mCRC, including the combination of neratinib plus trastuzumab or neratinib plus cetuximab in patients with wild-type RAS/RAF/PIK3CA mCRC. Furthermore, research into approaches to induce antitumor immunity are also underway, such as a phase 2 trial investigating the use of zanidatamab (ZW25) with standard first-line chemotherapy.

In highlighting the substantial progress achieved by many of the trials investigating the therapeutic approaches for HER2 targeting, some of which are already standard of care, the researchers concluded, “This head-spinning progress will continue to evolve, and in the near future, the addition of immune checkpoint inhibitors will likely further enhance the efficacy of these agents.”

Disclosures: Some authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Karan C, Tan E, Sarfraz H, et al. Human epidermal growth factor receptor 2–targeting approaches for colorectal cancer: clinical implications of novel treatments and future therapeutic avenues. JCO Oncol Pract . 2022;18(8):545-554. doi:10.1200/OP.21.00904