Dr Hays on the Significance of the Tucatinib/Trastuzumab Approval in HER2-Positive mCRC

John L. Hays, MD, PhD, assistant professor, Department of Internal Medicine, The Ohio State University, member, Translational Therapeutics Program, The Ohio State University Comprehensive Cancer Center–James, discusses the significance of the approval for tucatinib (Tukysa) and trastuzumab (Herceptin) for patients with HER2-positive metastatic colorectal cancer (mCRC).

Prior research into the treatment of patients with mCRC has revealed that a small patient subset of those with mCRC will express HER2. Within this population, patients who were heavily pretreated with standard-of-care 5-fluorouracil (5-FU)–based regimens were shown to respond well to HER2-targeted therapies, Hays begins. Several phase 2 trials have shown benefit with various combinations of small-molecule inhibitors, antibodies targeting HER2, or antibody-drug conjugates (ADCs), Hays adds. For example, the DESTINY-CRC01 trial (NCT03384940) of fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated the agent’s ability to produce durable responses in patients with HER2-positive mCRC. However, this and other trials have not yet led to approvals in this disease space.

The treatment armamentarium for these patients was recently expanded with the FDA accelerated approval of tucatinib in combination with trastuzumab in January 2023, Hays continues. This approval was based on data from the phase 2 MOUNTAINEER trial (NCT03043313), which included 84 patients with RAS wild-type, HER2-positive unresectable or metastatic disease that had progressed on treatment with fluoropyrimidine, oxaliplatin, and irinotecan, as well as an anti-vascular endothelial growth factor (VEGF) monoclonal antibody.

At a median follow-up of 20.7 months, results showed that the combination elicited an overall response rate of 38% (95% CI, 28%-49%). This consisted of 3.6% of patients who experienced a complete response, and 35% of patients who had a partial response, he reports. Moreover, the median duration of response with trastuzumab plus tucatinib was 12.4 months (95% CI, 8.5-20.5). No treatment-related deaths were reported, and 5.8% of patients discontinued treatment. Common adverse effects included diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia.

Prior to this approval, patients who progressed on standard 5-FU–based regimens had few avenues for continued treatment, Hays notes. This regimen provides another effective, tailored approach for this patient subset, he concludes.