Dr Foote on the Use of Tucatinib Plus Trastuzumab in HER2-Amplified mCRC

Michael Foote, MD, medical oncologist, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses the use of tucatinib (Tukysa) plus trastuzumab (Herceptin) compared with chemotherapy in the management of HER2-amplified metastatic colorectal cancer (mCRC).

Although mutations in HER2 can occur in mCRC, they are unlikely to be responsible for the initiation of HER2-positive cancer, Foote clarifies. Instead HER2 amplification has been implicated as the oncogenic driver and is therefore a clinically actionable target for treatment approaches, Foote says.

On January 19, 2023, the FDA granted accelerated approval to tucatinib and trastuzumab for the treatment of patients with RAS wild-type HER2-positive unresectable or metastatic colorectal cancer who progressed on prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This approval was based on efficacy data from the phase 2 MOUNTAINEER study (NCT03043313).

In this combination, trastuzumab works by binding to the extracellular HER2 receptor, Foote explains. Meanwhile, the TKI tucatinib operates intracellularly by inhibiting kinase signaling pathways, thereby preventing proliferation, he details.

According to data from the primary analysis of the MOUNTAINEER study, the combination of tucatinib and trastuzumab is well tolerated, and adverse effects (AEs) were deemed manageable, Foote reports. The combination regimen has a similar safety profile to that of chemotherapy, with the most common AE being diarrhea, followed by fatigue. However, the treatment discontinuation rate with the combination regimen is lower than that of chemotherapy, Foote states.

Notably, median overall survival (OS) with the combination in patients who were heavily pretreated and displayed resistance to chemotherapy was 2 years, Foote adds. This is substantially longer than the OS rate with chemotherapy, as chemotherapy resistance often develops within a few months of treatment initiation, Foote notes. Moreover, the overall response rate was 38.1%, and the median duration of response was 12.4 months in patients treated with the combination, Foote concludes.