Dr. Bekaii-Saab on the Rationale to Explore Tucatinib/Trastuzumab in HER2-Overexpressing mCRC

Tanios S. Bekaii-Saab, MD, FACP, medical oncologist, medical director, Cancer Clinical Research Office, vice chair and section chief, Medical Oncology, Department of Internal Medicine, Mayo Clinic, discusses the rationale to explore the combination of tucatinib and trastuzumab (Herceptin) in patients with HER2-overexpressing metastatic colorectal cancer (mCRC).

HER2 is relatively rare in mCRC, accounting for approximately 4% of patients with the disease, says Bekaii-Saab. However, preclinical and clinical studies have shown that dual blockade of HER2 is superior to single-agent blockade in HER2-overexpressing mCRC. For example, in the phase II HERACLES trial, the combination of lapatinib (Tykerb) and trastuzumab induced an objective response rate (ORR) in approximately 30% of patients with HER2-overexpressing disease. Moreover, in the phase IIa MyPathway trial, the combination of pertuzumab (Perjeta) and trastuzumab showed a similar ORR. However, lapatinib and pertuzumab have a significant incidence of off-target toxicities, adds Bekaii-Saab.

Tucatinib, however, is a potent and highly specific HER2 inhibitor with low off-target toxicity. As such, investigators launched the phase II MOUNTAINEER trial to evaluate its efficacy in combination with trastuzumab.