Positive topline results from the pivotal phase 2 MOUNTAINEER clinical trial investigating tucatinib (Tukysa®; Seagen/Merck/MSD), an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein, in combination with trastuzumab (Herceptin®; Genentech/Roche) in patients with previously treated HER2-positive metastatic colorectal cancer (mCRC) is expected to form the basis of a planned supplemental New Drug Application to the U.S. Food and Drug Administration (FDA) under the FDA’s Accelerated Approval Program.

Currently, tucatinib is indicated in combination with trastuzumab and capecitabine (Xeloda®; Genentech/Roche) for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

Merck, known as MSD outside the U.S. and Canada, is commercializing tucatinib in regions outside of the U.S., Canada and Europe and plans to discuss these results room the MOUNTAINEER study with health authorities as it continues to accelerate the filing of tucatinib in its territory.

Colorectal cancer is the third leading cause of cancer-related deaths in the U.S. and is anticipated to lead to about 52,580 deaths in 2022.[1] Approximately 22% of U.S. patients with colorectal cancer are diagnosed at the advanced stage.[2] Human epidermal growth factor receptor 2 (HER2) is overexpressed in 3-5% of patients with metastatic colorectal cancer.[3][4] There are currently no FDA-approved therapies that specifically target HER2 in colorectal cancer.

“People with HER2-positive previously treated metastatic colorectal cancer have a significant unmet need for new therapies. We are excited by the potential for this tucatinib combination to help patients based on the excellent anti-tumor activity with durable responses and a tolerable safety profile,” noted Roger Dansey, M.D., interim CEO and Chief Medical Officer, Seagen.

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Results from the MOUNTAINEER study, a U.S. and European multicenter, open-label, phase 2 clinical trial of tucatinib in combination with trastuzumab or as a single agent in 117 patients with HER2-positive metastatic or unresectable colorectal cancer following previous standard-of-care therapies, showed a 38.1% confirmed objective response rate (cORR) [95% Confidence Interval (CI): 27.7, 49.3] per blinded independent central review (BICR). The median duration of response (DoR) per BICR was 12.4 months [95% CI: 8.5, 20.5]. The combination of tucatinib and trastuzumab was generally well-tolerated, and the most common (greater than or equal to 20%) treatment-emergent adverse events were diarrhea, fatigue, nausea and infusion-related reaction, which were primarily low-grade.

“Based on the strength of these data, we are planning to engage in regulatory discussions with the FDA with the intent to submit a supplemental New Drug Application for tucatinib,” Dansey added.

Mechanism of action
In in vitro studies, tucatinib inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), tucatinib inhibited the growth of HER2-expressing tumors. The combination of tucatinib and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone.

Full data from the MOUNTAINEER trial will be presented by John H. Strickler, M.D., Duke University Medical Center, at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer in Barcelona, Spain from June 29 through July 2, 2022.

Clinical trial
Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer – NCT03043313

Highlight of prescribing information
Tucatinib (Tukysa®; Seagen/Merck/MSD)(Prescribing Information)
Trastuzumab (Herceptin®; Genentech/Roche)(Prescribing Information)
Capecitabine (Xeloda®; Genentech/Roche)(Prescribing information)

[1] American Cancer Society: Key Statistics for Colorectal Cancer-2022. Online. Last accessed on May 21, 2022.
[2] Wang J., et al. Metastatic patterns and survival outcomes in patients with stage IV colon cancer: A population‐based analysis. Cancer Med. 2020 Jan; 9(1): 361–373.
[3] Takegawa N and Yonesaka K (2017). HER2 as an emerging oncotarget for colorectal cancer treatment after failure of anti-epidermal growth factor receptor therapy. Clin Colorectal Cancer 16: 247-51.
[4] Valtorta E., et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol 28: 1481-91 2015.

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