Patients diagnosed with metastatic colorectal cancer (mCRC) have a poor prognosis with survival ranging 2-3 years. The prevalence of human epidermal growth factor receptor 2 (HER2) amplification is approximately 3-4% in mCRC and increases up to 8% in patients with KRAS/NRAS/BRAF wild-type (WT) CRC tumors. Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor that, in combination with trastuzumab, has demonstrated clinically meaningful activity in patients with chemotherapy-refractory, HER2-positive (HER2+), RAS WT mCRC in the MOUNTAINEER trial. The MOUNTAINEER-03 phase III trial is designed to investigate the efficacy and safety of first-line tucatinib in combination with trastuzumab and modified FOLFOX6 (mFOLFOX6) versus standard of care (mFOLFOX6 plus bevacizumab or cetuximab) in patients with untreated HER2+, RAS WT locally advanced unresectable or mCRC. MOUNTAINEER-03 will include two arms of approximately 400 patients randomized 1:1 to either treatment arm. The primary endpoint is progression-free survival per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints are overall survival and confirmed objective response rate (according to RECIST v1.1 per BICR). Safety assessments will include surveillance and recording of adverse events, physical examination findings, vital signs, cardiac assessments, Eastern Cooperative Oncology Group performance status, concomitant medications, and laboratory tests.Clinical trial registration: NCT05253651 (ClinicalTrials.gov).
Keywords: Bevacizumab; HER2; MOUNTAINEER-03; cetuximab; metastatic colorectal cancer; trastuzumab; tucatinib.
Colorectal cancer is a common and leading cause of cancer deaths worldwide. Patients who have colorectal cancer that has spread to other parts of the body (metastasized) only live for 2 to 3 years after their diagnosis. Tucatinib is a medicine that has shown promising anti-tumor activity when it is given in combination with trastuzumab in patients with metastatic colorectal cancer that is of a certain type, called HER2-positive. HER2 is a protein that, when present in amounts above normal in cancer cells, can cause them to grow more and survive longer. The MOUNTAINEER-03 study is a trial in progress of patients with HER2-positive metastatic colorectal cancer. In this trial, researchers are investigating if tucatinib in combination with trastuzumab and chemotherapy increases the length of time patients live before their cancer grows or spreads (also called progression-free survival) and how long a person is alive after the start of treatment (also called overall survival) compared to standard of care treatment (chemotherapy combination). Researchers are also investigating whether this new tucatinib combination treatment makes the colorectal cancer shrink and stop spreading and if it is safe to use in patients with HER2-positive metastatic colorectal cancer. If the findings of the MOUNTAINEER-03 phase III trial are positive, the tucatinib combination treatment could be a new option for the first-line treatment of a patient population with a high unmet medical need. This paper describes the study design of the MOUNTAINEER-03 trial.