Trial Enrolls Final Patient To Evlaluate Tucatinib/Trastuzumab for HER2-Positive mCRC

Roger D. Dansey, MD

The last patient has been enrolled in the phase 2 MOUNTAINEER trial, evaluating tucatinib (Tukusa) both as a monotherapy and in combination with trastuzumab (Herceptin) for the treatment of HER2-positive metastatic colorectal cancer (mCRC) following previous first- and second-line standard of care therapies, according to a press release by Seagen Inc.¹

Tucatinib, an inhibited phosphorylation of HER2 and HER2, causes the downstream inhibition of MAPK and KT signaling and cell proliferation. The agent has showed anti-tumor activity in HER2-expressing cells. In 2020, it was granted FDA approval for the treatment of adult patients with advanced unresectable or metastatic breast cancer who have received at least 1 prior line of therapy.

“Completing enrollment in the MOUNTAINEER trial is an important step toward potentially bringing this therapy to patients with HER2-positive metastatic colorectal cancer,” said Roger D. Dansey, MD, chief medical officer of Seagen, in a press release. “We previously expanded the size of this trial, with the intention of supporting registration under accelerated approval regulations in the United States. We look forward to receiving the trial results to potentially address a significant unmet medical need for patients.”

The MOUNTAINEER study (NCT03043313) has an actual enrollment of 117 participants and an estimated completion date of April 2023. The primary end point is objective response rate. Secondary end points include overall response rate (ORR) at 12 weeks, duration of response (DOR), progression-free survival (PFS), incidence of adverse events (AEs), incidences of dose modifications, and incidences of laboratory abnormalities.² 

The study is split into 2 parts. During part 1, patients will receive the experimental combination. In the second part of the study, patients will be randomized to receive the experimental combination of tucatinib and trastuzumab or tucatinib monotherapy.

Interim results presented at the European Society for Medical Oncology 2019 Congress found that the agent was well tolerated and showed anti-tumor activity.

The interim analysis included 26 patients, 62% of whom were male with a median age of 52.5 years (range, 24-70). Tumor origin sites included the right colon (n = 4), the left colon/rectum (n = 17), transverse colon (n = 3), and overlapping (n = 2). Of the 26 patients included, 22 were evaluable. The agent demonstrated an ORR of 55% and a clinical benefit rate of 64%. At the median follow-up of 10.6 months, the median PFS was 6.2 months (95% CI, 3.5 to not evaluable [NE]) and the median OS was 17.3 months (95% CI, 12.3-NE). The median DOR was not reached.³

Nine percent of patients experienced grade 3 treatment-related AEs. No grade 3/4 AEs were reported. The most common AEs were AST elevation (48%) ALT elevation (30%), and diarrhea (26%).

In order to participate, patients must have confirmed metastatic and/or unresectable adenocarcinoma of the colon or rectum, have progressive disease after the last systemic therapy or be intolerant to last systemic therapy, have RAS wild-type in primary or metastatic tumor tissue, have confirmed HER2-positive mCRC, have measurable disease, and a life expectancy greater than 3 months. Patients previously treated with anti-HER2 targeting therapy, clinically significant cardiopulmonary disease, known myocardia infraction, or are unable to swallow pills are not eligible to participate.

REFERENCES:

_{1.Seagen announces last patient enrolled in phase 2 MOUNTAINEER trial evaluating TUKYSA® (Tucatinib) regimen in HER2-positive metastatic colorectal cancer. Seagen. News release. September 28, 2021. Accessed September 29, 2021. https://bit.ly/3F1XQIX.}

_{2.Tucatinib plus trastuzumab in patients with HER2+ colorectal cancer. ClinicalTrials.gov. Accessed September 29, 2021. https://bit.ly/2XWUyWj.}

_{3.Stickler J, Zemla T, Ou F, et al. Trastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): Initial results from the MOUNTAINEER trial. Ann. Oncol. 2019; 30(5):V200 DOI:https://doi.org/10.1093/annonc/mdz246.005}