Tucatinib Plus Trastazumab Yields Positive Results in Patients with HER2-Positive mCRC


The phase 2 MOUNTAINEER trial of tucatinib plus trastazumab in patients with previously treated HER2-positive metastatic colorectal cancer demonstrates positive results.

Tucatinib (Tuksya) in combination with trastazumab (Herceptin) demonstrated positive topline results in the pivotal phase 2 MOUNTAINEER trial (NCT03043313) examining patients with previously treated HER2-positive metastatic colorectal cancer (mCRC), according to Seagen Inc.1 

Investigators found a confirmed objective response rate (cORR) of 38.1% (95% 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 tucatinib plus trastuzumab combination was generally well-tolerated, and the most common treatment-emergent adverse events were diarrhea, fatigue, nausea, and infusion-related reaction, all of which were low grade.

Past research revealed HER2 to be overexpressed in 3% to 5% of patients with mCRC.2,3 Currently, there are no FDA-approved therapies that specifically target HER2 in colorectal cancer.

“[Patients] 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,” said Roger Dansey, MD, interim chief execultive officer and chief medical officer at Seagen Inc, said in the press release. “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 TUKYSA.”

John H. Strickler MD, of the Duke University Medical Center, will present the full data from the MOUNTAINEER trial at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer hosted in Barcelona Spain this summer.

The MOUNTAINEER trail is a multicenter, open-label, phase 2 study using tucatinib as a single agent or in combination with trastazumab in 117 patients. The primary end point of the study is cORR by RECIST version 1.1 criteria per BICR in patients receiving the combination. Secondary end points include DoR, progression-free survival, overall survival, and safety and tolerability of the treatment combination.

The study is split between 3 cohorts: cohorts A, B, and C. Cohort A is a non-randomized cohort which receives tucatinib orally twice per day on days 1 through 21 as well as intravenous trastazumab on day 1 of the cycle, which repeats every 21 days. Cohort B is a randomized cohort that receives the same treatment regimen as cohort A, and cohort C receives tucatinib orally twice per day as monotherapy. It is also noted that patients in cohort C who do not respond to therapy have the option to receive the combination.4

The combination of tucatinib and trastazumab led to increased anti-tumor activity in both in vitro and in vivo studies compared to either medicine. Alone, tucatinib inhibited phosphorylation of HER2 and HER3 which inhibited downstream MAPK and AKT signaling and proliferation and showed anti-tumor activity in tumor cells expressing HER2 in vitro studies. Whereas in vivo, tucatinib inhibited the growth of HER2-expressing tumors.

The MOUNTAINEER data will form the basis of a planned supplemental new drug application to the FDA under the FDA’s Accelerated Approval Program. Merck plans to discuss these results with health authorities as it continues to accelerate the filing of tucatinib in its territory.

1. Seagen announces positive topline results of pivotal phase 2 clinical trial of TUKYSA® (tucatinib) in combination with trastuzumab in HER2-positive metastatic colorectal cancer. News release. Seagen; May 23, 2022. Accessed May 24, 2022. https://bit.ly/3LCarEF
2. Takegawa N, Yonesaka K. HER2 as an emerging oncotarget for colorectal cancer treatment after failure of anti-epidermal growth factor receptor therapy. Clin Colorectal Cancer. 2017;16(4):247-251. doi:10.1016/j.clcc.2017.03.001
3. Valtorta E, Martino C, Sartore-Bianchi A, et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol. 2015;28(11):1481-1491. doi:10.1038/modpathol.2015.98
4. Tucatinib plus trastuzumab in patients with HER2+ colorectal cancer. ClinicalTrials.gov. Updated May 17, 2022. Accessed May 24, 2022. https://clinicaltrials.gov/ct2/show/record/NCT03043313?term=MOUNTAINEER&draw=2&rank=3
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