Tucatinib Plus Trastuzumab Elicits Positive Results in HER2+ Metastatic CRC

The combination of tucatinib and trastuzumab produced promising response rates in patients with previously treated HER2-positive metastatic colorectal cancer.

The combination of tucatinib (Tukysa) and trastuzumab (Herceptin) produced promising response rates in patients with previously treated HER2-positive metastatic colorectal cancer (CRC), according to topline results from the phase 2 MOUNTAINEER trial (NCT03043313).1

Data showed tucatinib plus trastuzumab achieved a confirmed objective response rate (ORR) of 38.1% (95% CI, 27.7%-49.3%) per blinded independent central review (BICR). Additionally, the combination generated a median duration of response (DOR) of 12.4 months (95% CI, 8.5-20.5) per BICR.

Seagen has planned to submit a supplemental new drug application to the FDA based on the findings from MOUNTAINEER.

“People with HER2-positive previously treated metastatic CRC 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 antitumor activity with durable responses and a tolerable safety profile,” Roger Dansey, MD, interim chief executive officer and chief medical officer of Seagen, stated in a 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 [tucatinib].”

HER2 overexpression presents in approximately 3% to 5% of patients with metastatic CRC, and there are currently no therapies approved by the FDA that specifically target HER2 in CRC.2 Previously, in April 2020, the FDA approved tucatinib plus trastuzumab and capecitabine (Xeloda) for the treatment of unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following at least 1 prior anti–HER2-based regimen in the metastatic setting.3 The approval was based on findings from the phase 2 HER2CLIMB trial (NCT02614794).

MOUNTAINEER was a multicenter, open-label trial evaluating tucatinib with or without trastuzumab in patients with HER2-positive metastatic or unresectable CRC following prior standard-of-care therapies.

To be eligible for the trial, patients were required to be at least 18 years of age with histologically and/or cytologically documented metastatic and/or unresectable adenocarcinoma of the colon or rectum, plus radiographically measurable disease assessable by RECIST v1.1 criteria.4 Other key inclusion criteria were confirmed HER2-positive disease; progression of unresectable or metastatic CRC after the last systemic therapy; RAS wild-type disease in the primary or metastatic tumor tissue; an ECOG performance status of 2 or lower; a life expectancy greater than 3 months; and adequate hematologic, hepatic, renal, coagulation, and cardiac function.

Key exclusion criteria included previous treatment with an anti-HER2 therapy; prior treatment with any systemic anti-cancer therapy within 3 weeks of the first dose of study treatment; clinically significant cardiopulmonary disease; known myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery with 6 months of the first dose of study treatment; and a major surgical procedure, open biopsy, or significant injury within 28 days prior to enrollment.

Patients were not permitted to enroll if they had remaining toxicities related to prior anti-cancer treatment that had not resolved to grade 1 or lower, except for alopecia, neuropathy, anemia, and decreased absolute neutrophil count, which needed to resolve to grade 2 or lower. Notably, in patients who had congestive heart failure as a toxicity to prior anti-cancer treatment, the adverse effect (AE) needed to be grade 1 or lower at the time of occurrence and must have resolved completely prior to trial enrollment.

In the first part of the trial, patients were enrolled into cohort A and received tucatinib plus trastuzumab. In the second part of the trial, patients were randomized to cohort B to receive the combination or cohort C to receive tucatinib alone. Notably, patients in cohort C who did not respond to therapy were permitted to receive tucatinib plus trastuzumab.

In cohort A, patients received oral tucatinib twice per day, plus intravenous trastuzumab on day 1 of every 21-day cycle. Following randomization, cohort B followed same dosing protocol, and patients in cohort C received oral tucatinib twice per day.

The primary end point of the trial was confirmed ORR per RECIST v1.1 criteria, according to BICR. Secondary end points included ORR at 12 weeks of treatment and DOR per RECIST v1.1 criteria, according to BICR. Progression-free survival and overall survival were also secondary end points, with pooled data from cohorts A and B. Other secondary objectives were incidence of AEs, dose modifications, and laboratory abnormalities.

Regarding safety in HER2CLIMB, serious AEs occurred in 26% of patients who received tucatinib, including diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal AEs occurred in 2% of patients who received tucatinib, including sudden death, sepsis, dehydration, and cardiogenic shock. The most common AEs of any grade in patients who received tucatinib included diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash, with all occurring in at least 20% of patients.

Treatment discontinuation due to AEs occurred in 6% of patients who received tucatinib, including hepatotoxicity (1.5%) and diarrhea (1%). Additionally, 21% of patients given tucatinib experienced AEs that led to dose reduction, including hepatotoxicity (8%) and diarrhea (6%).

Full data from MOUNTAINEER will be presented at the 2022 ESMO World Congress on Gastrointestinal Cancer on June 29 through July 2 in Barcelona, Spain.


  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 23, 2022. https://bit.ly/3LFdex9
  2. 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):1481-91. doi:10.1038/modpathol.2015.98
  3. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. News release. FDA. April 17, 2020. Accessed May 23, 2022. https://bit.ly/3yT5dSd
  4. Tucatinib plus trastuzumab in patients with HER2+ colorectal cancer. ClinicalTrials.gov. Updated May 17, 2022. Accessed May 23, 2022. https://www.clinicaltrials.gov/ct2/show/NCT03043313