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Tucatinib Plus Trastuzumab Approved for RAS Wild-type, HER2+ Unresectable or Metastatic CRC


The combination of tucatinib and trastuzumab received accelerated approval from the FDA to treat adults with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer (mCRC) that advances after treatment with specific types of chemotherapy.

The FDA Thursday granted accelerated approval for tucatinib (Tukysa) when given with trastuzumab to treat adults with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer (mCRC) that progresses following treatment with specific types of chemotherapy.

Approval of this chemotherapy-free combination is based on results from the phase 2 MOUNTAINEER trial (NCT03043313), which found a 38% overall response rate (95% CI, 28-49) among 84 patients, based on a blinded independent central review. Complete responses were seen in 3.6% (3 patients) and partial responses were seen in 35% (29 patients). The median duration of response was 12.4 months (95% CI, 8.5-20.5).1

Data for MOUNTAINEER were presented in July 2022 at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancers.

Colorectal cancer (CRC) is among the more common cancers in the United States, with the American Cancer Society estimating about 153,000 people will be diagnosed in 2023.2 Rates are increasing among younger adults, with experts attributing this to rising rates of obesity. About 22% of those diagnosed already have advanced cancer; HER2 is overexpressed in 3% to 5% of patients and 10% have RAS wild type in mCRC.3

Tucatinib, available in tablets of 50 or 150 mg, is an oral tyrosine kinase inhibitor of the HER2 protein. It blocks phosphorylation of HER2 and HER3, which results in inhibition of downstream MAPK and AKT signaling and cell growth, as well as anti-tumor activity. It was approved in April 2020 in combination with trastuzumab and capecitabine to treat adults with advanced unresectable or metastatic HER2-positive breast cancer if they have received at least 1 prior anti-HER2-based regimen for metastatic disease.

“Historically, patients with HER2-positive metastatic colorectal cancer who have progressed following frontline therapy have had poor outcomes,” John Strickler, MD, associate professor of medicine, Duke University Medical Center, and lead investigator for the MOUNTAINEER trial, said in a statement. “The FDA approval of a chemotherapy-free combination regimen that specifically targets HER2 is great news for these patients.”4

Biomarker testing now allows clinicians to identify patients with RAS-wild type HER2+ disease, and Michael Sapienza , CEO of the Colorectal Cancer Alliance, emphasized the need for both doctors and patients to embrace comprehensive biomarker testing at diagnosis, “because it can inform treatment decisions and help improve outcomes.”

Adverse events (AEs) reported during the MOUNTAINEER trial—and included in prescribing warnings—included diarrhea, hepatoxicity, and embryo-fetal toxicity. In MOUNTAINEER, serious AEs occurred in 22% of patients, with the common being intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia, abdominal pain, and rectal perforation (2.3% each).

Common AEs from the regimen were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions and pyrexia, each affecting at least 20% of patients. AEs led to discontinuation of tucatinib in 6% of patients.


1. Strickler JH, Cercek A, Siena S, et al: MOUNTAINEER: Open-label, phase 2 study of tucatinib in combination with trastuzumab for HER2-positive metastatic colorectal cancer. ESMO World Congress on Gastrointestinal Cancers 2022. Abstract LBA-2. Presented July 2, 2022. http://bit.ly/3WsuQl0

2. American Cancer Society: Key Statistics for Colorectal Cancer. January 13, 2023. Accessed January 19, 2023. https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html

3. Wang J, Li S, Liu Y, Zhang C, Li H, Lai B. Metastatic patterns and survival outcomes in patients with stage IV colon cancer: A population‐based analysis. Cancer Med. 2020 Jan; 9(1): 361–373. doi: 10.1002/cam4.2673

4. Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS Wild-type, HER2-positive metastatic colorectal cancer. News release. Seagen. January 19, 2023. http://bit.ly/3XFJjv1

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