MOUNTAINEER: Tucatinib plus trastuzumab demonstrates good efficacy for the treatment of HER2-positive metastatic colorectal cancer

In the U.S., colorectal cancer (CRC) is the third leading cause of cancer-related deaths and is expected to lead to approximately 52,580 deaths in 2022.[1] Human epidermal growth factor receptor 2 (HER2) is overexpressed in 3–5% of patients with metastatic CRC (mCRC).[2],[3] However, there are currently no U.S. Food and Drug Administration (FDA)-approved therapies which specifically target HER2 for the treatment of CRC.

Tucatinib, a tyrosine kinase inhibitor (TKI), inhibits the phosphorylation of the HER2 and HER3 proteins, which causes downstream inhibition of MAPK and AKT signalling and subsequent inhibition of cell proliferation. Tucatinib has previously shown anti-tumor activity in HER2-expressing tumor cells and has shown to inhibit the growth of HER2-expressing tumors in other non-CRC cancer types.[4] The combination of tucatinib plus the anti-HER2 antibody trastuzumab has shown increased anti-tumor activity both in vitro and in vivo compared with either drug alone.

The open-label, randomised, Phase II MOUNTAINEER trial (NCT03043313)[5] assessed the safety and efficacy of tucatinib in combination with trastuzumab, as a potential novel treatment for pre-treated HER2-positive mCRC. In this study, patients with HER2+ metastatic or unresectable CRC, who had previously received standard of care therapies, were randomised to receive either tucatinib (orally) plus trastuzumab (intravenously; n = 86) or tucatinib monotherapy (n = 30).     

The primary endpoint was the confirmed object response rate (cORR) according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria per blinded independent central review (BICR) in patients receiving the combination of tucatinib and trastuzumab. Secondary objectives of the trial included the duration of response (DoR), progression-free survival (PFS), overall survival (OS), as well as safety and tolerability. The results of MOUNTAINEER were presented by Jonathan Strickler, MD, Duke Cancer Institute, Durham, NC at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer (ESMO WCGIC) 2022 in Barcelona, Spain.[6] In patients randomized to receive tucatinib plus trastuzumab at a median duration of follow-up of 20.7 months, there was a 38.1% cORR per BICR [95% CI, 27.7–49.3], a median DoR per BICR of 12.4 months [95% CI, 8.5–20.5], a median PFS per BICR of 8.2 months [95% CI, 4.2–10.3], and a median OS of 24.1 months [95% CI, 20.3–36.7]. In comparison, patients randomised to receive tucatinib monotherapy had a cORR per BICR by 12 weeks of 3.3% [95% CI, 0.1–17.2].

The most common treatment-emergent adverse events (AEs) in patients receiving tucatinib plus trastuzumab were diarrhea, fatigue, nausea, and infusion-related reaction, all of which were primarily low-grade. AEs leading to discontinuation of treatment occurred in 5.8% of patients, and no fatalities due to AEs were reported in this trial.

VJOncology caught up with Dr Jonathan Strickler, MD of Duke Cancer Institute, Durham, NC about the MOUNTAINEER trial, at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer (ESMO WCGIC) 2022 annual meeting.

“Overall, the findings have shown a strong clinical activity of this regimen – but also, we were pleased to see is that the regimen was overall very well tolerated as well…and it is something that could eventually be a new standard of care for patients with HER2+ mCRC.” 

In summary, the MOUNTAINEER trial demonstrates that tucatinib plus trastuzumab is well-tolerated and has durable responses in patients with previously treated HER2+ mCRC. Data from this trial will form the basis of a planned supplemental New Drug Application to the FDA, as well as opening a future avenue for the development of other novel HER2-targeting agents in the treatment of HER2+ mCRC.  


[1] Key Statistics for Colorectal Cancer 2022. [Internet]. 2022 [cited 13 July 2022]. Available from:

[2] Takegawa N, Yonesaka K. HER2 as an Emerging Oncotarget for Colorectal Cancer Treatment After Failure of Anti-Epidermal Growth Factor Receptor Therapy. Clinical Colorectal Cancer. 2017;16(4):247-251.

[3] Valtorta E, Martino C, Sartore-Bianchi A, Penaullt-Llorca F, Viale G, Risio M et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Modern Pathology. 2015;28(11):1481-1491.

[4] Seagen Announces Results from Pivotal MOUNTAINEER Trial Demonstrating Clinically Meaningful Antitumor Activity of TUKYSA® (tucatinib) in Combination with Trastuzumab in Previously Treated HER2-Positive Metastatic Colorectal Cancer [Internet]. 2022 [cited 13 July 2022]. Available from:

[5] Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer – Full Text View – [Internet]. 2022 [cited 13 July 2022]. Available from:

[6] Strickler J, Cercek A, Siena S, André T, Ng K, Van Cutsem E et al. LBA-2 Primary analysis of MOUNTAINEER: A phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC. Annals of Oncology. 2022;33:S375-S376.

Written by Isabelle Goodall-Summers