Tucatinib Plus Trastuzumab Shows Durable Efficacy and Manageable Safety for HER2-Posititive Metastatic Colorectal Cancer: MOUNTAINEER Trial
Key Clinical Summary:
- Design/Population: The phase 2 MOUNTAINEER trial was a global, multicenter, open-label study evaluating tucatinib plus trastuzumab of 84 patients with chemotherapy-refractory, HER2-positive, RAS wild-type metastatic colorectal cancer (mCRC); median age 56 years and median follow-up 32.4 months.
- Key Outcomes: The combination achieved a confirmed ORR of 39.3% (95% CI, 28.8 to 50.5) with a median duration of response of 15.2 months, median PFS 8.1 months, and median OS 23.9 months. Responses were consistent across HER2 testing modalities and independent of co-occurring biomarker alterations. Grade ≥ 3 adverse events occurred in 33.7% of patients, most commonly hypertension (7.0%) and diarrhea (3.5%), with grade 4 events in 7.0%.
- Clinical Relevance: Dual HER2 blockade with tucatinib and trastuzumab provided a durable, chemotherapy-free option with a favorable safety profile for HER2-positive, RAS wild-type mCRC after chemotherapy failure, supporting further evaluation in earlier treatment lines.
The combination of tucatinib and trastuzumab demonstrated sustained clinical benefit and a favorable safety profile among patients with chemotherapy-refractory, HER2-positive, RAS wild-type metastatic colorectal cancer (mCRC), according to results from the phase 2 MOUNTAINEER trial published in Nature Communications.
Previous research has found tucatinib and trastuzumab to be efficacious for the treatment of HER2-positive, RAS wild-type mCRC refractory to chemotherapy. Researchers reported updated results from a global, multicenter, open-label trial evaluating the safety and efficacy of tucatinib and trastuzumab for HER2-positive mCRC with an additional 16.1 months of additional follow up.
A total of 84 patients received tucatinib plus trastuzumab, of which the median age was 56 years. The median follow up was 32.4 months (interquartile range [IQR], 25.1 to 46.7). The confirmed objective response rate (ORR) was 39.3% (95% confidence interval [CI], 28.8 to 50.5), and the median duration of response was 15.2 months (95% CI, 8.9 to 20.5). The median progression-free survival (PFS) was 8.1 months (95% CI, 4.2 to 10.2), and the median overall survival (OS) was 23.9 months (95% CI, 18.7 to 28.3).
Treatment responses were consistent across different HER2 testing modalities and were not clearly influenced by co-occurring biomarker alterations.
In terms of safety, the most common treatment-emergent adverse events were diarrhea (66.3%), fatigue (44.2%), and nausea (34.9%). Grade 3 treatment-emergent adverse events occurred in 33.7%, the most common being hypertension (7.0%), diarrhea (3.5%), and abdominal pain (3.5%). Additionally, 7.0% of patients had grade 4 treatment-emergent adverse events, the most common were alanine aminotransferase (2.3%), elevated aspartate aminotransferase (2.3%), and COVID19 pneumonia (2.3%).
The researchers concluded, “Tucatinib and trastuzumab showed durable and clinically meaningful efficacy that can be achieved with a dual HER2-targeted chemotherapy-free strategy.”
They added, “This analysis supports further investigation of tucatinib in combination with trastuzumab in earlier lines of therapy.”
Source:
Strickler JH, Cercek A, Siena S, et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2 + , RAS wild-type metastatic colorectal cancer (MOUNTAINEER): final analysis. Nature Communications. Published online January 12, 2026. doi:10.1038/s41467-025-67824-z
