Final MOUNTAINEER Data Reinforce Role of Tucatinib Plus Trastuzumab in HER2+ mCRC

According to final data from the phase 2 MOUNTAINEER trial (NCT03043313), tucatinib (Tukysa) combined with trastuzumab (Herceptin) exhibited durable, clinically meaningful efficacy and favorable safety in patients with chemotherapy-refractory HER2-positive (HER2+), RAS wild-type unresectable or metastatic colorectal cancer.¹

The findings, published recently in Nature Communications, demonstrate that patients receiving the dual-agent regimen achieved a confirmed objective response rate (ORR) of 39.3% (95% CI, 28.8%-50.5%). The median duration of response for those who responded to the combination was 15.2 months (95% CI, 8.9-20.5), proving the combination’s durability. Investigators noted that the depth of response was consistent across various subgroups, regardless of the site of the primary tumor or the presence of liver metastases.

Beyond the primary end point of confirmed ORR, the study reported a median progression-free survival (PFS) of 8.1 months (95% CI, 4.2-10.2) and a median overall survival (OS) of 23.9 months (95% CI, 18.7-28.3).

Regarding safety, the safety profile of tucatinib and trastuzumab remained manageable throughout the extended follow-up period. The most frequently reported treatment-emergent adverse events (TEAEs) were diarrhea (66.3%), fatigue (44.2%), and nausea (34.9%). Most TEAEs were low-grade, with grade 3 or higher TEAEs occurring in 40.7% of patients.

Only 5.8% of patients discontinued tucatinib due to AEs, and no treatment-related deaths were reported. This favorable safety profile suggests that dual HER2 inhibition may offer a higher quality of life compared with the toxicity profiles associated with traditional cytotoxic salvage therapies.

In January 2023, the FDA granted accelerated approval to tucatinib plus trastuzumab in this indication.² Taken together, the final results serve as further support for dual HER2 inhibition as a potent, chemotherapy-free strategy.

“The findings from this final analysis of the MOUNTAINEER trial are consistent with the primary analysis demonstrating that tucatinib plus trastuzumab is clinically active and well tolerated in patients with HER2+, RAS wild-type [metastatic colorectal cancer],” wrote authors Strickler et al.¹ “This further strengthens the clinical rationale for dual HER2 inhibition.”

MOUNTAINEER Trial: Overview and Design

The MOUNTAINEER trial was a global, multicenter, open-label phase 2 trial that was designed to assess the efficacy and safety of tucatinib plus trastuzumab in 117 patients with HER2+, RAS wild-type metastatic colorectal cancer who have previously progressed on standard chemotherapy.³

Patients were enrolled across 3 cohorts; the primary analysis focused on cohorts A and B (n = 84), where patients received tucatinib 300 mg orally twice daily plus trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks). Cohort C served as a tucatinib monotherapy group to evaluate the contribution of each agent; however, monotherapy showed limited activity (confirmed ORR, 3.3%), leading to the conclusion that dual blockade is necessary for optimal tumor suppression.

Advancing Development: MOUNTAINEER-03

Based on positive data from MOUNTAINEER, the ongoing phase 3 MOUNTAINEER-03 trial (NCT05253651) was initiated to further confirm the efficacy of the combination. MOUNTAINEER-03 is a randomized study evaluating tucatinib and trastuzumab plus modified FOLFOX6 (mFOLFOX6) chemotherapy vs standard-of-care mFOLFOX6 with or without either cetuximab (Erbitux) or bevacizumab (Avastin) as first-line treatment for patients with HER2+ metastatic colorectal cancer.⁴ Patient accrual is ongoing globally for an estimated total of 400 patients.

The primary end point of the study is PFS, while secondary end points include OS, confirmed ORR, duration of response, time to second progression or death, safety, and quality of life.

REFERENCES

1. Strickler JH, Cercek A, Siena S, et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2 + , RAS wild-type metastatic colorectal cancer (MOUNTAINEER): final analysis. Nat Commun. 2026;17(1). doi:10.1038/s41467-025-67824-z

2. FDA grants accelerated approval to tucatinib with trastuzumab for colorectal cancer. News release. FDA. Updated January 19, 2023. Accessed February 10, 2026. https://tinyurl.com/3u9craux

3. Tucatinib plus trastuzumab in patients With HER2+ colorectal cancer. ClinicalTrials.gov. Updated November 26, 2024. Accessed February 10, 2026. https://clinicaltrials.gov/study/NCT03043313

4. A study of tucatinib with trastuzumab and mFOLFOX6 versus standard of care treatment in first-line HER2+ metastatic colorectal cancer (MOUNTAINEER-03). ClinicalTrials.gov. Updated December 17, 2025. Accessed February 10, 2026. https://clinicaltrials.gov/study/NCT05253651