The combination of tucatinib (Tukysa) and trastuzumab (Herceptin) continued to show clinically meaningful efficacy and tolerability with an additional 16.1 months of follow-up in patients with HER2-positive metastatic colorectal cancer (mCRC), according to data from the final analysis of the phase 2 MOUNTAINEER trial (NCT03043313) published in Nature.1
After a median follow-up of 32.4 months (IQR, 25.1-46.7), patients who received tucatinib plus trastuzumab in cohorts A and B (n = 84) achieved a confirmed overall response rate (cORR) by blinded independent central review (BICR) of 39.3% (95% CI, 28.8%-50.5%). The median duration of response (DOR) in this population was 15.2 months (95% CI, 8.9-20.5), the median progression-free survival (PFS) by BICR was 8.1 months (95% CI, 4.2-10.2), and the median overall survival (OS) was 23.9 months (95% CI, 18.7-28.3).
Moreover, among patients with available baseline and post-baseline lesion measurements in cohorts A and B (n = 80), 65% achieved a target lesion size reduction per BICR.
Of note, 28 patients crossed over from the tucatinib monotherapy cohort (cohort C) to receive tucatinib plus trastuzumab. After crossover, the cORR among these patients was 28.6%, the median DOR was not reached, and the median OS was 21.1 months (95% CI, 17.0−not estimable). Exploratory analyses also confirmed that efficacy was observed irrespective of central HER2-positivity testing methods and heterogeneous tumor biomarker profiles.
“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-positive, RAS wild-type mCRC,” investigators wrote. “This further strengthens the clinical rationale for dual HER2 inhibition, [as] tucatinib and trastuzumab showed durable and clinically meaningful efficacy that can be achieved with a dual HER2-targeted chemotherapy-free strategy.”
Topline Takeaways From the Final Analysis of MOUNTAINEER
- After 32.4 months of median follow-up, tucatinib plus trastuzumab produced a cORR of 39.3%, median DOR of 15.2 months, median PFS of 8.1 months, and median OS of 23.9 months in patients with HER2-positive mCRC.
- Among those who crossed over from tucatinib monotherapy to the combination, the cORR was 28.6%, and the median OS was 21.1 months; activity was consistent across HER2 testing methods and biomarker subgroups.
- Primary results from MOUNTAINEER supported the January 2023 FDA approval of tucatinib plus trastuzumab for RAS wild-type, HER2-positive unresectable or metastatic CRC after prior chemotherapy, and the dual HER2-targeted regimen is now being studied in the first-line setting alongside mFOLFOX in the phase 3 MOUNTAINEER-03 trial.
What prior data have been reported from MOUNTAINEER?
Prior findings from MOUNTAINEER showed that patients treated with the doublet (n = 84) achieved an ORR of 38% (95% CI, 28%-49%) per BICR.2 The median DOR by BICR was 12.4 months (95% CI, 8.5-20.5), the median PFS by BICR was 8.2 months, and the median OS was 24.1 months.1 Notably, these data supported the January 19, 2023, FDA approval of tucatinib plus trastuzumab for adult patients with RAS wild-type, HER2-positive unresectable or mCRC that has progressed after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.2
What was the design of MOUNTAINEER?
The multicenter, open-label, phase 2 trial evaluated the efficacy and safety of tucatinib plus trastuzumab in patients at least 18 years of age with HER2-positive, RAS wild-type unresectable or metastatic CRC who had been previously exposed to fluoropyrimidine, oxaliplatin, irinotecan, and an anti-VEGF monoclonal antibody.1,2 Patients with mismatch repair–deficient or microsatellite instability-high tumors must also have received an anti-PD-1 antibody.2 Those who received prior anti-HER2 targeting therapy were not permitted to enroll.
The MOUNTAINEER trial began with a pilot cohort (cohort A; n = 45).1 However, an expansion amendment after an interim analysis resulted in the addition of a randomized expansion cohort (cohort B; n = 29) and the randomized monotherapy cohort (cohort C; n = 30).
Those treated with the combination received 300 mg of oral tucatinib twice daily alongside trastuzumab, which was intravenously administered at a loading dose of 8 mg/kg on day 1 of cycle 1, followed by a maintenance dose of 6 mg/kg on day 1 of each subsequent 21-day cycle.2 Treatment was continued until disease progression or unacceptable toxicity. Notably, patients in cohort C were permitted to crossover to receive trastuzumab in combination with tucatinib if they had radiographic tumor progression at any time point or if they had not achieved a complete or partial response per investigator assessment by 12 weeks.
The study’s primary end point in cohorts A and B was cORR by BICR per RECIST 1.1 criteria. Secondary end points included DOR per BICR, ORR per BICR at 12 weeks, PFS per BICR, and OS.
What were the baseline characteristics of patients in this study?
The data cutoff for the current analysis was November 2, 2023. Between August 8, 2017, and September 22, 2021, 117 patients were enrolled onto the study, 114 of whom had locally assessed HER2-positive disease and received at least 1 dose of study treatment. Across all 3 cohorts, the median age was 56 years.1 The majority of patients were male (58%), White (77%), and had an ECOG performance status of 0 (cohorts A and B, 60%; cohort C, 57%). Left-sided primary tumors were reported in 85% of patients in cohorts A and B, and 90% of those in cohort C. In cohorts A and B, patients received a median of 3 prior lines of therapy in any setting, and 2 prior lines in metastatic or recurrent settings.
What additional safety data were reported?
The median treatment duration in cohorts A and B was 7.9 months with tucatinib and 7.5 months with trastuzumab. In this patient population (n = 86), the most common treatment- emergent adverse effects (TEAEs) were diarrhea (66.3%), fatigue (44.2%) and nausea (34.9%).
The majority of TEAEs were low-grade (54.7%) and not related to tucatinib. However, 33.7% of patients experienced grade 3 TEAEs and 7.0% experienced grade 4 TEAEs. The most common grade 3 TEAEs were hypertension (7.0%), diarrhea (3.5%) and abdominal pain (3.5%). Grade 4 TEAEs that occurred in more than 1 patient included elevated alanine aminotransferase levels, elevated aspartate aminotransferase levels and COVID-19 pneumonia (2.3% each). Five patients (5.8%) discontinued tucatinib due to an AE, and no TEAEs resulted in death.
The most common tucatinib-related TEAEs in both cohorts were diarrhea (52.3%), fatigue (29.1%) and nausea (18.6%), most of which were grade 1/2. Common grade 3 or higher tucatinib-related TEAEs were diarrhea and elevated alanine aminotransferase levels (2.3% each).
TEAEs occurred in 82.1% of patients in cohort C. Most were low-grade (50.0%), although 32.1% of patients had grade 3 TEAEs. The most common grade 3 TEAE was elevated aspartate aminotransferase (10.7%). No grade 4 or grade 5 TEAEs occurred.
What Next Steps Are Planned for the Investigation of Dual HER2-Targeted Strategies in mCRC?
Investigators stated that results from the final analysis of MOUNTAINEER support further evaluation of tucatinib plus trastuzumab in earlier lines of therapy in the phase 3 MOUNTAINEER-03 trial (NCT05253651). This study will compare the efficacy and safety of tucatinib plus trastuzumab in combination with mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) vs standard-of-care chemotherapy in the first-line treatment of patients with HER2-positive mCRC.
References
- 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):1068. doi:10.1038/s41467-025-67824-z
- FDA grants accelerated approval to tucatinib with trastuzumab for colorectal cancer. FDA. January 19, 2023. Accessed February 3, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tucatinib-trastuzumab-colorectal-cancer
