MOUNTAINEER: What the Colorectal Cancer Trial Found

Why anyone looked for HER2 in a bowel cancer

HER2 is best known in breast cancer. It is a receptor on the cell surface that signals growth, and when the gene making it is amplified, the signal never stops.

A small subset of colorectal cancers carry the same amplification. For years that finding had nowhere to go, because no HER2-targeted treatment was approved for the bowel.

MOUNTAINEER tested whether two drugs already aimed at HER2 would work there. Tucatinib is a small-molecule kinase inhibitor, taken as a tablet. Trastuzumab is an antibody, given by infusion. Both block HER2, by different mechanisms.

Who was enrolled, and how

MOUNTAINEER was a global, open-label phase 2 study at 34 sites in Belgium, France, Italy, Spain, and the United States. Its ClinicalTrials.gov record is NCT03043313.

Everyone had HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer that had stopped responding to chemotherapy. RAS wild-type means the tumor does not carry a mutation in the RAS gene family. That was an entry requirement, not an incidental detail.

The design changed midstream, which matters for reading the result.

It began as a single-group study: cohort A, 45 patients, all given tucatinib plus trastuzumab. After an interim look, it expanded. New participants were randomly assigned in a 4-to-3 ratio to cohort B, tucatinib plus trastuzumab, or cohort C, tucatinib alone.

Enrollment ran from August 2017 to September 2021 and reached 117 patients. In the full analysis set, 114 had locally confirmed HER2-positive disease and received treatment. Median age was 56.

What was reported

The primary endpoint was confirmed objective response rate, judged by blinded independent central review, for cohorts A and B combined.

Among those 84 patients, 38.1% responded. The 95% confidence interval ran from 27.7% to 49.3%. Three patients had a complete response and 29 had a partial response.

That confidence interval is worth sitting with. The true rate is consistent with anything from roughly one in four to roughly one in two. Small trials produce wide intervals, and this is what one looks like.

What it costs

In cohorts A and B, the most common side effect was diarrhea, in 64% of 86 patients.

The most common grade 3 or worse event was high blood pressure, in 7%. Three percent had a serious side effect attributed to tucatinib: acute kidney injury, colitis, and fatigue, one each.

No deaths were attributed to side effects. All deaths among treated patients were caused by the cancer itself.

In cohort C, on tucatinib alone, diarrhea affected 33% of 30 patients.

What happened next

On 19 January 2023 the FDA granted accelerated approval to tucatinib in combination with trastuzumab. The letter, NDA 213411 supplement 4, covers adults with RAS wild-type, HER2-positive, unresectable or metastatic colorectal cancer that has progressed after fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Accelerated approval is a specific status. It is granted on a measure thought likely to predict benefit — here, response rate — with confirmation of clinical benefit expected from later trials. It is not a full approval on survival data.

The trial's authors describe this as the first FDA-approved anti-HER2 regimen for metastatic colorectal cancer.

When to get checked

For anyone on this combination, diarrhea is the side effect that most often derails treatment. It should be reported early rather than managed alone, because dehydration and dose interruptions follow quickly. Blood pressure needs monitoring on the schedule the team sets.

For colorectal cancer itself, NCI says to check with a doctor about blood in the stool, either bright red or very dark; a change in bowel habits; diarrhea; constipation; a feeling that the bowel does not empty completely; stools that are narrower or differently shaped than usual; general abdominal discomfort such as frequent gas pains, bloating, fullness, or cramps; unexplained weight loss; fatigue; and vomiting.

One point overrides the whole list. NCI's screening summary states, on solid evidence, that screening for colorectal cancer reduces deaths from it, and that some screening methods also reduce how many cases occur at all. That second effect is unusual: removing a polyp prevents the cancer rather than catching it.

So the more useful question than "do I have symptoms" is "am I up to date on screening." Our page on colorectal cancer screening covers the test options.

Rates in younger adults have been shifting. NCI's SEER registry records put about 16% of colorectal cancer cases in people aged 45 to 54. Blood in the stool at 40 is not something to attribute to hemorrhoids without a look.

The population behind the trial

For 2026 the American Cancer Society projects about 158,850 new colorectal cancer diagnoses and 55,230 deaths in the United States; SEER, NCI's surveillance program, carries that projection alongside its own data. From those registry records, the median age at diagnosis is 66.

Thirty-four percent is found while still confined to the bowel wall, 37% after spread to nearby lymph nodes, and 23% after spread to distant sites.

Five-year relative survival is 91.3% for localized disease, 75.2% for regional, and 16.9% for distant. Across all stages it is 65.4% for people diagnosed from 2016 through 2022.

MOUNTAINEER enrolled from the last of those groups, and from a small molecular subset within it. Those registry figures describe a population, not the trial's participants and not any reader. Our overview of colorectal cancer covers staging.

What this trial cannot tell you

The headline number has no comparison group behind it. Cohort A was single-arm, and its results were pooled with the randomized cohort B. Nothing here is a head-to-head test against standard care.

Eighty-four patients produced the primary result. That is a small number, and the wide confidence interval is the honest expression of it.

The trial also reports response rate, not survival. Tumor shrinkage on a scan and living longer are related but not the same, which is precisely why the FDA approval is accelerated rather than full.

And eligibility is narrow twice over: HER2-positive and RAS wild-type. Patients with RAS mutations were excluded, so this says nothing about them.

Sources

• Strickler JH et al., Lancet Oncol 2023, MOUNTAINEER (NCBI E-utilities)
• FDA accelerated approval letter, NDA 213411/S-004 (TUKYSA), 2023
• ClinicalTrials.gov record for NCT03043313 (MOUNTAINEER)
• NCI PDQ: Colorectal Cancer Screening (Health Professional Version)
• NCI PDQ: Colon Cancer Treatment (Patient Version)
• NCI SEER Stat Facts: Colorectal Cancer

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

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