Clinical trialPhase 2Colorectal cancer

Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study

Lancet Oncol · 2023117 patients enrolled (45 in cohort A, 41 in cohort B, 31 in cohort C); 84 patients in the primary analysis (cohorts A and B)

Strickler JH, Cercek A, Siena S, et al. Lancet Oncol. 2023. 24:496-508

Study type: Clinical trial
Study name: MOUNTAINEER
Phase: Phase 2
Design: Open-label, global, phase 2 study (34 centres in Belgium, France, Italy, Spain and the USA); non-randomised cohort A, then 4:3 randomisation to cohort B (tucatinib + trastuzumab) or C (tucatinib alone)
Sample size: 117 patients enrolled (45 in cohort A, 41 in cohort B, 31 in cohort C); 84 patients in the primary analysis (cohorts A and B)
Source: Lancet Oncol · 2023
Trial registration: NCT03043313

In plain words

In a small share of bowel cancers that have spread, a protein called HER2 is overactive (as in one type of breast cancer). In this study, patients whose other usual chemotherapies were no longer working took a combination of a tablet (tucatinib) and an injected anti-HER2 drug (trastuzumab). The tumour shrank in about 4 in 10 patients and the treatment was usually well tolerated; the most common side effect was diarrhoea. This study shows why testing for HER2 matters in bowel cancer that has spread.

Key results

38.1%

Confirmed objective response (cohorts A+B)

95% CI 27.7–49.3; 3 complete and 29 partial responses in 84 patients

Diarrhoea 64%

Most common adverse event (cohorts A+B)

Most common grade 3 or higher event: hypertension 7%

Drugs in this study:Trastuzumab (Herceptin)

Dose and schedule cards

Tucatinib + trastuzumab (MOUNTAINEER)

HER2-positive, RAS wild-type metastatic colorectal cancer, after fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapyEach drug’s schedule in the tableOn the page “Colorectal cancer” · Metastatic colorectal cancer: later lines by biomarker (HER2-positive, KRAS G12C)

HER2-positive, RAS wild-type metastatic colorectal cancer, after fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy

Drug	Dose	Route	Schedule
Tucatinib	300 mg twice daily	Oral	Continuous
Trastuzumab	Loading dose 8 mg/kg, then 6 mg/kg	IV	Day 1 of the first cycle; then day 1 every 21 days

Cycle schedule: Trastuzumab every 21 days; tucatinib daily and continuously
Duration: Until disease progression or unacceptable toxicity

Doses from the FDA label for tucatinib (accelerated approval); evidence: MOUNTAINEER.

In severe hepatic impairment (Child-Pugh C), tucatinib 200 mg twice daily. Trastuzumab: assess cardiac function before starting and during treatment.

On the page “Colorectal cancer” · Metastatic colorectal cancer: later lines by biomarker (HER2-positive, KRAS G12C)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Tucatinib + trastuzumab — cohorts A and B

Tucatinib 300 mg orally twice daily; trastuzumab IV with a loading dose of 8 mg/kg, then 6 mg/kg every 21 days; until disease progression.

2Tucatinib alone — cohort C

Oral tucatinib twice daily alone; patients who did not respond could cross over to tucatinib + trastuzumab (per ClinicalTrials.gov).

Source of the regimen details: Doses from the published abstract (Lancet Oncol 2023); cohort C schedule from the ClinicalTrials.gov record NCT03043313

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults (18 years or older) with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer. Median age 56 years.

Endpoints

Primary outcome: confirmed objective response rate by blinded independent central review (BICR) in cohorts A and B combined.

Other: safety in all patients who received at least one dose.

Safety and side effects

In cohorts A and B, the most common adverse event was diarrhoea (55 of 86, 64%) and the most common grade 3 or higher event was hypertension (6 of 86, 7%); three patients (3%) had serious adverse events related to tucatinib (acute kidney injury, colitis and fatigue). In cohort C, the most common adverse event was diarrhoea (33%). No deaths were attributed to adverse events.

Clinical significance and place in guidelines

According to the paper, tucatinib + trastuzumab is the first FDA-approved anti-HER2 regimen for metastatic colorectal cancer and is an important treatment option for chemotherapy-refractory HER2-positive disease. The evidence comes from a phase 2 study without a comparator control group. Approval status in other countries may differ.

Limitations

Phase 2 study without a comparator control group (cohort C received tucatinib alone only); the primary outcome is tumour response, not survival; small number of patients; definitions and methods for determining HER2 positivity in colorectal cancer are not yet harmonised.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.