Clinical trialBreast cancerBrain tumours

Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial

JCO · 2020291 patients with brain metastases (198 in the tucatinib group and 93 in the control group)

Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, et al. JCO. 2020. 38:2610-2619

Study type: Clinical trial
Study name: HER2CLIMB
Design: Exploratory analysis of the subgroup of patients with brain metastases from a randomised (2:1), placebo-controlled trial
Sample size: 291 patients with brain metastases (198 in the tucatinib group and 93 in the control group)
Source: JCO · 2020

In plain words

This study looked at patients with HER2-positive breast cancer that had also spread to the brain. Adding the drug tucatinib to the drugs trastuzumab and capecitabine made the brain tumours shrink in more patients. It also lengthened the time until the disease grew in the brain, and patients lived longer. Median survival was 18.1 months versus 12.0 months.

Key results

HR 0.32 (95% CI 0.22–0.48); 68% risk reduction

CNS-PFS (risk of intracranial progression or death)

P<0.0001

9.9 months vs 4.2 months

Median CNS-PFS

Tucatinib group vs control group

HR 0.58 (95% CI 0.40–0.85); 42% reduction in the risk of death

Overall survival (OS)

P=0.005

18.1 months vs 12.0 months

Median overall survival

Tucatinib group vs control group

47.3% (95% CI 33.7%–61.2%) vs 20.0% (95% CI 5.7%–43.7%)

Confirmed intracranial objective response rate (ORR-IC)

P=0.03

Drugs in this study:Capecitabine (Xeloda)Trastuzumab (Herceptin)

Dose and schedule cards

Tucatinib + trastuzumab + capecitabine (HER2CLIMB)

Metastatic HER2-positive breast cancer previously treated with trastuzumab, pertuzumab and trastuzumab emtansine; brain metastases (even untreated or progressing) with stable neurological status and no immediate need for radiotherapy or surgery; no leptomeningeal involvementEach drug’s schedule in the tableOn the page “Brain tumours” · Brain metastases: systemic therapy with intracranial activity

Drug	Dose	Route	Schedule
Tucatinib	300 mg twice daily	Oral	Continuously, about 12 hours apart
Trastuzumab	Loading dose 8 mg/kg on day 1 of cycle 1 (if needed), then 6 mg/kg; or 600 mg SC	IV or SC	Day 1, every 21 days
Capecitabine	1000 mg/m² twice daily	Oral	Days 1 to 14, every 21 days

Cycle schedule: Trastuzumab and capecitabine in 21-day cycles; tucatinib daily and continuously
Duration: Until progression or unacceptable toxicity

Tucatinib: severe diarrhoea may occur (antidiarrheal treatment); ALT, AST and bilirubin before starting and every 3 weeks; 200 mg twice daily in severe hepatic impairment. Capecitabine: before starting, test for DPYD gene variants (DPD deficiency carries a risk of severe and fatal toxicity) unless treatment is urgently needed; reduce the dose by 25% for creatinine clearance 30 to 50 mL/min, and no dose has been established below 30; take within 30 minutes after a meal. Dose source: tucatinib label.

On the page “Brain tumours” · Brain metastases: systemic therapy with intracranial activity

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 group

Tucatinib 300 mg orally twice daily, with trastuzumab at a loading dose of 8 mg/kg IV on day 1 of cycle 1 (if needed), then 6 mg/kg on day 1 of each 21-day cycle (or 600 mg subcutaneously on day 1 of each cycle), and capecitabine 1000 mg/m² orally twice daily on days 1 to 14 of each 21-day cycle; until progression or unacceptable toxicity.

2Control group

Oral placebo twice daily with the same trastuzumab and capecitabine (same dose and schedule).

Source of the regimen details: FDA label for tucatinib (TUKYSA, DailyMed; HER2CLIMB trial section)

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

Patients with previously treated HER2-positive breast cancer. All patients had brain MRI at baseline, and patients with brain metastases were classified as "active" or "stable". CNS-PFS and overall survival were analysed in all patients with brain metastases, and the confirmed intracranial objective response rate was assessed in patients with measurable intracranial disease.

According to the FDA label: prior treatment with trastuzumab, pertuzumab and trastuzumab emtansine; brain metastases, including untreated or progressing lesions, were allowed if the patient was neurologically stable and did not need immediate radiotherapy or surgery; leptomeningeal disease was excluded. According to the full text, dexamethasone up to 2 mg a day was allowed for symptom control.

Endpoints

This analysis was exploratory. Central nervous system progression-free survival (CNS-PFS; intracranial progression or death) and overall survival (OS) were assessed in all patients with brain metastases. The confirmed intracranial objective response rate (ORR-IC) was assessed in patients with measurable intracranial disease. Efficacy was measured by applying RECIST 1.1 criteria to central nervous system target lesions, with investigator assessment.

Safety and side effects

Safety data are not reported in the abstract of this paper; for grade ≥3 adverse events, see the full text of the paper and the main HER2CLIMB paper.

Clinical significance and place in guidelines

Based on the abstract, this is the first regimen to show improved antitumour activity against brain metastases in HER2-positive breast cancer in a randomised controlled trial. These results support the use of tucatinib with trastuzumab and capecitabine in patients with brain metastases. The status of approvals and clinical guideline recommendations should be checked in up-to-date sources, as they are not given in the abstract.

Limitations

This analysis was exploratory and limited to the subgroup of patients with brain metastases. Efficacy was assessed by the investigators. ORR-IC was assessed only in patients with measurable intracranial disease, so the number of patients in this analysis was smaller and the confidence intervals are wide. Safety data are not reported in the abstract.

Original article (DOI)PubMed

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.