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

Abstract

Purpose: In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs.

Patients and methods: Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease.

Results: There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03).

Conclusion: In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.

Trial registration: ClinicalTrials.gov NCT02614794.

FIG 1.

Kaplan-Meier curves for patients with brain metastases. (A) CNS progression-free survival (CNS-PFS) per investigator assessment. (B) Overall survival (OS). Hazard ratio (HR) computed from the Cox proportional hazards model using stratification factors (Eastern Cooperative Oncology Group performance status [0 or 1], region of world [North America or rest of world]) at random assignment. Two-sided P value calculated from stratified log-rank test.

FIG 2.

Kaplan-Meier curves for patients with active brain metastases. (A) CNS progression-free survival (CNS-PFS) per investigator assessment. (B) Overall survival (OS). Hazard ratio (HR) computed from the Cox proportional hazards model using stratification factors (Eastern Cooperative Oncology Group performance status [0 or 1], region of world [North America or rest of world]) at random assignment. Two-sided P value calculated from stratified log-rank test.

FIG 3.

Kaplan-Meier curves for patients with stable brain metastases. (A) CNS progression-free survival (CNS-PFS) per investigator assessment. (B) Overall survival (OS). Hazard ratio (HR) computed from the Cox proportional hazards model using stratification factors (Eastern Cooperative Oncology Group performance status [0 or 1], region of world [North America or rest of world]) at random assignment. Two-sided P value calculated from stratified log-rank test.

FIG 4.

Outcomes in patients with isolated progression in the brain who continued with assigned study treatment. (A) Duration on treatment. (B) Time from random assignment to second disease progression (PD) by investigator assessment or death. (C) Time from first PD to second PD by investigator assessment or death. Hazard ratio (HR) computed from the Cox proportional hazards model using stratification factors (Eastern Cooperative Oncology Group performance status [0 or 1], region of world [North America or rest of world]) at random assignment.

FIG A1.

CONSORT diagram. BM, brain metastasis. (^a) Two enrolled patients did not undergo baseline brain magnetic resonance imaging (1 in tucatinib arm and 1 in placebo arm).