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Tucatinib is a small-molecule oral tyrosine kinase inhibitor that is selective for HER2 and is able to efficiently penetrate the blood-brain barrier. Based upon the , tucatinib in combination with trastuzumab and capecitabine was approved in April 2020 by the Food and Drug Administration for patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases.

Following the primary study publication, an exploratory analysis that focused on intracranial efficacy and survival of patients with brain metastases who received tucatinib, trastuzumab, and capecitabine was published in the .

In this exploratory study analysis, Dr. Lin and colleagues evaluated the 291 patients with brain metastases enrolled in HER2CLIMB. Patients were randomly assigned 2:1 tucatinib/trastuzumab/capecitabine (n = 198) and placebo/trastuzumab/capecitabine (n=93).

Tumor response in the brain was evaluated by applying RECISTv1.1 to brain lesions in isolation from visceral metastases based on investigator assessment. Exploratory endpoints included confirmed intracranial response rate (ORR-IC; defined as confirmed complete or partial response), duration of intracranial response in measurable baseline lesions (DOR-IC; defined as time from confirmed response to intracranial disease progression or death), central nervous system progression-free survival (CNS-PFS; defined as the time from random assignment to disease progression in the brain or death resulting from any cause) and CNS-overall survival (CNS-OS).

Baseline demographics and disease characteristics were well balanced among patients with brain metastases on the tucatinib and the placebo (control) arms.

This exploratory analysis has important clinical implications, and the results are encouraging for patients with brain metastases. Across almost all assessments of clinical efficacy in this exploratory analysis of the HER2CLIMB study results, patients with brain metastases and specifically patients with active brain metastases (defined as untreated or treated and progressing), who received tucatinib with trastuzumab and capecitabine had significantly better clinical outcomes than those who received trastuzumab and capecitabine.

Among patients with active brain metastases and measurable intracranial disease at baseline, confirmed ORR-IC was 47.3% in the tucatinib arm and 20.0% in the control arm. In these patients, the DOR-IC was 6.8 months in the tucatinib arm and 3.0 months in the control arm.

The clinical impacts of tucatinib added to trastuzumab and capecitabine are impressive. The estimated 1-year CNS-PFS was 40.2% in the tucatinib arm and 0% in the placebo arm among all patients with brain metastases (P <0.00001), was 35.0% in the tucatinib arm and 0% in the placebo arm among patients with active brain metastases (P<0.00001) and was 53.3% in the tucatinib arm and 0% in the placebo arm in patients with stable brain metastases (P =0.002).

Furthermore in patients with brain metastases, tucatinib significantly reduced the risk of progression in the brain or death by 64% to 69%, irrespective of if the brain metastases were active or stable at the time of enrollment.

A small number of patients (30) experienced isolated progression in the brain and were continued on study assigned treatment following local therapy. Median time from progression in the brain to secondary progression (brain or body) was 7.6 months in the tucatinib arm and 3.1 months in the control arm (P =0.02), which highlights the potential for synergy with radiation.

CNS-OS was also significantly improved in patients with brain metastases (median OS 18.1 vs 12.0 months; P=0.005) and active brain metastases (median OS 20.7 vs 11.6 months; P=0.004) on the tucatinib arm compared with the control arm.

To date very few clinical trials have included patient with brain metastases. Within recent years, both ASCO and the FDA have strongly encouraged the inclusion of patients with brain metastases in clinical trials. HER2CLIMB is a strong example of the potential clinical breakthroughs that can occur with more inclusive clinical trial eligibility.

Margaret Gatti-Mays, MD, MPH, FACP, is assistant professor of Internal Medicine, Division of Medical Oncology, at the Pelotonia Institute for Immuno-Oncology, The James Cancer Hospital and The Ohio State Comprehensive Cancer Center in Columbus.

Read the study here and an interview about it here.