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HER2-Directed Combination Improves Outcomes in Advanced HER2-Positive Breast Cancer, Including Patients With Brain Metastases

January 2024, Vol 14, No 1

San Antonio—Dual HER2-directed therapy with tucatinib and trastuzumab emtansine (T-DM1) extended progression-free survival (PFS) compared with T-DM1 alone in patients with previously treated, resectable, locally advanced or metastatic HER2-positive breast cancer.

In the HER2CLIMB-02 study, the tucatinib and T-DM1 doublet improved median PFS to 9.5 months from 7.4 months with T-DM1 monotherapy, corresponding to a 24% improvement in median PFS (hazard ratio, 0.76; P=.0163), said Sara A. Hurvitz, MD, professor and division head, Hematology and Oncology, University of Washington, Seattle, at the 2023 San Antonio Breast Cancer Symposium.

The advantage to adding tucatinib to T-DM1 was maintained in patients with brain metastases at baseline, in whom median PFS was 7.8 months in the tucatinib plus T-DM1 arm compared with 5.7 months in the T-DM1 plus placebo arm, thereby reducing the risk for disease progression or death by 36.1% (statistical significance not tested due to hierarchical testing design).

“It is notable that about 44% of patients enrolled in this study had brain metastases, and approximately half of these patients had active brain metastases,” said Dr Hurvitz.

Sara A. Hurvitz, MD

[HER2CLIMB-02] is the second randomized study which included patients with brain metastases to demonstrate that a tucatinib-containing regimen delays disease progression in HER2- positive locally advanced disease.

—Sara A. Hurvitz, MD

“This is the second randomized study which included patients with brain metastases to demonstrate that a tucatinib-containing regimen delays disease progression in HER2-positive locally advanced disease,” she said, the first being HER2CLIMB, which showed that the addition of tucatinib to a regimen containing trastuzumab and chemotherapy (capecitabine) significantly improved PFS and overall survival (OS) in heavily pretreated patients, including those with brain metastases.

On the basis of HER2CLIMB, the combination of tucatinib, trastuzumab, and capecitabine was approved by the FDA in 2020, but advances in HER2-targeting therapies prompted the investigation of other tucatinib-based combinations.

The goal of HER2CLIMB-02 was to build on previous data from preclinical and phase 1/2 studies showing enhanced antitumor activity of the tucatinib plus T-DM1 doublet compared with either agent alone, Dr Hurvitz said.

OS data in HER2CLIMB-02 are immature at the first planned interim analysis (median follow-up of 24.4 months, 53% of prespecified OS events reached), with a second interim OS analysis planned when 80% of final OS events are reached. Most patients received subsequent therapy, Dr Hurvitz noted. Approximately half in each arm received subsequent trastuzumab deruxtecan (T-DXd) and 15% in each arm received subsequent tucatinib.

“You have to consider what patients received after the study, and with the notable activity of T-DXd…I think we are just seeing patients live a lot longer,” she said.

In HER2CLIMB-02, 463 patients with locally advanced/metastatic breast cancer that had progressed after treatment with trastuzumab and a taxane in any setting were randomly assigned to 21-day cycles of either oral tucatinib or placebo twice daily combined with intravenous T-DM1 given every 3 weeks. Patients with previously treated stable, progressing, or untreated brain metastases not requiring immediate local therapy were also eligible. Initial stage at diagnosis was 0-III in 55% and stage IV in 45%.

Types of adverse events were consistent with those previously reported for tucatinib and T-DM1. The most common grade 3-4 adverse events in the tucatinib arm included transaminase elevation, anemia, thrombocytopenia, and fatigue. Higher rate of hepatic events were observed in the T-DM1 plus tucatinib arm; these events were generally transient, manageable, and reversible, Dr Hurvitz said.

Routine screening for asymptomatic brain metastases is not a standard of care for patients with breast cancer, noted Dr Hurvitz. “At screening, every patient had brain imaging, so some patients were identified with brain metastases who wouldn’t otherwise have been picked up,” she said. “It isn’t what we do in practice.”

Current guidelines state that brain imaging is indicated only in symptomatic patients, but with the discovery of drugs that have activity intracranially, which may help delay the need for whole brain radiation or surgery, “perhaps we should be relooking at those guidelines,” she said.

“HER2CLIMB gives us level I evidence for the use of tucatinib in the context of patients with active or progressing brain metastases,” said Dr Hurvitz. “In my own practice, I would utilize tucatinib before T-DXd in that particular setting. In patients without brain metastases, we have to use our clinical judgment and look at the level of disease outside of the brain. Right now, T-DXd is the standard second-line therapy after trastuzumab and a taxane. I don’t think these data change that at this point.”

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