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Tucatinib Combo Explored in HER2-Positive Breast Cancer

Danielle Bucco
Published: Wednesday, Jan 31, 2018

Rashmi K. Murthy, MD, MBE
Rashmi K. Murthy, MD, MBE
Central nervous system (CNS) metastases is a prevalent issue for patients with HER2-positive breast cancer, as approximately 50% of patients will experience them, according to Rashmi K. Murthy, MD, MBE. However, a novel agent has been in development to pass the blood-brain barrier and holds promise to potentially improve outcomes for this patient population.1,2

An ongoing phase II trial, HER2CLIMB (NCT02614794), is randomizing patients with HER2-positive breast cancer with/without CNS metastases to tucatinib (ONT-380) plus capecitabine and trastuzumab (Herceptin) versus placebo plus capecitabine and trastuzumab. The primary endpoint of the study is progression-free survival (PFS) with secondary outcomes including overall survival and quality of life.

A pooled analysis of 2 phase Ib studies demonstrated a prolonged PFS when patients with or without brain metastases were treated with tucatinib. The median PFS was 8.2 months and 7.8 months in the respective studies. Nearly 20% of patients treated with tucatinib combinations demonstrated a prolonged PFS, defined as ≥16 months. Baseline brain metastases did not differentiate patients who achieved an extended PFS.3

In an interview with OncLive, Murthy, an assistant professor in the Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the role of tucatinib in CNS metastases for patients with HER2-positive breast cancer.

OncLive: Can you give an overview of tucatinib and the HER2CLIMB trial?

Murthy: Tucatinib is a molecule that is exciting for the HER2 field. One of the challenges in the treatment of HER2-positive breast cancer is the frequent development of brain metastases, which can occur in up to 50% of patients. Tucatinib in combination has shown some early signs of activity in the CNS in addition to systemically.2,3 It is an oral HER2-specific tyrosine kinase inhibitor that is well tolerated. Because it blocks only HER2, there are fewer off-target effects, such as rash and diarrhea, which are common with some of the other tyrosine kinase inhibitors.1 It is currently being evaluated in a randomized clinical trial with capecitabine and trastuzumab.

The HER2CLIMB trial is currently enrolling patients who have metastatic HER2-positive breast cancer with prior exposure to taxane, trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla). Patients can be enrolled with or without CNS metastases. This is a unique feature of the trial, as patients with brain metastases who have not had any of the standard local therapies may be enrolled; enrollment also allows for patients with progressive brain metastases and allows patients to stay on the study post-progression.

How prevalent of an issue is CNS metastases in HER2-positive breast cancer?

Up to 50% of women with HER2-positive metastatic breast cancer experience CNS metastases. When they arise, they can compromise survival and impact quality of life for patients. There remains an unmet medical need for patients with HER2-positive metastatic breast cancer whose disease has metastasized to the brain. The current systemic therapies do not penetrate the blood-brain barrier well, so there is a need for anti-HER2 agents that successfully do cross over.

What is your therapy of choice when treating CNS metastases?

The current approach to management involves a multidisciplinary team, including a medical oncologist, a CNS radiation oncologist, and in some cases, a neurosurgeon to decide upon the best local therapy.

In some cases, the patient could receive Gamma Knife or stereotactic radiotherapy to the lesions if there are few lesions, or whole-brain radiation therapy if there are multiple lesions.

Currently, there are no systemic drugs specifically developed to treat the CNS. The standard of care right now is to consider local therapy and then if there is no progression systemically, the patient is continued on the current systemic therapy, even after local treatment of CNS disease. If there is a systemic progression of disease in addition to the CNS progression, then that would warrant a change in systemic therapy.

What are some of the first things you take into consideration when treating a patient with HER2-positive disease?

With a new patient with metastatic HER2-positive breast cancer, we need to consider their performance status, lab abnormalities, amount of visceral versus nonvisceral involvement, and cardiac function. Their cardiac history becomes especially important because we start thinking about the fact that they are going to need to be on lifelong HER2-targeted therapy. 

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Online CME Activities
TitleExpiration DateCME Credits
Miami Breast Cancer Conference®: Attendee Tumor Board OnlineNov 30, 20181.5
Community Practice Connections™: 1st Annual Paris Breast Cancer Conference™Dec 31, 20181.5
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