Lapatinib Plus Whole-Brain Radiotherapy May Control Brain Metastases in HER2+ Breast Cancer

Julia White, MD

An investigation of the tyrosine kinase inhibitor lapatinib (Tykerb) plus whole-brain radiotherapy has entered into a phase II trial in the treatment of patients with brain metastases from HER2-positive breast cancer.

The researchers are specifically evaluating the use of stereotactic radiosurgery (SRS) in this setting, which is a specialized type of radiation therapy that delivers a single, high dose of radiation directly to the tumor. This method may kill more tumor cells and cause less damage to normal tissue.

Lapatinib halts the growth of tumor cells by blocking some of the enzymes needed to stimulate that growth.

“The long-standing treatment for brain metastases is radiotherapy issued to the whole brain, and now there's SRS that just targets the cancer itself with conformal radiation,” said Julia White, MD. “So this is a question really asking that if we add lapatinib to these patients together with their radiation, can we extend cancer control in their brain.”

OncLive: Can you give an overview of the ongoing phase II study of whole-brain radiotherapy with concurrent lapatinib in patients with brain metastases from HER2-positive breast cancer?

In an interview with OncLive, Julia White, MD, professor of Radiation Oncology, Ohio State University, discussed this ongoing phase II trial, the toxicity profile of the treatment, and the potential for control of these brain metastases.White: The RTOG1119 clinical trial is really trying to ask a question for HER2-positive patients who have brain metastases, and that is: does adding lapatinib to brain radiation improve their cancer control in the brain? As we know, there's a lot of good news in HER2-positive metastatic breast cancer in that we have an increasing number of agents that extend progression free (PFS) and overall survival (OS), but there's still a high rate of failure in the brain for HER2-positive breast cancer patients. A significant portion of them actually die from central nervous system (CNS) progression, so it's clear that we need better strategies for managing brain metastases for HER2-positive breast cancer patients.

The long-standing treatment for brain metastases is radiotherapy issued to the whole brain, and now there's stereotactic radio surgery (SRS) that just targets the cancer itself with conformal radiation. So this is a question really asking that if we add lapatinib to these patients together with their radiation, can we extend cancer control in their brain.

Women can have either whole brain radiotherapy, or SRS, and then they take 6 weeks of lapatinib. There's 3 weeks of radiation, and if it's whole brain radiation they get their lapatinib with their radiation and again 3 weeks afterward. If they're having the SRS, which can be 1 to 3 treatments, they will get their lapatinib prior to their SRS and continue it for 6 weeks.

How many patients are participating and when can we expect results?

Besides lapatinib being added, will other small molecule inhibitors be added?

What is the incidence of brain metastases?

How do we foresee from a safety standpoint how patients tolerate the whole brain radiotherapy alone, and then in combination?

The primary endpoint is whatever the MRI appearance is at 12 weeks. We're looing to have an improved complete response in the brain as our primary endpoint.We're hoping soon. It's a randomized phase II trial. We're looking for 143 patients and we have 95 so far. Just this year we amended the trial to allow SRS. We've seen a great change in how we deliver radiotherapy for brain metastases, so increasingly a large proportion are getting SRS for first radiotherapy and for salvage. We think opening it up to SRS on this trial will help us get it accrued.That's our goal. First is a proof of concept that you can add an agent in this subtype of breast cancer and show an improvement in CNS control in addition to radiotherapy, but I think this opens the way for other small molecules within this and other subtypes of breast cancer. For a long time we have done just radiotherapy by itself without anything, and that is the standard in metastatic breast cancer. It's just radiotherapy. We're hoping to show that by combining radiation with newer agents, especially small molecule agents that have CNS penetration, that we have an opportunity to improve CNS control. Which is very important in HER2-positive breast cancer where our system agents are getting better.Overall, it's about 20% to 25%, but in HER2-positive breast cancer it's more than 50%. It's a hard number to put our finger on because it used to be clinical symptoms, we would obtain imaging. Now in certain subtypes such as HER2-positive or triple negative where the incidence is higher, we're screening for metastases. So we're finding asymptomatic metastases that we didn't know were there before. It presents a challenge and an opportunity, and certainly when looking at effectiveness of systemic therapy agents in combination with radiation, it's an opportunity.Whole brain radiotherapy has side effects like alopecia and fatigue, which can be quite profound in a small subset of patients. That's why we are looking for a pretty significant improvement in complete response, to give us the signal that we need to go on to a phase III trial or look at additional agents. We want to make sure that the trade off is there. There is the added toxicities of lapatinib with whole brain radiotherapy. SRS has less long-term toxicity, but we want to make sure there's enough benefit that it's clinically meaningful to patients.