As many as half of patients diagnosed with metastatic HER2-positive breast cancer will see their cancer spread to their brain. Though brain metastases are rare, they are exceedingly difficult to treat, so breast cancer patients with “brain mets” experience poor outcomes. To make matters worse, breast cancer patients with brain mets are, in the words of BCRF investigator Dr. Nancy Lin, “almost universally excluded” from trials.
At this year’s American Society of Clinical Oncology (ASCO) meeting, Dr. Lin, associate chief of the division of breast oncology at Dana-Farber Cancer Institute, presented results from the HER2CLIMB trial. This randomized phase II study of patients with advanced HER2-positive breast cancer included patients with brain metastases who experienced significant improvement in progression-free survival.
We spoke with Dr. Lin about her research focus, HER2CLIMB’s findings, and her hopes that more researchers and drug manufacturers will include breast cancer patients with brain mets.
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My clinical and research focus has been on metastatic breast cancer. I lead both the EMBRACE (Ending Metastatic Breast Cancer for Everyone) program at Dana-Farber, as well as the hospital’s program for patients with breast cancer brain metastases. Clinically, I see people with all stages of breast cancer, but my research is focused on two main areas: developing more-effective treatment options for patients whose cancer has spread to the brain and understanding therapeutic resistance.
For patients who have HER2-positive metastatic breast cancer, initial therapies can be effective—but eventually, treatments can stop working. Traditionally, the first treatment patients might receive would be Herceptin® (trastuzumab), Perjeta® (pertuzumab), and chemotherapy. And then when the disease worsens, the next treatment typically would be Kadcyla® (T-DM1). When we get to the third, fourth, fifth treatments, we don’t know the best one to sequence next. National and international guidelines have suggested a variety of options.
The HER2CLIMB study involved patients who had received Herceptin®/Perjeta®/chemotherapy and T-DM1—but whose disease worsened on these drugs. We wanted to understand whether adding a new drug called tucatinib (Tukysa®), which is an oral pill that targets the HER2 protein and reduces the activity of that protein, to a traditional regimen of IV Herceptin® and an oral chemo called Xeloda® (capecitabine) would be beneficial. And importantly, the trial included both patients with and without brain metastases.
Tucatinib seems to cross into the brain more effectively than some of the other existing HER2-targeted drugs. This is important because up to half of patients with metastatic HER2-positive breast cancer will eventually develop brain metastases. For a long time, we have wanted more effective treatment options for these patients.
Starting in about 2013, with support from BCRF, we launched a phase I study at Dana-Farber that combined tucatinib with IV Herceptin®. It was unique because it only enrolled patients whose cancer had worsened in the brain. There was no chemotherapy in this study; it tested purely HER2-directed treatment. We found that patients experienced tumor shrinkage in their brain with this regimen, and we noticed that some patients’ cancer stabilized, both in the brain and in their bodies for up to two years. This was attributable to tucatinib because the patients on the study whose cancer worsened were on Herceptin. And again, since we didn’t include any chemotherapy, we could be quite certain that tucatinib was leading to the brain. This gave the manufacturer of tucatinib confidence to include patients with brain metastases in all of their subsequent trials, including our HER2CLIMB study.
Brain metastases are still very uncommon. I don't want to overly alarm patients who have early-stage breast cancer—the majority of whom will be cured.
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But when HER2-positive breast cancer metastasizes, about half of patients will develop cancer in the brain over their lifetime. What is very unfortunate is that until HER2CLIMB, essentially every large clinical trial in breast cancer, and the majority of small clinical trials in breast cancer, have excluded patients who have active or worsening brain metastases, making progress difficult.
The overall HER2CLIMB results, which included patients with or without brain metastases, showed significant improvements in the duration of tumor control and overall survival. For our ASCO presentation, we focused on the nearly 300 patients with brain metastases who were allowed to enroll in HER2CLIMB. And again, what we found is that the regimen of tucatinib/Herceptin®/Xeloda® more than doubled the chance of tumor shrinkage in the brain. It also significantly delayed the next brain progression and improved survival overall.
To give you a sense of the impact of this treatment, let’s look at the most-difficult-to-treat subset of patients—those who have been almost universally excluded from all other trials in breast cancer and who had new or worsening brain metastases when they entered the trial. One year after starting on the trial treatment, 72 percent of patients in the tucatinib group were alive, compared to only 41 percent of patients in the no-tucatinib group.
HER2CLIMB is the first large, randomized trial to demonstrate quite definitively that systemic treatment, in the form of a HER2-targeting pill, can improve outcomes, including overall survival in patients with active brain metastases from breast cancer. It demonstrates that by including these patients in clinical trials, it is actually possible to make significant progress.
Until this point, there has been a fair amount of nihilism that these treatments are not going to be enough or they're not going to work for patients with brain metastases. So, I hope that this result will really open up the door to more active inclusion of patients with brain metastases in clinical trials.
In April, the FDA granted approval to the HER2CLIMB regimen for the treatment of metastatic HER2-positive breast cancer. It's the first-ever FDA approval in breast cancer that specifically noted the activity of the drug in patients with brain metastasis. My hope is that this is just the first step and that these results will incentivize other investigators and drug manufacturers to more actively include these patients.
We know that most patients, even if they have initial responses to these medicines, will eventually experience worsening of their cancer in the brain and elsewhere. We want to understand why that happens.
With BCRF support, we are using some of the specimens collected from patients in the trials to understand what happens when cancers become resistant to treatments. Then, in collaboration with fellow BCRF investigator Dr. Jean Zhao, we are trying to develop new regimens in the lab to overcome this resistance and bring them to the clinic. We have a number of ongoing clinical trials and additional trials planned over the next year.
Ultimately, we want to not just to treat patients with brain metastases, but to prevent brain metastases from happening altogether. We will analyze the genetic patterns of patients’ original breast tumors to try to find patterns of genes, or gene changes, that could predict a high risk of brain metastases—and then potentially consider some studies for those patients focused on prevention.
This interview has been edited and condensed. Watch more interviews with BCRF researchers on our YouTube channel. Read the rest of BCRF's 2020 ASCO annual meeting coverage here.
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