Broader Trial Eligibility Criteria Expands Options for Brain Mets in Breast Cancer

Carey K. Anders, MD

Broadening clinical trial eligibility criteria has provided more patients with brain metastases access to targeted agents that are showing promising blood-brain barrier penetrability, explained Carey K. Anders, MD.

“Initially, the rationale [to exclude patients with brain metastasis from clinical trials was really based on safety and a preconceived notion that systemic therapies did not reach the central nervous system (CNS),” explained Anders. “In both the preclinical and clinical space, we’ve shown concentrations of different anticancer drugs in the CNS, as well as their efficacy therein.”

For example, data from the phase III NALA trial demonstrated a 24% reduction in the risk of progression or death with the combination of neratinib (Nerlynx) and capecitabine (Xeloda) versus lapatinib (Tykerb) and capecitabine in patients with HER2-positive metastatic breast cancer who received ≥2 prior lines of HER2-targeted therapy. Based on these results, a supplemental new drug application was submitted to the FDA in July 2019 for the agent in this setting. Moreover, in September 2019, the FDA granted an orphan drug designation to neratinib for patients with breast cancer that has metastasized to the brain.

Moreover, etirinotecan pegol (NKTR-102), a novel pegylated form of irinotecan, is being evaluated against physician’s choice in patients with metastatic breast cancer who have stable brain metastases and have been previously treated with an anthracycline, a taxane, and capecitabine in the ongoing phase III ATTAIN trial (NCT02915744).

In choosing the right systemic therapy, Anders emphasized the importance of knowing the genomic makeup of the brain lesion, as this could differ from the breast lesion.

In an interview during the 2019 OncLive State of the Science Summit on Breast Cancer, Anders, director, Brain and Spine Metastasis Program, Duke Cancer Institute, discussed current approaches in the management of patients with breast cancer that has metastasized to the brain.

OncLive: Could you discuss the prevalence of brain metastases in those with breast cancer?

Anders: Brain metastases arising from breast cancer is a challenging clinical scenario, and it's associated with a lot of morbidity for our patients; it’s also associated with shorter survival. We've been working hard to try and develop systemic therapies along with our local therapies, such as radiation and neurosurgery, to complement the care of our patients with brain metastases. About one-third of our patients with advanced HER2-positive disease develop brain metastasis. In triple-negative breast cancer, we see an incidence of brain metastases as high as 50% in the advanced setting.

Are clinical trial criteria becoming more inclusive for patients with brain metastases?

We are seeing a lot of efforts made to include patients with brain metastases in clinical trials. There have been papers from both ASCO as well as the National Cancer Institute indicating that unless there's a safety issue, we should be including patients with brain metastases in these trials. That way, we can offer these patients access to novel therapies and determine whether or not there's CNS activity.

What are some of the available treatments for patients with brain metastases?

[There are available options] as per the National Comprehensive Cancer Network compendia of recommended therapies. At present, there are no therapies that are specifically FDA approved for patients with brain metastases. However, we do use therapies that are approved for use in the metastatic setting that have brain penetrability. In the HER2-positive space, that can include lapatinib, which we typically pair with capecitabine; that is also listed in the compendia. Neratinib was added to the list in 2018. Our chemotherapies include platinums. In 2018, intrathecal trastuzumab (Herceptin) was added to the list; it’s a targeted agent against HER2. This is in addition to our standard intrathecal methotrexate.

What is the role of whole brain radiation therapy in this space?

Whole brain radiation therapy is generally reserved for patients who have diffuse disease throughout the brain. The number of lesions that should be considered for whole brain radiation as opposed to radiosurgery changes on a regular basis. Initially, the studies with radiosurgery included up to 3 lesions in the CNS, and now the studies include up to 10 lesions. The rationale to avoid whole brain radiation as much as we can is due to the negative impact it can have on neurocognition compared with stereotactic radiosurgery alone.

What studies have shown the benefit of radiosurgery?

Stereotactic radiosurgery is generally reserved for discrete lesions throughout the CNS. However, studies indicate safety up to 10 lesions. In the initial studies of stereotactic radiosurgery, the question was whether that should be followed with whole brain radiation therapy. A landmark paper based on the results of the NCCTG N107C/CEC·3 trial demonstrated that the addition of whole brain radiation therapy to radiosurgery doesn’t improve survival. It did, however, have a negative impact on quality of life (QoL) and neurocognitive function. Generally, if a patient is eligible for radiosurgery, we start with radiosurgery followed by systemic therapy. We reserve whole brain radiation therapy for down the road if there are additional lesions that are too numerous for radiosurgery.

What do those sequencing strategies currently look like?

Currently, when a patient is diagnosed with brain metastases, we generally have our radiation therapist, and often, our neurosurgeons, involved in the initial decision making. If a patient has a solitary lesion, if it's mass-occupying and causing significant symptoms, or we don't know what the histology is, many times we'll lead with a neurosurgical resection and follow that resected cavity with radiosurgery. If a patient doesn't undergo neurosurgery, radiation therapy is a very good local therapy. Then we try to be very selective about the systemic therapy we sequence following local therapy. In a patient with HER2-positive disease who has been treated with local therapy and doesn’t have progression in the extracranial compartment, we tend to continue the same systemic therapy. That’s based on our ASCO guidelines in the setting of HER2-positive brain metastases. If a patient has concurrent progressive extracranial disease, we tend to switch our agents so that we're not only treating the intercranial, but also the extracranial, disease progression.

Neratinib has shown a lot of promise for patients with brain metastases. Could you discuss the results of the NALA trial?

Results from the NALA trial were presented at the 2019 ASCO Annual Meeting. Investigators compared the combination of neratinib—an irreversible [pan-HER] TKI—and capecitabine, with the combination of lapatinib—a reversible TKI—and capecitabine. Patients with or without brain metastases enrolled in the study. The study showed that the combination of neratinib and capecitabine yielded an improvement in progression-free survival in all-comers. Importantly, for patients with brain metastases, it appeared that the time to intervention for CNS metastases was improved among the patients who received neratinib.

This is a very important study because it tells us that in the absence of a contraindication, we would likely move toward the combination of neratinib and capecitabine as opposed to the combination of lapatinib and capecitabine for a patient with HER2-positive brain metastases. The caveat to that is the toxicity profile of the combination. We have to be very cautious with both agents in terms of diarrhea. Prophylaxis for diarrhea is required, particularly in the first 2 cycles with neratinib, as well as frequent phone calls and education from our nurse partners.

Are there any emerging agents you’re keeping an eye out for?

One of the agents that's very exciting is the NKTR-102 compound; it’s essentially a liposomal prodrug of irinotecan called etirinotecan pegol. This compound is being assessed in the phase III ATTAIN trial. Investigators are evaluating patients with stable brain metastases, patients who have received local therapy will either receive the NKTR compound or physician's choice. That trial is currently ongoing. If it is positive, NKTR-102 could potentially be an agent approved specifically for patients with brain metastases. That would be very exciting and it would be the first of its kind.

What are the next steps for research in this setting?

We’re trying to develop a better understanding of the biology of brain metastases and why certain cells are home to the CNS. One of the things that is being shown, even outside of breast cancer, is that HER2, which we're now seeing in many gastrointestinal malignancies and some rare lung cancer cases, is that those patients tend to have higher rates of brain metastases. What is it about cells in circulation that allow them to home to the CNS? If we understand that better, we could potentially prevent them [from occurring].

The other piece of the puzzle that we're trying to explore is how we can delay the time to the next event. This will come from careful selection of systemic therapies after radiosurgery with the hope of avoiding whole brain radiation therapy. We’re trying to sequence systemic therapies so that we can prolong the time to the next event while preserving QoL and neurocognition.

Are the current guidelines sufficient, or is there an area that you would like to see better addressed?

One of the outstanding questions that remains is, “How do we manage patients with HER2-negative disease after radiation therapy to the brain?” We have very nice guidelines for the HER2-positive population which taught us that we can maintain the same systemic agent if a patient’s extracranial disease is stable after local therapy. If we see progression in extracranial disease, we end up changing the agent. That is a little less clear in the HER2-negative space. We tend to rely on what we've done in the HER2-positive space [in that regard], but the natural history of the disease is quite different. That is an area where more guidance would be appreciated.

One of the things that's become very apparent in the preclinical studies of brain metastases is that many times, the brain metastases harbor a genetic alteration that's different from what is seen in the extracranial disease. This is really important to understand because we may not be targeting the correct oncogenic pathway without looking at the genomic material from the brain metastases.

In a case where a neurosurgical resection is clinically indicated, we're able to garner this information through next-generation sequencing platforms. It becomes much trickier when neurosurgical resection is not clinically indicated because research biopsies of the brain carry too high of a risk. Having a blood-based circulating tumor [DNA] assay would be fantastic. The challenge is trying to determine which cells came from the CNS as opposed to not. I don't believe that we're quite there yet.

Hopefully, that can be a direction we head toward in the future. The genomic material from the brain metastases can change the recommendation for systemic therapy beyond what is known in the extracranial disease. There is a clinical trial that's going to be running through our ALLIANCE consortium, which will look at genomically targeting the alterations within brain metastases to see if we can improve patient outcomes.

Saura C, Oliveira M, Feng Y-H, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: findings from the multinational, randomized, phase III NALA trial. J Clin Oncol. 2019;37(15 suppl; abstr 1002). doi: 10.1200/JCO.2019.37.15_suppl.1002.