Newer Treatments and Combinations Emerging for Breast Cancer Brain Metastases

Carey K. Anders, MD

Carey K. Anders, MD

Multiple treatment options are emerging for patients with breast cancer that has metastasized to the brain, looking to improve upon the standards of care for patients with breast cancer—related brain metastases (BM) across breast cancer subtypes.

A phase II study looking at abemaciclib (Verzenio), a CDK4/6 inhibitor, in patients with HR-positive, HER2-negative metastatic breast cancer (MBC) with secondary BM was presented at the 2019 ASCO Annual Meeting.¹Abemaciclib has already been approved by the FDA when used in combination with an aromatase inhibitor for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

Of 58 patients who received 200 mg of abemaciclib orally twice a day, 52 were evaluable for objective intracranial response rate (OIRR), which was the primary endpoint. The patients had received a median of 4 prior systemic therapies in the metastatic setting.

Three patients had a confirmed response for an OIRR of 6%, and 38% demonstrated a reduction in the sum of their intracranial targeted lesions. The intracranial clinical benefit rate, which consisted of patients with response and those who had stable disease for at least 6 months, was 25%. The median progression-free survival (PFS) was 4.4 months (95% CI, 2.6-5.5). 

Additionally,a phase II trial is investigating the combination of neratinib (Nerlynx) and capecitabine (Xeloda) for patients with HER2-positive MBC and BM.²There were 37 lapatinib (Tykerb)-naïve patients (cohort 3A) and 12 lapatinib-pretreated patients (cohort 3B) who were treated with the combination regimen. Each patient received 240 mg neratinib orally once a day and 750 mg/m²capecitabine orally twice a day for 14 days and then 7 days off. The primary endpoint was central nervous system (CNS) overall response rate (ORR).

In cohort 3A, the CNS ORR was 49% and was 33% in cohort 3B. The median PFS was 5.5 and 3.1 months in cohorts 3A and 3B, respectively. Median overall survival (OS) was 13.3 and 15.1 months, respectively. The most common adverse effect was grade 3 diarrhea in 29% of both cohorts.

A supplemental New Drug Application to the FDA for the approval of the combination of neratinib plus capecitabine as treatment for patients with previously treated, HER2-postive MBC.

Carey K. Anders, MD, an instructor at the Duke Cancer Institute, worked on both of these studies, and spoke with Targeted Oncologyabout these and other studies that are looking to improve outcomes for patients with MBC and secondary BM.

TARGETED ONCOLOGY: How would you advise community oncologists on the management of brain metastases in patients with breast cancer in today's landscape?

Anders:The management of our patients with breast cancer brain metastases really requires a multi-disciplinary approach. That involves patients seeing neurosurgical colleagues, radiation oncologists, and medical oncologists. At the initial stages, when patients are diagnosed, many times we'll move forward with neurosurgical resection if there is a solitary lesion, or if the diagnosis is in question, or if there is a large space-occupying lesion that's causing the patient mass effect. Depending on whether or not neurosurgical resection is required, we then typical go to radiation therapy and that landscape, I think, may be changing in the future as our systemic therapies continue to advance. But traditionally, patients with a limited number of brain metastases will receive stereotactic radiosurgery to each of those lesions. 

If there are multiple lesions, and that number is debatable, potentially over 10, or diffuse dural-based disease, then patients will receive whole-brain radiation therapy. And then at that point, in consultation with the medical oncologist, based on the patient’s subtype and presence or absence of extracranial disease, I will recommend extra therapies that are most appropriate. 

The timing of each of these is as important for each of the modalities of care to be discussed and I think there are multiple clinical trials looking at the timing [of treatment] and combinations, particularly of radiation therapy with systemic agents, ongoing presently. 

TARGETED ONCOLOGY: What challenges are oncologists still facing when managing brain metastases and what's being done to address these issues?

Anders:There are many challenges related to systemic therapy delivery for brain metastases. I think one of the greatest challenges is overcoming the blood-brain barrier. Although we do believe now that the blood-brain barrier is less intact in the setting of intercranial malignancy, termed the blood-tumor barrier. But we also have efflux pumps inherent to the blood-brain barrier that can pump certain therapeutics out of the central nervous system. So once we find the agent that matches the patient’s subtype and is hopefully brain-permeable, we also have to consider the challenge of extracranial disease and trying to balance the extra- and intracranial disease control concurrently.

The other challenges include quality of life and neurocognition related to a diagnosis of brain metastases, and depending on the area of the lesion, the neurologic sequelae can be quite difficult for patients to manage, as well as the neurocognitive sequelae of therapies, such as whole-brain radiation therapy.

TARGETED ONCOLOGY: Can you expand on the current treatments for breast cancer past the blood-brain barrier?

Anders:Possibly the most commonly delivered therapies past the blood-brain barrier are in the anti-HER2 family. Starting back with lapatinib, we knew that lapatinib was a small molecule inhibitor that inhibited both HER1 and HER2 and has since been FDA approved in combination with capecitabine in the setting of extracranial advanced HER2-positive disease. But based on activity that we've seen as a single agent in the CNS, of around 6%, but in combination with capecitabine, [the response rate is] around 30%. It represents one of the therapies that we can pull from our toolkit for our patients with HER2-positive breast cancer [that is metastatic to the] brain.

More recently, we've also seen data for neratinib, which is a small molecule inhibitor also for HER1 and HER2. In the NALA study at ASCO, which illustrated improved PFS for neratinib with capecitabine versus lapatinib and capecitabine, and the time to next therapy for CNS disease was lower in the neratinib group. As a class effect, however, we do have to manage diarrhea and rash in these patients because both of these compounds hit both HER1 and HER2. HER1 being EGFR, and we do see an adverse-effect profile that needs attention when we're delivering these therapies for our patients.

TARGETED ONCOLOGY: Can you discuss the new systemic regimens for treating brain metastases and how they compare with some of the previous treatments?

Anders:When thinking about what's on the horizon for brain metastases, we have multiple ongoing studies where we're awaiting results. In the HER2-positive space, we're anxiously awaiting the results of the HER2CLIMB study, which is capecitabine, trastuzumab [Herceptin], with or without the brain-permeable compound tucatinib, which is more selective for HER2 as opposed to HER1 and HER2, thus [it has] a lower adverse-effect profile.

In the triple-negative space, there have been the advent of PARP inhibitors and there's several studies ongoing right now evaluating PARP inhibitors in triple-negative disease, including in patients with brain metastases. One that is notable is the SWOG 1416 study, which is cisplatin with or without veliparib, a brain-permeable PARP inhibitor. That study did have a CNS metastasis cohort for patients with either stable and/or progressive brain metastases. We're very curious to see what the results of those studies will show—how they'll read out and whether or not we'll be able to implement these therapies along with our standard practice today. 

One other compound to think about is the NKTR-102 compound, which is a Nektar compound. It is a liposomal prodrug of irinotecan or etirinotecan. This study, called the ATTAIN study, is evaluating the etirinotecan pegol compared to physician's choice in patients with stable brain metastases, and it's a very interesting mechanism of action given that it's a topoisomerase inhibitor with DNA-damaging capacity, but in its pegylated form has superior CNS permeability. We're anxious to see how NKTR-102 compares to standard-of-care chemotherapy in that setting.

In the setting of ER-positive metastatic breast cancer that's HER2-negative, which is really our most common subtype of breast cancer, brain metastases—while less common than in our triple-negative and HER2-postive subtypes—can still become problematic, particularly once the metastases become endocrine therapy resistant.

We've recently seen data for abemaciclib, which is a brain-permeable CDK4/6 inhibitor, at ASCO, and while the overall response rate in that study was around 6%, the rate of those with clinical benefit or disease control stability out past 6 months was around 25%. So that does offer a very nice oral therapy with a relatively non-toxic adverse-effect profile. We need to watch out for neutropenia and diarrhea with abemaciclib, but compared to cytotoxic chemotherapy, it is a gentler agent for our patients with ER-positive metastatic breast cancer and brain metastases.

TARGETED ONCOLOGY: Do you think these systemic therapies should be supplemented with radiation?

Anders:Whether or not we should combine systemic therapies with radiation is a great question, and I think, ultimately, we would love to do so safely to try to improve intracranial control. Not only the lesion that's being treated with radiation, but also protecting distant areas within the brain. The caveat there is that the safety of these approaches is extremely important because radiation therapy necrosis is a real challenge for our patients post-radiosurgery, and the literature is very varied on the incidents of radiation therapy necrosis. I've seen incidences of 5% in some series, all the way up to 50%. We certainly want to maintain intracranial control and prevent new metastases with systemic therapy, but carefully design prospective studies evaluating safety are needed before we combine systemic therapies with radiosurgery.

TARGETED ONCOLOGY: What other areas are of concern with regards to CNS metastases?

Anders:Leptomeningeal disease is quite a difficult scenario across multiple solid tumor types where patients have circulating tumor cells within the cerebral spinal fluid, which can cause a lot of morbidity from an adverse effect or neurotoxicity perspective, but also very short survival estimates out to maybe only 6 to 8 weeks if untreated, and sometimes even with treatment. There's an upcoming national study called the ANGLeD study, which is looking at a compound called ANG1005, which is a brain-permeable taxane, [in comparison with] physician's choice and patients with HER2-negative metastatic breast cancer and leptomeningeal disease. It would be wonderful to have a systemic agent beyond intrathecal therapy that could help patients with leptomeningeal carcinomatosis. 

References:

1. Anders CK, Le Rhun E, Bachelot TD, et al. A phase II study of abemaciclib in patients (pts) with brain metastases (BM) secondary to HR+, HER2- metastatic breast cancer (MBC). J Clin Oncol.2019;37(suppl; abstr 1017). https://meetinglibrary.asco.org/record/174775/abstract.
2. Freedman RA, Gelman RS, Anders CK, et al. A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2—Positive Breast Cancer and Brain Metastases. J Clin Oncol.2019;37(13): 1081-1089. doi 10.1200/JCO.18.01511.