Systemic Therapies Improve Breast Cancer With Brain Metastases Management

Kamran A. Ahmed, MD

Novel systemic therapies and alternative treatment strategies have elicted a potential survival advantage for patients with breast cancer–related brain metastases, said Kamran A. Ahmed, MD, who added that more work is needed to tease out optimal treatment strategies for these patients.

“We are seeing more and more from the data coming out, particularly from the HER2CLIMB and the NALA studies, that there is a potential role for systemic therapy in the management of patients with breast cancer brain metastases,” said Ahmed. “We have limited data and continue to [face] limitations within this patient population, so we have a strong need for improved therapies and enrollment into clinical trials as a means to obtain data from these patients and determine new treatment options.”

For example, in April 2020, the FDA approved tucatinib (Tukysa) in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, following at least 1 prior HER2-directed treatment in the metastatic setting.¹

The approval was based on findings from the phase 2 HER2CLIMB study, in which treatment with the triplet led to a 34% reduction in the risk of death compared with trastuzumab and capecitabine alone in patients who were previously treated with trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla; HR, 0.66; 95% CI, 0.50-0.88; P <.005).²

Moreover, the regimen reduced the risk of disease progression or death by 52% in patients with baseline brain metastases (HR, 0.48; 95% CI, 0.34-0.69; P <.00001). Updated findings presented at the 2020 ASCO Virtual Scientific Program showed a 68% reduction in the risk of central nervous system (CNS) progression or death in the tucatinib arm compared with the control arm (HR, 0.32; 95% CI, 0.22-0.48; P <.00001).³

Data from other key trials including the phase 2 TBCRC 022 and the phase 3 NALA studies, both evaluating neratinib (Nerlynx), have also provided growing evidence for the role of systemic therapy in the management of patients with breast cancer and brain metastases.

In an interview with OncLive as part of the virtual Institutional Perspectives in Cancer^™ on Breast Cancer, Ahmed, an assistant member in the Department of Radiation Oncology and the Department of Immunology at Moffitt Cancer Center, and an assistant professor in the Department of Oncologic Sciences at the University of South Florida, discussed the evolution of treatment for patients with breast cancer brain metastases, recent pivotal findings that have significantly improved survival for these patients, and a number of agents on the horizon.

OncLive: Could you provide an overview of the incidence and impact of brain metastases in breast cancer?

Ahmed: In recent years, we have seen an increase in the incidence of brain metastases in breast cancer. We have had a number of systemic agents that have improved progression-free survival (PFS) and overall survival (OS) in the metastatic setting. However, with that, we have seen an increasing number of patients being diagnosed with brain metastases.

Now that patients with brain metastases are potentially living longer due to systemic control, there has been an increasing awareness that new treatment options for these patients are important. A number of drugs are under investigation in that space.

What are some of the key strategies that are currently being used to manage brain metastases?

The primary strategy that is in place for the majority of patients who have breast cancer that has spread to the brain is local therapy. The cornerstone is still radiation therapy and potentially surgery. With that, we’ve seen a number of agents in the breast cancer space that have shown good outcomes and the potential to improve intracranial progression. Certainly, in the HER2-positive space, there are data with some of the HER2[-directed] TKIs, as well as some other targeted agents.

In addition to that, there are a number of other agents under investigation in the hormone receptor–positive, HER2-negative as well as triple-negative breast cancer (TNBC) spaces that will hopefully show positive outcomes in the future.

The HER2CLIMB study was very impactful for patients with brain metastases. Could you discuss the key findings that were seen in that study?

The HER2CLIMB study was a phase 3 trial that evaluated tucatinib, an irreversible TKI targeting HER1 and HER2, in combination with trastuzumab and capecitabine compared with placebo plus capecitabine and trastuzumab. This was a study of patients who were treated in the third-line setting after receiving trastuzumab and pertuzumab, and T-DM1.

About half of patients had brain metastases at the time of enrollment. In addition to the PFS benefits, which were recently reported in the New England Journal of Medicine, the intracranial response data were presented at the 2020 ASCO Virtual Scientific Program showing quite provocative findings. The median CNS-PFS was more than doubled from 4.2 months in the control arm to 9.9 months in the tucatinib arm. Additionally, patients with brain metastases had an improvement [with tucatinib] compared with placebo at 18.1 months and 12 months, respectively. These findings were significant in patients who had both active and stable brain metastases.

How has the approval of tucatinib impacted the HER2-positive breast cancer treatment paradigm?

The data we saw from the HER2CLIMB trial was quite provocative and has shown us that tucatinib has a role in the metastatic space. What is interesting to see from the CNS data presented at the 2020 ASCO Virtual Scientific Program is the potential role that systemic therapies, such as tucatinib, have in the management of patients with active brain metastases who have not received prior local therapy.

As a radiation oncologist, [I wonder if] tucatinib could potentially have a role in the primary management of patients with small asymptomatic brain metastases. We’ll have to wait for the full publication to come out to look at the intracranial response rate data in greater detail, but certainly what we have seen so far is quite intriguing.

Switching gears, what findings were important from the TBCRC 022 study?

The TBCRC 022 evaluated neratinib and capecitabine in patients with HER2-positive brain metastases. Neratinib is an irreversible pan-HER TKI. TBCRC 022 was a phase 2 study of 49 patients with untreated HER2-positive brain metastases.

In the lapatinib (Tykerb)-naïve cohort, the CNS overall response rate (ORR) was 49% and the PFS was 5.5 months. These findings indicate a role for neratinib in the management of patients with HER2-positive brain metastases.

How have the results of the NALA trial added to what we know of neratinib in patients with brain metastases?

The phase 3 NALA trial compared neratinib and lapatinib both in combination with capecitabine in patients with HER2-positive metastatic breast cancer who had previously received 2 lines of HER2-directed regimens.

In terms of CNS response, the time to intervention for symptomatic CNS disease was improved in the neratinib arm, at 23% versus 29%. Additionally, the risk of disease progression or death was reduced by 24% with neratinib plus capecitabine.

Grade 3 diarrhea was higher in the neratinib arm, at 24% versus 15% in the lapatinib arm. This potentially shows the role of neratinib in [patients with CNS involvement].

Could you shed light on some of the work being done regarding leptomeningeal disease in HER2-positive breast cancer and TNBC?

In a similar way in which we’re seeing larger incidence and diagnosis of brain metastasis, the same is true of leptomeningeal disease. Patients with TNBC and HER2-positive breast cancer are potentially more prone to develop leptomeningeal disease.

Historically, patients’ survival has been measured in weeks to months. Now, there are single-institution data, as well as data from a phase 1/2 study, that has been reported on the use of intrathecal trastuzumab in HER2-positive leptomeningeal disease. That has shown good results; the median OS with intrathecal trastuzumab was 12.1 months. Compared with what we’ve seen in historical cohorts of patients, these are quite intriguing data. Certainly, for these patients who have HER2-positive leptomeningeal disease, intrathecal HER2-targeted therapy should be considered.

More work is going on in this space as well. We’re going to be opening a phase 1/2 study with the combination of intrathecal pertuzumab plus a fixed dose of trastuzumab. That study is going to have escalating doses of pertuzumab to see whether we can improve upon the outcomes that were achieved in the intrathecal trastuzumab study.

Other trials are being conducted in the leptomeningeal disease space, including ANG1005 which is enrolling patients who have HER2-negative leptomeningeal disease based off the results of a phase 2 study showing a median OS of 8 months. That is quite an improved survival from what we’ve seen in historical cohorts. Therefore, we look forward to that study coming out, as well as additional research going on in this space.

Now that more patients are being diagnosed with leptomeningeal disease, systemic control may be improved.

What are some emerging agents that are under investigation in this space currently?

An area in which continued improvement needs to be made are therapies for patients with HER2-negative breast cancer and brain metastases. These patients, particularly those with TNBC, continue to have poor outcomes, and certainly new treatment options are needed.

Etirinotecan pegol (NKTR-102) is a PET polymer conjugate with irinotecan. Preliminary data was presented from the phase 3 BEACON trial. Although the BEACON trial didn’t show improvement in the primary end point of OS for the whole cohort, there was an improvement in OS for the patients who had brain metastasis.

Based on those data, there is a phase 3 study, known as the ATTAIN trial, that is ongoing that’s looking at using etirinotecan pegol in patients with breast cancer who have brain metastases.

A phase 1 study evaluating nanoliposomal irinotecan has been completed. A small cohort of about 10 patients with breast cancer were included in this study. The study showed an ORR of 30%. These are intriguing data that we need to assess in a larger cohort of patients to see whether the preliminary phase 1 data stand up in terms of CNS response rate.

Tesetaxel is an oral blood brain barrier permeable taxane. Current data exists in animal models and suggest that the drug can penetrate the blood–brain barrier. There are ongoing studies in the setting of brain metastases in advanced breast cancer to determine whether there is a role for tesetaxel in the management of these patients.

Another agent that has been studied in the HR-positive, HER2-negative space has been abemaciclib (Verzenio). Data were presented at the 2019 ASCO Annual Meeting showing a 25% intracranial benefit rate with abemaciclib, a selective CDK4/6 inhibitor. The benefit was defined as a complete response, partial response, or stable disease greater than or equal to 6 months. The study did not meet its primary end point of an overall intracranial response rate of 11%. Rather, a 6% [rate was reported]. However, the study did note that 38% of patients experienced a decrease in size of their intracranial target lesion. As such, there might be a potential role for abemaciclib in the management of patients with HR-positive, HER2-negative brain metastases.

Could you speak to the Alliance A071701 trial and explain the rationale for using a genomically guided brain metastases protocol?

Alliance A071701 is an intriguing trial. It’s enrolling patients not only with breast cancer and brain metastases, but also lung cancer brain metastases and other [histologic types of] brain metastases. Basically, it’s utilizing tissue from patients’ brain metastases and systemic metastases, and then determining whether genomically guided treatment may have a role in the management of their brain metastases. We’ve seen studies that have shown a number of mutations in brain metastases that could be potential targets for treatment. This type of study will be quite interesting and will reveal the role that a targeted systemic approach could have in the management of patients with brain metastases.

What is your take-home message regarding the management of patients with brain metastases?

Multidisciplinary care is key in the management of this difficult patient population. Discussions between the radiation oncologist, neurosurgeons, and breast medical oncologists who are guiding systemic care and potential treatment options [is critical].

Radiation oncologists continue to play a central role in the management of patients with breast cancer who have brain metastases. More and more we are trying to treat patients with targeted stereotactic radiation therapy. We are also studying [alternative] techniques, such as the use of memantine and hippocampal-sparing [radiotherapy] to avoid the late adverse effects of whole brain radiation therapy.

References:

1. Seattle Genetics announces U.S. FDA approval of Tukysa™ (tucatinib) for people with advanced unresectable or metastatic her2-positive breast cancer. News release. Seattle Genetics, Inc; April 17, 2020. Accessed May 29, 2020. https://bit.ly/2xtQeBe
2. Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Eng J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
3. Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(suppl 15):1005. doi:10.1200/JCO.2020.38.15_suppl.1005