Progress in Treating Brain Metastases in Breast Cancer Puts Multidisciplinary Approaches Into Focus

Barbara O’Brien, MD

Brain metastases are a common complication in patients with breast cancer, and although systemic therapies for patients with HER2-positive disease have displayed promise in penetration of the blood-brain barrier, work remains for subsets of patients with central nervous system (CNS) metastases, according to Barbara O’Brien, MD.¹

“For most patients, the treatment [for brain metastases has been] with local therapy with radiation or surgery. Historically, there has been very limited role for systemic therapy, in part [because of] this unique environment. For the most part, these patients are excluded from clinical trials,” O’Brien said in a presentation at the 40th Annual Miami Breast Cancer Conference^®.

Although considerable progress has been made in the treatment of patients with HER2-positive breast cancer with brain metastases, O’Brien said that questions remain regarding the sequencing of therapy, primary and secondary intervention, and the approach for HER2-low disease.

“We have increasingly complex decisions to make, and multidisciplinary approaches are critical,” O’Brien, who is an associate professor of neuro-oncology at The University of Texas MD Anderson Cancer Center in Houston.

In her presentation, O’Brien highlighted the efficacy displayed by systemic therapies for patients with HER2-postive breast cancer with brain metastases, detailed the exploration of systemic therapies in non–HER2-positive disease, and addressed for the need for a continued multidisciplinary approach in treating patients with brain metastases.

HER2-Positive Breast Cancer

In April 2020, the FDA approved tucatinib (Tukysa) for use in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following at least 1 prior anti–HER2-based regimen in the metastatic setting, based on data from the phase 2 HER2CLIMB trial (NCT02614794).²

Data from an exploratory analysis of HER2CLIMB of 291 patients with asymptomatic stable/active brain metastases showed that those treated with the combination of tucatinib plus trastuzumab and capecitabine experienced a median overall survival (OS) of 21.6 months, compared with 12.5 months for those given placebo plus trastuzumab and capecitabine.³

Additionally, the those in the tucatinib arm achieved a median intercranial progression-free survival (IC-PFS) of 9.9 months vs 4.2 months for those in the placebo arm. Among 66 patients who deferred radiotherapy, the median IC-PFS was 8.1 months.

Furthermore, patients with active brain metastases and measurable intracranial lesions at baseline treated with the tucatinib regimen (n = 55) experienced a confirmed intracranial overall response rate (IC-ORR) of 47.3% (95% CI, 33.7%-61.2%), compared with 20.0% (95% CI, 5.7%-43.7%) for those given the placebo regimen (n = 20). The median intracranial duration of response (IC-DOR) was 8.6 months (95% CI, 5.5-10.3) and 3.0 months (95% CI, 3.0-10.3) for the tucatinib and placebo arms, respectively. The brain metastases–free survival was 24.9 months in the tucatinib group and 13.8 months in the placebo group.

The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu), which received regular approval from the FDA in May 2022 for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received an anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within 6 months of therapy completion, has also displayed CNS activity.⁴

In a subanalysis of the phase 2 DESTINY-Breast01 trial (NCT03248492), 14 patients with stable brain metastases treated with trastuzumab deruxtecan achieved an IC-ORR of 50%.⁵ Furthermore, in a subanalysis of the phase 3 DESTINY-Breast03 trial (NCT03529110), the antibody-drug conjugate (ADC) elicited an IC-ORR of 64%, including 10 complete responses, in patients with stable brain metastases (n = 43), compared with 33% for ado-trastuzumab emtansine (T-DM1; Kadcyla; n = 39).⁶ The median PFS was 15 months for the trastuzumab deruxtecan arm vs 3 months for the T-DM1 arm.

Additional studies have further demonstrated the efficacy of trastuzumab deruxtecan in patients with HER2-postive breast cancer with brain metastases. Among 15 patients with active brain metastases treated with the ADC in the phase 2 TUXEDO-1 trial (NCT04752059), the IC-ORR was 73%.⁷

In the retrospective ROSET-BM trial, patients with active brain metastases (n = 37) experienced an IC-ORR of 54.1% (95% CI, 36.9%-70.5%) with a 6-month intracranial clinical benefit rate (IC-CBR) of 62.2% (95% CI, 44.8%-77.5%).⁸ Those with stable brain metastases (n = 5) had an IC-ORR of 100% (95% CI, 47.8%-100%) and a 6-month IC-CBR of 100% (95% CI, 47.8%-100%). Those with leptomeningeal carcinomatosis (n = 9) achieved an IC-ORR of 77.8% (95% CI, 40.0%-97.2%) and a 6-month IC-CBR of 88.9% (95% CI, 51.8%-99.7%).

O’Brien explained that sequencing of systemic therapy for patients with HER2-positive disease can included trastuzumab plus pertuzumab (Perjeta) in the first line, followed by trastuzumab deruxtecan or the tucatinib regimen in the second line.

"It’s important to note that the standard of care [for brain metastases] is still local therapy. So, it's important to have that multidisciplinary discussion when approaching patients with brain metastases,” O’Brien said.

CNS Management in HER2–Non-Specific Breast Cancer

Although significant strides have been made in the treatment of patients with brain metastases in the HER2-positive space, data supporting the benefit of systemic therapies in HER2–non-specific disease are limited, according to O’Brien.

“Unfortunately, there aren’t many systemic options [in non–HER2-positive disease], and we do lean heavily on local therapy,” O’Brien said. “In terms of the role of immunotherapy and checkpoint inhibitors, we just don’t know [what it is] yet.”

In HER2-low disease, the phase 2 DEBBRAH trial (NCT04420598) produced the first prospective data on trastuzumab deruxtecan for patients with HER2-low breast cancer with brain metastases. Among 12 total patients from cohort 2 (n = 6) and cohort 4 (n = 6), the IC-ORR was 50%, and the IC-CBR was 66.7%.⁹

Further, data from a phase 2 study (NCT02308020) evaluating abemaciclib for patients with hormone receptor–positive/HER2-negative breast cancer with brain metastases (n = 58) showed that the CDK4/6 inhibitor produced an IC-ORR of 5.2%, an IC-CBR of 24%, and a median overall survival of 12.5 months.¹⁰

In the phase 3 EMBRACA trial (NCT01945775) evaluating the PARP inhibitor talazoparib (Talzenna) vs chemotherapy in HER2-negative breast cancer harboring a BRCA1/2 mutation, 15% of patients had stable brain metastases at baseline, and a subgroup analysis showed that 70% of patients in the talazoparib arm had stable intracranial disease compared with 33% in the chemotherapy arm.¹¹

The ADC sacituzumab govitecan-hziy (Trodelvy) produced therapeutically relevant concentrations of SN-38 at 150-fold mean IC50s for breast cancer with brain metastases in an early phase 1 small window study (NCT03995706).¹²

Additionally, in the phase 3 ASCENT trial (NCT02574455) of sacituzumab govitecan vs chemotherapy for patients with relapsed/refractory triple-negative breast cancer (TNBC), 12% of enrolled patients (n = 61) had stable brain metastases.13 Those treated with the ADC had median PFS of 2.8 months, compared with 1.6 months for chemotherapy. The median OS was 6.8 months and 7.5 months for sacituzumab govitecan and chemotherapy, respectively, showing that the ADC was not superior to conventional chemotherapy for patients with brain metastases.

Enrollment is currently ongoing for the phase 2 SWOG S2007 trial (NCT04647916) evaluating sacituzumab govitecan in patients with HER2-negative breast cancer with brain metastases.

Given the lack of benefit with systemic therapies in non–HER2-positive breast cancer with brain metastases, O’Brien emphasized that a multidisciplinary approach is necessary for these patients. Along with clinical trials, managing these patients involves the use of local therapy with radiation and or resection prior to systemic therapy, and symptom management is key.

Management of neurologic symptoms for these patients can included corticosteroids such as dexamethasone at the minimum possible dose. Anticonvulsants are typically reserved for patients with seizures, and prophylactic use can be considered in some cases.

Leptomeningeal Metastasis

Treatments strategies for patients with leptomeningeal metastases can include radiation, intrathecal chemotherapy, systemic chemotherapy, and palliative care or hospice. O’Brien explained that practice patterns vary widely for these patients, and there are limited clinical trials.

Intrathecal trastuzumab was evaluated in a pair of phase 2 trials in Japan for patients with HER2-positive breast cancer with leptomeningeal metastases. One study showed that among 19 patients, the median leptomeningeal metastases–related PFS was 5.9 months, with a median OS of 7.9 months.14 Another study showed that 23 patients experienced median PFS of 2.8 months and a median OS of 10.5 months.¹⁵

The phase 2 TBCRC049 trial (NCT03501979) investigated the combination of tucatinib plus trastuzumab and capecitabine in patients with HER2-positive breast cancer with leptomeningeal metastases and demonstrated a median OS of 10 months and a median time to CNS progression of 6.9 months.¹⁶

“This is the first prospective evidence of clinical benefit for a systemic regimen for HER2-positive [breast cancer with] leptomeningeal metastases,” O’Brien said.

References

1. O’Brien B. Medical management of CNS metastasis in patients with breast cancer. Presented at: 40th Annual Miami Breast Cancer Conference®; March 2-5, 2023; Miami Beach, FL.
2. FDA approves first new drug under international collaboration, a treatment option for patients with HER2-positive metastatic breast cancer. FDA. April 17, 2020. Accessed March 4, 2023. https://www.fda.gov/news-events/press-announcements/
3. Lin NU, Murthy RK, Abramson V, et al. Tucatinib vs placebo, both in combination with trastuzumab and capecitabine, for previously treated ERBB2 (HER2)-positive metastatic breast cancer in patients with brain metastases: updated exploratory analysis of the HER2CLIMB randomized clinical trial. JAMA Oncol. 2023;9(2):197-205. doi:10.1001/jamaoncol.2022.5610
4. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Accessed March 4, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
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