Systemic Therapies Are Now Preferred in Some Patients With HER2+ Breast Cancer Brain Metastases

The high level of intracranial activity seen with novel HER2-targeted therapies has created a new paradigm that defers local therapy in favor of systemic options to treat small asymptomatic brain metastases in patients with metastatic breast cancer, explained Sara A. Hurvitz, MD, FACP, at the 42nd Annual Miami Breast Cancer Conference.1

The newer agents that cross the blood-brain barrier for HER2-positive metastatic breast cancer include tucatinib (Tukysa) and fam-trastuzumab deruxtecan-nxki (Enhertu), with several other TKIs also showing promise. A meta-analysis of 97 studies found that HER2-targeted therapies significantly improved overall survival (OS) compared with non-targeted treatments for patients with HER2+ breast cancer with intracranial metastatic disease (HR, 0.47; 95% CI, 0.39-0.56).2

"When we have a patient develop brain metastases, we should refer patients or work very closely with our multidisciplinary colleagues in radiation oncology and neurosurgery. There are a number of factors that will weigh into treatment decision-making in terms of extracranial disease, how symptomatic the patient is, the number and the location of lesions," said Hurvitz, head of the Division of Hematology/Oncology at University of Washington School of Medicine and senior vice president of Clinical Research Division at Fred Hutchinson Cancer Center in Seattle. "we are still in an era where we rely pretty heavily on locoregional therapy, but for HER2-positive central nervous system [CNS] disease, we now have the availability of systemic therapies that work."

TKIs With CNS Activity

Several studies have assessed TKI-based regimens for patients with brain metastases utilizing a variety of agents, each showing different levels of intracranial response. Hurvitz noted that intracranial responses in these studies have ranged from 8% to as high as 75%.

The phase 2 HER2CLIMB study (NCT02614794) examined capecitabine plus trastuzumab (Herceptin) combined with the TKI tucatinib or placebo for patients with HER2-positive metastatic breast cancer, including those with brain metastases. An updated exploratory analysis specifically looked at the 291 patients enrolled in the study with brain metastases.3 In those receiving tucatinib, the risk of developing a new brain lesion was significantly reduced compared with patients given placebo (HR, 0.55; 95% CI, 0.36-0.85).

The median OS was longer with the tucatinib regimen compared with placebo for patients with active brain metastases (21.4 months vs 11.8 months, respectively). Additionally, of the 66 patients enrolled with untreated brain metastases, the median OS was 19.7 months with tucatinib compared with 13.4 months with placebo.

Another TKI of interest for brain metastases is pyrotinib, Hurvitz noted. This agent showed activity when used in combination with capecitabine for patients with HER2-positive metastatic breast cancer. In the phase 2 PERMEATE study (NCT03691051),4 which was conducted in China, the intracranial response rate was 74.6% in those who had not received prior radiation therapy, and it was 42.1% in those who had received prior radiation. Pyrotinib is currently being explored in a variety of combinations and settings but is not yet approved in the United States.

Antibodies and Antibody-Drug Conjugates for Brain Metastases

Antibody therapies like pertuzumab (Perjeta) and trastuzumab have also been explored in combination as a treatment for brain metastases. As have their armored counterparts, the antibody-drug conjugates (ADCs) ado-trastuzumab emtansine (T-DM1; Kadcyla) and trastuzumab deruxtecan.

In the phase 2 PATRICIA trial (NCT02536339),5 the combination of pertuzumab plus high-dose trastuzumab showed a confirmed CNS response of 11% (95% CI, 3.0-25.4). The median CNS-PFS was 4.6 months, and the median OS was 27.2 months with this combination.

"The PATRICIA study is overlooked in a lot of cases," said Hurvitz. "I think these are notable data especially to keep in mind for our patients whose disease has progressed in the brain."

The first ADC for HER2-positive breast cancer, T-DM1, was explored for patients with brain metastases in the phase 3 KAMILLA study (NCT01702571).6 In this study, the best overall response rate was 21.4%, which included both CNS and non-CNS responses. There was a 30% or greater reduction in the sum of the largest brain lesions observed in nearly one-third of patients treated with T-DM1 after radiotherapy (32.7%). In those who received T-DM1 without prior radiotherapy, a 30% or greater reduction in brain lesions was seen in 49.3% of patients.

These data set the stage for trastuzumab deruxtecan, which has significantly disrupted the treatment of HER2-positive breast cancer across several settings. A few studies have shown significant improvement in brain metastases with trastuzumab deruxtecan, including the phase 2 TUXEDO-1 (NCT04752059) and DEBBRAH (NCT04420598) trials, and the retrospective, real-world ROSET-BM study (UMIN000044995) conducted in Japan, Hurvitz detailed.

The DESTINY-Breast trials were foundational in the establishment of trastuzumab deruxtecan for HER2+ breast cancer. A pooled analysis of the phase 2 DESTINY-Breast01 (NCT03248492), phase 3 DESTINY-Breast02 (NCT03523585), and phase 3 DESTINY-Breast03 (NCT03529110) studies examined the efficacy of the trastuzumab deruxtecan in patients with brain metastases.7 Across these studies, 148 patients with brain metastases received the ADC compared with 83 patients with brain metastases in the control arms.

In this pooled analysis, for those who had previously treated or stable brain metastases, the intracranial response rate was 45.2% with trastuzumab deruxtecan. In those with untreated or active asymptomatic brain metastases, the intracranial response rate was 45.4% with trastuzumab deruxtecan. In the comparison arms for these trials, which included T-DM1, lapatinib (Tykerb) plus capecitabine, and trastuzumab plus capecitabine, the intracranial response rates were 27.6% and 12% in the same patient groups, respectively.

"What is notable here is how bad the comparator arms [are] doing in the patients with untreated and active brain metastases," Hurvitz noted.

The most recent study showing a benefit for trastuzumab deruxtecan was the phase 3b/4 DESTINY-Breast12 trial (NCT04739761).8 The open-label study enrolled patients with or without brain metastases to compare outcomes between both groups. In those with baseline brain metastases, the median progression-free survival (PFS) was 17.3 months. The 12-month CNS PFS was 58.9%.

Intracranial tumor shrinkage was seen with trastuzumab deruxtecan in almost all patients with measurable brain metastases at baseline, with confirmed CNS responses for 62.3% of those with active brain metastases. Those with previously untreated brain metastases had an intracranial response rate of 82.6% with trastuzumab deruxtecan.

"I think we see clear evidence of activity in the brain with this molecule," said Hurvitz.

Next Steps for Systemic Treatment of Brain Metastases

For patients with HER2-positive metastatic breast cancer, the brain is the most common site of metastatic disease, with nearly half of patients developing this condition, Hurvitz noted. With such a high rate of brain metastases, guidelines have grappled with the notion of screening all patients with HER2-positive metastatic disease, regardless of symptoms. Although this is not the current standard of care, studies are underway to assess the long-term benefits of screening asymptomatic patients with HER2-positive metastatic breast cancer for brain metastases (NCT04030507, NCT05115474). With enough evidence, Hurvitz believes screening asymptomatic patients with metastatic breast cancer could be added to future guidelines.

The ideal candidate for systemic vs local therapy is one with no symptomatic mass effect, a single lesion less than 2 cm, or multiple lesions less than 2 cm. In many cases, the use of systemic therapies avoids the adverse effects associated with radiation; however, the use of these agents vs a local therapy does require careful consideration of a multidisciplinary team to arrive at the optimal treatment choice.

“There are ongoing studies that may address this important question of whether we should screen asymptomatic patients with HER2-positive breast cancer for brain metastases,” said Hurvitz. “Hopefully, there will be data forthcoming in the not-too-distant future.”

If during the multidisciplinary assessment, a poor prognosis is determined, the goals of therapy and best supportive care should be considered, she noted. If a fair or good prognosis is determined, there are several options based on the extent and location of the disease. Local therapy has long been considered the standard of care for those lacking extracranial spread, a single lesion, a limited number of small lesions, or even extensive large lesions.

References

1. Hurvitz SA. Managing Brain Metastases in HER2+ Breast Cancer. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami, Florida.
2. Erickson AW, Ghondrati F, Habbous S, et al. HER2-targeted therapy prolongs survival in patients with HER2-positive breast cancer and intracranial metastatic disease: a systematic review and meta-analysis. Neuro-Oncol Adv. 2020;2(1):1-17. doi:10.1093/noajnl/vdaa136.
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. Yan M, Ouyang Q, Sun T, et al. Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single-arm, two-cohort, phase 2 trial. Lancet. 2022;23(3):353-361. doi:10.1016/S1470-2045(21)00716-6.
5. Lin N, Kumthekar P, Sahebjam S, et al. Pertuzumab plus high-dose trastuzumab for HER2-positive breast cancer with brain metastases: PATRICIA final efficacy data. NPJ Breast Cancer. 2023;9(1):94. doi:10.1038/s41523-023-00587-2.
6. Montemurro F, Decalogue S, Barrios CH, et al. Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial. Ann Oncol. 2020;31(10):1350-1358. doi:10.1016/j.annonc.2020.06.020.
7. Hurvitz SA, Modi S, Li W, et al. A pooled analysis of trastuzumab deruxtecan in patients with HER2 positive metastatic breast cancer with brain metastases (BMs) from DESTINY-Breast01, -02, and -03. Presented at: 2023 ESMO Congress. October 20-24, 2023. Madrid, Spain. Abstract 3770.
8. Harbeck N, Ciruelos E, Jerusalem G, et al. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nat Med. 2024;30(12):3717-3727. doi:10.1038/s41591-024-03261-7.