Research Moves Full Steam Ahead With Brain Metastases, Leptomeningeal Disease in Breast Cancer

Michelle E. Melisko, MD

Targeted agents and chemotherapy regimens are at the crux of systemic research efforts focused on improving outcomes for patients with breast cancer who have brain metastases and/or leptomeningeal disease, according to Michelle E. Melisko, MD, in a virtual presentation during the 38th Annual Miami Breast Cancer Conference.¹

Most importantly, the diagnoses should not serve as the end of the road for patients, according to Melisko, an associate clinical professor in the Department of Medicine (Hematology/Oncology), of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, who encouraged practitioners to try one of the novel approaches backed by impressive data or enroll patients onto a clinical trial.

Local Therapy

Over the past few decades, there has been an increased use of stereotactic radiosurgery as local therapy for patients with brain metastases. However, there continues to be a question of how many brain metastases can be treated with stereotactic radiosurgery alone before patients require the addition of whole brain radiation (WBRT), Melisko explained.

Data published in the Lancet Oncology showed that overall survival (OS) outcomes did not differ between patients who had 2 to 4 brain metastases vs those who had 5 to 10 brain metastases, which was 10.8 months in both groups.²

Yet, some patients do need to undergo whole brain radiation, which Melisko added is a very challenging treatment due to the cognitive decline patients experience from the aggressive treatment approach.

“As we are experiencing improvements in OS, even in those with [brain metastases], patients are living longer to suffer the consequence of whole brain radiation [with] the cognitive dysfunction,” Melisko said.

Studies have evaluated ways to improve cognitive function and decline, as well as survival outcomes, in these populations. In the phase 33 RTOG 0614 trial (NCT00566852), 508 patients with brain metastases were randomized to receive WBRT at 37.5 Gy in 15 fractions with oral memantine at 20 mg daily or placebo.

Out of the 149 analyzable patients at 24 weeks, which translated to only at 35% statistical power, results showed that the memantine arm had a longer time to cognitive decline vs placebo (HR, 0.78; 95% CI, 0.62-0.99; P = .01).³ Additionally, the probability of cognitive function failure at 24 weeks was 53.8% with memantine vs 64.9% with placebo. No differences in PFS or OS were reported.

“Typically, I do offer this [approach] to my patients to take for 6 months if they have the unfortunate need for WBRT,” said Melisko.

Systemic Approaches

Chemotherapy

Chemotherapy regimens are standard for patients with brain metastases and breast cancer, especially for those who do not have HER2 expression. These approaches include but are not limited to: cisplatin/etoposide with or without bevacizumab (Avastin), capecitabine/temozolomide (Temodar), liposomal irinotecan, and irinotecan/temozolomide.

Combinations with chemotherapy and HER2 TKIs have also been utilized, such as the triplet regimen comprised of vinorelbine, trastuzumab (Herceptin), and everolimus (Afinitor) or capecitabine, lapatinib (Tykerb), and everolimus. Ado-trastuzumab emtansine (T-DM1; Kadcyla) has also demonstrated efficacy, with a 30% objective response rate (ORR) and a median OS that had not been reached in this patient subset.⁴

“My practical advice...is that even if a patient has progressed on some of the more effective agents in the HER2-positive setting, we need to try something for these patients,” said Melisko.

Breast Cancer Subtypes: HER2+

Positive data have read out with TKIs in HER2-positive breast cancer with brain metastases, specifically with lapatinib, neratinib (Nerlynx), tucatinib (Tukysa), fam-trastuzumab deruxtecan-nxki (Enhertu), and T-DM1. Moreover, lapatinib, neratinib, and tucatinib are listed in the National Comprehensive Cancer Network guidelines for the treatment of patients with HER2-positive breast cancer and brain metastases.

Neratinib, a potent irreversible-binding inhibitor of ERBB, is indicated for use in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting. The agent is also approved for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab–based therapy.

In the multicohort, phase 2 TBCRC 022 trial (NCT01494662), neratinib was tested alone at 240 mg/daily in those with HER2-positive breast cancer with progressive brain metastases (n = 40); at 240 mg/day until surgery followed by the agent at 240 mg/daily in patients who are candidates for craniotomy (n = 5); at 240 mg/daily plus capecitabine at 750 mg/m² on days 1 to 14 of 3-week cycles (n = 37, no prior lapatinib; n = 11, prior lapatinib); and at 150 mg/daily plus T-DM1 at 3.6 mg/kg every 3 weeks (n = 20, previously untreated disease and no prior T-DM1; n = 20, progressive central nervous system [CNS] disease and no prior T-DM1; n = 23, progressive HER2-positive CNS disease and prior T-DM1).

Data showed that the CNS ORR was 8% (95% CI, 2%-22%) in cohort 1, which did not meet the prespecified threshold to prompt further investigation.⁵ However, in a neratinib/capecitabine cohort, the CNS ORR was 49% (95% CI, 32%-66%) when measured by best CNS volumetric response. When measured by sum of longest diameters, the CNS ORR was 24% (95% CI, 12%-41%).⁶

Additional data looked at the impact of neratinib on the development of CNS metastases in the NALA (NCT01808573), NEfERT-T (NCT00915018), and TBCRC 022 trials. The progression of CNS was 22.8% with neratinib/capecitabine vs 29.2% with lapatinib/capecitabine (P = .043) in NALA. In NEFERT-T, these rates were 10.1% with neratinib/paclitaxel and 20.2% with trastuzumab/paclitaxel (P = .002).⁷

Tucatinib became available in April 2020, when the FDA approved the use of the TKI in combination with trastuzumab and capecitabine in patents with unresectable, locally advanced, or metastatic HER2-positive breast cancer, including those with brain metastases. The approval was based on early data from the phase 2 HER2CLIMB trial (NCT02614794). Updated findings showed that the triplet resulted in a 52% reduction in risk of progression or death per blinded independent central review vs trastuzumab/capecitabine and placebo in patients with brain metastases (HR, 0.48; 95% CI, 0.34-0.69; P <.00001).⁸

Moreover, trastuzumab deruxtecan was added to the HER2-positive breast cancer treatment arsenal in December 2019 for the treatment of adult patients with unresectable or metastatic disease who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.

Results of a subgroup analysis of the DESTINY-Breast01 trial (NCT03248492), which were presented at the 2020 ASCO Virtual Scientific Program, showed that in 48 of 184 patients with HER2-positive breast cancer who had disease progression as of the data cutoff date, metastases were most commonly reported in the liver, lung, and lymph nodes.⁹ Eight percent (n = 4) of patients had progression involvement in the brain upon disease progression.

In patients with recurrence or disease progression of isolated brain metastasis, Melisko advised that for patients with stable extracranial disease, the same systemic therapy should be continued if the patient is tolerating it well and if the CNS progression is limited and treated with stereotactic radiosurgery.

“However, consider switching to a different therapy with better CNS penetration if there are multiple episodes of CNS progression while on current therapy,” Melisko added.

Breast Cancer Subtypes: ER+

Abemaciclib (Verzenio) has been an active agent in the arena of brain metastases for patients with estrogen receptor–positive breast cancer. The CDK4/6 inhibitor was tested in a phase 2 trial of this patient population at a 200 mg twice-daily dose as a single agent or with endocrine therapy. In a subset of patients who had HER2-positive disease, abemaciclib was combined with a 150-mg, twice-daily dose of trastuzumab.

Results showed that the brain metastases concentration of total active abemaciclib analytes were 96- and 19-fold above in vitro IC50 for CDK4 and CDK6, respectively. The study, however, did not meet its primary end point of achieving an intracranial ORR (iORR) of 6% or greater in the overall population.¹⁰ In the HR-positive, HER2-negative cohort (n = 58), the intracranial ORR was 5.2% and the median OS was 12.5 months; in the HER2-positive cohort (n = 27), the iORR was 0%, and the median OS was 10.1 months.

“Nonetheless, even though this did not meet its primary end point, if you did happen to have a patient who had not received abemaciclib and they don’t have any other options or clinical trials, this might be worth a try,” Melisko noted.

Leptomeningeal Disease

Leptomeningeal disease is the diagnosis that “you never want to make for a patient with breast cancer,” Melisko explained, as it carries a very poor prognosis.

However, research efforts are ongoing with a goal to improve outcomes for this population. In a phase 1/2 dose-escalation trial with a 3+3 design, investigators assessed the safety of intrathecal trastuzumab in patients with HER2-positive disease who have leptomeningeal metastases. Findings showed no dose-limiting toxicities with the recommended phase 2 dose of the treatment at 80 mg intrathecally.¹¹

In the phase 2 portion, which was a Simon 2-stage design and comprised Ommaya with intrathecal trastuzumab twice-weekly for 4 weeks, followed by weekly for 4 weeks, and then maintenance therapy 1 to 2 times weekly.

In the HER2-positive breast cancer subset (n = 23), the median PFS was 2.8 months, but the median OS was 12.0 months. When compared with the historical control of 4.7 months, Melisko said the results were impressive in this population.

ANGIO-1005 (GRN-1005), which is paclitaxel conjugated to angiopep-2 and is thought to cross the blood–brain barrier, was being studied in a trial (NCT02048059) of patients with breast cancer who have brain metastases with or without leptomeningeal disease. In the cohort of patients with leptomeningeal carcinomatosis (n = 28) who received ANG1005 intravenously at 600 mg/m2 every 3 weeks, the median OS was 7.95 months (95% CI, 5.30-9.43).¹²

The data have led to the ongoing, phase 3 ANGLeD study (NCT03612181), which is not yet recruiting, of ANG1005 in patients with HER2-negative breast cancer who have newly diagnosed leptomeningeal carcinomatosis and previously treated brain metastases.

“Despite the literature suggesting otherwise, some patients do experience more prolonged survival, so please try something,” concluded Melisko. “Look for a trial. Consider standard chemotherapy for patients, and don’t send them to hospice if they have good performance status.”

References

1. Melisko ME. Management of brain metastasis and leptomeningeal disease. Presented at: 38th Annual Miami Breast Cancer Conference; March 4-7, 2020; virtual.
2. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15(4):387-395. doi:10.1016/S1470-2045(14)70061-0
3. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15(10):1429-1437. doi: 10.1093/neuonc/not114
4. Bartsch R, Berghoff AS, Vogl U, et al. Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin Exp Metastasis. 2015;32(7):727-737. doi:10.1007/s10585-015-9740-3
5. Freedman RA, Gelman RS, Wefel JS, et al. Translational Breast Cancer Research Consortium (TBCRC) 022: a phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2016;34(9):945-952. doi:10.1200/JCO.2015.63.0343
6. Freedman RA, Gelman RS, Melisko ME, et al. TBCRC 022: phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM). J Clin Oncol. 2017;35(suppl 15):1005. doi:10.1200/JCO.2017.35.15_suppl.1005
7. Awada A, Brufsky A, Saura C, et al. Impact of neratinib on development and progression of central nervous system metastases in patients with HER2-positive metastatic breast cancer: Findings from the NALA, NEfERT-T, and TBCRC 022 trials. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract P2-20-01.
8. Wardley A, Mueller V, Paplomata E, et al. Impact of tucatinib on health-related quality of life in patients with HER2+ metastatic breast cancer with stable and active brain metastases. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD13-04.
9. Modi S, Andre F, Krop IE, et al. Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis. J Clin Oncol. 2020;38(suppl 15):1036. doi:10.1200/JCO.2020.38.15_suppl.1036
10. Tolaney SM, Sahebjam S, Le Rhun E, et al. A phase II study of abemaciclib in patients with brain metastases secondary to hormone receptor–positive breast cancer. Clin Canc Res. 2020;26(20):5310-5319. doi: 10.1158/1078-0432.CCR-20-1764
11. Kumthekar P, Gradishar W, Lin N, et al. Intrathecal (IT) trastuzumab (T) for the treatment of leptomeningeal disease (LM) in patients (pts) with human epidermal receptor-2 positive (HER2+) cancer: a multicenter phase 1/2 study. Neuro Oncol. 2018;20(suppl 6):vi58. doi:10.1093/neuonc/noy148.234
12. Kumthekar P, Tang S-C, Brenner AJ, et al. ANG1005, a brain-penetrating peptide–drug conjugate, shows activity in patients with breast cancer with leptomeningeal carcinomatosis and recurrent brain metastases. Clin Cancer Res. 2020;26(12):2789-2799. doi:10.1158/1078-0432.CCR-19-3258