Brain Metastases Are Now More Treatable in HER2+ Metastatic Breast Cancer

Mark D. Pegram, MD

The treatment of patients with HER2-positive metastatic breast cancer can now be tailored based on the presence of active central nervous system (CNS) disease, due to substantial advances made in the past few years into small molecule inhibitors and macromolecule biologics, according to a presentation by Mark Pegram, MD, at the 39th Annual Miami Breast Cancer Conference®.¹

“Macromolecule biologics, such as monoclonal antibodies or antibody-drug conjugates [ADCs], can penetrate the blood–brain barrier, resulting in objective responses,” Pegram, an associate dean for Clinical Research Quality, Stanford University School of Medicine, said during his lecture. “Tucatinib [Tukysa]-based therapy improves overall survival [OS] for patients with HER2-positive breast cancer with brain metastases, while maintaining overall health-related quality of life, with some potential benefit also seen in leptomeningeal metastasis.”

There are several risk factors associated with brain metastasis, Pegram noted, including triple-negative histology, high histological grade, increased Ki-67, nodal involvement, number of metastatic sites, short time to distant relapse, a tumor size smaller than 2 cm, and young age.

Another risk factor, however, is HER2 gene amplification/overexpression. There is an approximate 4-time greater risk of CNS disease in HER2-positive disease, Pegram said, with brain metastasis appearing in approximately 50% of patients with HER2-positive metastatic disease. Within the HER2 subtype, the SystHERs study of 977 patients further identified an age of less than 50 years, recurrent metastatic breast cancer, and hormone receptor negative status as additional risk factors for CNS metastases.²

While local therapy is commonly employed to treat patients with brain metastases, this option is commonly associated with adverse events, Pegram noted. A reduction in the adverse events associated with local therapy was seen with stereotactic radiosurgery (SRS), which avoids the hippocampus, when compared with whole brain radiotherapy (WBRT), according to data from a phase 3 study of patients with 1 resected brain metastasis and a resection cavity less than 5 cm.³ In these findings, grade 3 or higher cognitive disturbances were seen in 3% of patients with SRS compared with 5% for WBRT, hearing impairment in 3% vs 9%, respectively, and grade 1/2 events were 16% and 23%, respectively.

“Brain metastases often occur quickly during the course of HER2-positive metastatic breast cancer, and negatively impacts quality of life and OS,” Pegram said. “Local therapy, while effective, does not prevent recurrence and can cause significant toxicities.”

Systemic Therapies for Brain Metastases

The blood-brain barrier has long been a key obstacle to developing effective systemic therapies to treat CNS disease; however, newer agents have shown signs of overcoming this challenge. Studies with 89zirconium-trastuzumab (89Zr-trastuzumab) have shown the ability of monoclonal antibodies to cross the blood-brain barrier. In these studies, a high-dose version of trastuzumab (Herceptin) was tested in combination with pertuzumab (Perjeta) for patients with HER2-positive metastatic breast cancer with progressive brain metastases, with promising results demonstrated in the phase 2 PATRICIA study (NCT02536339).⁴ Here, the CNS objective rate (ORR) was 11% (95% CI, 3%-25%) and the median duration of response was 4.6 months; the 4- and 6-month clinical benefit rates were 68% and 51%, respectively.

The HER2-targeted ADC ado-trastuzumab emtansine (T-DM1; Kadcyla) has also shown efficacy in patients with brain metastases and HER2-positive metastatic breast cancer.⁵ ORRs in this retrospective study were similar between those with brain metastases (35.1%) and for those without (38.3%), demonstrating the efficacy of ADCs in this space. Additionally, the disease control rates were 53.3% and 66.6%, respectively. The median OS was 14.0 months (95% CI, 12.2-15.8) in the patients with brain metastases compared with 32.0 months (95% CI, 24.4-39.6) in those without (P < .0001).

The ability of ADCs to cross the blood-brain barrier to elicit intracranial responses was further demonstrated with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in the phase 3 DESTINY-Breast03 study (NCT03529110), with intriguing efficacy noted in patients with brain metastases that was superior for T-DXd over T-DM1.⁶ In data from this pivotal study, the intracranial response rate was 63.9% with T-DXd compared with 33.3% for T-DM1. Moreover, T-DXd remained superior to T-DM1 across several efficacy end points in addition to response for patients with brain metastases.

In addition to biologics, the small molecule inhibitor tucatinib, in combination with trastuzumab and capecitabine, has also demonstrated efficacy for patients with brain metastases in the HER2CLIMB study (NCT02614794). In this study, the confirmed intracranial ORR with tucatinib was 47.3% compared with 20.0% with placebo, trastuzumab, and capecitabine.⁷ In updated results, this also translated to a marked improvement in progression-free survival and OS.⁸

Based on the HER2CLIMB results, the FDA approved tucatinib in April 2020 for use in combination with trastuzumab and capecitabine, for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who have received 1 or more prior anti–HER2-based regimens in the metastatic setting.⁹

This tucatinib regimen was also explored as a potential treatment for patients with HER2-positive breast cancer and leptomeningeal metastasis, in the phase 2 TBCRC049 study.¹⁰ In data from this study, 35% of patients remained alive at a median follow-up of 18 months. The median OS was 10 months (95% CI, 4.1-not reached) and the median time to CNS progression was 6.9 months (95% CI, 2.3-13.8).

“Following taxane, trastuzumab, and pertuzumab therapy, T-DXd is now the preferred regimen for those without CNS disease. For those with active CNS disease, clearly tucatinib, trastuzumab, and capecitabine is a strong consideration, because there's level 1 evidence of OS benefit with statistical confidence,” Pegram said. “For those with stable CNS disease, it is probably more of a toss-up.”

With the number of agents now available with proven efficacy in brain metastases, Pegram noted that screening guidelines should be updated to look for CNS involvement more frequently. “Screening guidelines recommend screening for CNS metastases only in symptomatic patients, but this may not adequately capture all patients with brain metastases,” he concluded.

References

1. Pegram M. Advances in the treatment of brain metastases and leptomeningeal disease in HER2+ breast cancer. Presented at: 39th Annual Miami Breast Cancer Conference®; March 3-6, 2022; Miami, FL.
2. Hurvitz SA, O'Shaughnessy JA, Ginny M, et al. Central nervous system metastasis in patients with HER2-positive metastatic breast cancer: patient characteristics, treatment, and survival from SystHERs. Clin Cancer Res. 2019;25(8):2433-2441. doi:10.1158/1078-0432.CCR-18-2366
3. Brown PD, Ballman KV, Cretan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18(8):1049-1060. doi:10.1016/S1470-2045(17)30441-2
4. Lin NU, Pegram M, Sahebjam S, et al. Pertuzumab plus high-dose trastuzumab in patients with progressive brain metastases and HER2-positive metastatic breast cancer: primary analysis of a phase II study. J Clin Oncol. 2021;39(24):2667-2675. doi:10.1200/JCO.20.02822
5. Fabi A, Alesini D, Valle E, et al. T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer. Breast. 2018;41:137-143. doi:10.1016/j.breast.2018.07.004
6. Hurvitz S, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS3-01. Accessed March 4, 2022. https://www.abstractsonline.com/pp8/#!/10462/presentation/649
7. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775
8. Curigliano G, Mueller V, Borges VF, et al. Updated results of tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB). J Clin Oncol. 2021;39(suppl 15);1043. doi:10.1200/JCO.2021.39.15_suppl.1043
9. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. News release. FDA. April 17, 2020. Accessed March 5, 2022. https://bit.ly/3vCYdr1
10. Murthy RK, O'Brien B, Berry DA, et al. Safety and efficacy of a tucatinib-trastuzumab-capecitabine regimen for treatment of leptomeningeal metastasis (LM) in HER2-positive breast cancer: results from TBCRC049, a phase 2 non-randomized study. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS3-01. Accessed March 4, 2022. https://www.abstractsonline.com/pp8/#!/10462/presentation/480