Episode Notes

It has been our policy from the start not to shy away from the most difficult subjects.

This season is no different. Brain metastases are unfortunately an all too common and devastating complication of HER2 positive breast cancer. Local radiation therapy has long been the mainstay of treatment, but recent years have seen growing interest in systemic treatments as well. We would like to end this season on a positive note. Our guest Dr. Nancy Lin will review the latest advances in the systemic treatment of CNS metastases.

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.

“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.”

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). 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. 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 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.

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. 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.

Subjects and Terms Included in This Episode

Receptor tyrosine kinases (RTKs) regulate important biological processes, including cell proliferation, differentiation, metabolism, and survival. In other words, they cause cells to grow and divide.
Activation of RTK just like any receptor begins with the binding of growth factors and hormones also known as ligands. It is followed by cross-linking with adjacent RTKs and finally the initiation of downstream signaling pathways
The ERBB family of RTKs consists of four members, EGFR (epidermal growth factor receptor, also known as ERBB1/HER1), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). These proteins are made up of extracellular ligand-binding domain, a transmembrane domain, and intracellular tyrosine kinase domains and are found on the surface of some normal cells as well as cancer cells. Although ERBB receptors are critical regulators for normal cellular processes, it has become evident that their dysregulation, as a consequence of gene amplification, protein overexpression, or activating mutations, leads to the development of cancers.
Of the ERBB family members, HER2 and EGFR are frequently overexpressed in breast cancer. Two main classes of anticancer agents affect HER2 and EGFR. They are monoclonal antibodies like Herceptin which target the ligand binding domain, and small molecule tyrosine kinase inhibitors like Lapatinib and Tukatinib that target intracellular TK domain. Contrary to other ERBB family members, HER2 does not directly bind to any known ligands. Instead, activation of HER2-mediated signaling pathways occurs by cross-linking with adjacent ligand-activated EGFR or ERBB3. By blocking the EGFR and HER2, the growth of cancer cells can be curbed significantly.
The epidermal growth factor receptor (EGFR) is often considered the “prototypical” receptor tyrosine kinase (RTK) and has been intensively studied. It is one of a family of four RTKs in humans, the others being ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. EGFR and its relatives are known oncogenic drivers in breast cancer
Human epidermal growth factor receptor-2 (HER2/neu, c-erbB2), one of a family of four membrane tyrosine kinases, was found to be amplified in a human breast cancer cell line twenty five years ago and this amplification was shown to be important in the pathogenesis and progression of human breast cancer two years later . Since that time, HER2 amplification and resultant HER2 protein overexpression have been linked to important tumor cell proliferation and survival pathways; several drugs have been developed to target the pathway; and, the detection of HER2 has become a routine prognostic and predictive factor in breast cancer.
The HER2 pathway is a complex biological network comprised of three layers, an input layer of membrane receptors and their ligands to trigger the signal coming from outside the cell, a core system processing layer of protein kinases transmitting the signal to the nucleus, and an output layer of transcription factors regulating genes that affect various cellular functions (8) (Fig. 1). In turn, the genes and gene products regulating the activity of the pathway have been and are being defined. The input layer is comprised of 4 membrane receptors/tyrosine kinases (TKs) (HER1–4) and their many ligands (at least 11) In breast cancer, HER2 is the dominant TK receptor, being amplified in 20% of cases
89Zr-trastuzumab is composed of the native trastuzumab, an FDA-approved HER2-targeting monoclonal antibody, conjugated with desferrioxamine and labeled with the positron-emitting metalloradionuclide 89Zr. 89Zr has a half-life of 78 hours, long enough to allow favorable biodistribution of radiolabeled intact antibodies. 89Zr-trastuzumab is a potential agent to use PET/CT imaging

Novel Therapies Mentioned in the Episode

Tucatinib, sold under the brand name Tukysa, is a small molecule inhibitor of HER2 for the treatment of HER2-positive breast cancer. It was developed by Array BioPharma and licensed to Cascadian Therapeutics (formerly Oncothyreon, subsequently part of Seattle Genetics)
Tucatinib is a kinase inhibitor indicated in combination with trastuzumab and capecitabine for the treatment of adults with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.
In the European Union, it is indicated in combination with trastuzumab and capecitabine for the treatment of adults with HER2‑positive locally advanced or metastatic breast cancer who have received at least two prior anti‑HER2 treatment regimens.

Clinical Trials Mentioned in this Episode

Phase 2 PATRICIA study (NCT02536339)
Phase 3 DESTINY-Breast03 study (NCT03529110)

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