Dr. Nancy Lin: Are CNS Mets Becoming More Treatable? What’s New with STOP-HER2?

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.”

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.

Episode Notes

Subjects and Terms Included in This Episode

• Receptor Tyrosine Kinases (RTKs)

  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

• ERBB Family of RTKs

  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.

• EGFR

  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

• HER2

  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.

• HER2 Pathway

  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

• 89zirconium-trastuzumab (89Zr-trastuzumab)

  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

• Tukatinib (Tukisa)

  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

• Phase 3 DESTINY-Breast03 study

• Phase 2 HER2CLIMB study

• Phase 3 HER2CLIMB-02 study

• Phase 2 Non-randomized Study to Assess the Safety and Efficacy of the Combination of Tucatinib and Trastuzumab and Capecitabine for Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer

• Phase 2 Screening MRI of the brain in patients with metastatic breast cancer managed with first through fourth line chemotherapy or inflammatory breast cancer managed with definitive intent: A prospective study

• Phase 2 A Single Arm, Open Label Phase 2 Study of Tucatinib in Combination with Trastuzumab Deruxtecan in Subjects with Previously Treated Unresectable Locally-Advanced or Metastatic HER2+ Breast Cancer

• Phase 3 THE COMPASSHER2 TRIALS (COMPREHENSIVE USE OF PATHOLOGIC RESPONSE ASSESSMENT TO OPTIMIZE THERAPY IN HER2-POSITIVE BREAST CANCER): COMPASSHER2 RESIDUAL DISEASE (RD), A DOUBLE-BLINDED, PHASE III RANDOMIZED TRIAL OF T-DM1 AND PLACEBO COMPARED WITH T-DM1 AND TUCATINIB

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Meet the Guest of this Episode

Nancy U. Lin, MD

• Associate Chief, Division of Breast Oncology, Susan F. Smith Center for Women's Cancers

• Director, Metastatic Breast Cancer Program

• Director, Program for Patients with Breast Cancer Brain Metastases

• Senior Physician

• Associate Professor of Medicine, Harvard Medical School

Dr. Lin is a medical oncologist specializing in the care of patients with all stages of breast cancer. Her research focuses upon improving the outcomes of people living with metastatic breast cancer, including a particular focus on the challenge of breast cancer brain metastases. She has led multiple clinical trials which have led to new treatment options for patients with breast cancer that has metastasized to the brain.Dr. Lin received her MD from Harvard Medical School in 1999. She completed her residency in internal medicine at Brigham and Women's Hospital and went on to complete fellowships in medical oncology and hematology at Dana-Farber. In 2005, she joined the staff of Brigham and Women's and Dana-Farber, where she is a medical oncologist and clinical investigator in the Breast Oncology Center.

Twitter:  @nlinmd