HER-2 REVIEW/ FROM MEDSCAPE Mechanisms and Actions of HER2-Targeting Agents in Breast Cancer Dear Dr. Mutombo Kankonde, Below are some key learning points to help reinforce the educational impact of this activity. Recommended Activities Clinical Application of HER2-Directed Therapies in Breast Cancer Oncology Exchange: Emerging Agents in HER2-positive Breast Cancer Case Challenges: First-Line Treatment for Newly Diagnosed HER2-Positive Metastatic Breast Cancer Emerging HER2-Targeted Options for Advanced Breast Cancer Targeting HER2: Developmental Milestones More than 20 years have passed since the discovery that patients with breast cancer who overexpressed the HER2 protein or had amplification of this gene had a poor prognosis, and since the clinical development of the anti-HER2 monoclonal antibody trastuzumab, which has revolutionized the treatment of this disease, began. In 2005, data from 2 large randomized trials (NSABP B-31 and  NCCTG N9831) that evaluated a conventional adjuvant cytotoxic regimen, plus or  minus trastuzumab,  were reported. The success with trastuzumab led to further research and development  of pertuzumab,  a novel monoclonal antibody that was recently approved for first-line  treatment of  metastatic breast cancer in conjunction with trastuzumab and  docetaxel based on  the results of the CLEOPATRA trial. Trastuzumab and Pertuzumab: Mechanisms of Action Trastuzumab inhibits ligand-independent HER2 signaling, activates  antibody-dependent  cellular cytotoxicity, and prevents HER2 extracellular domain shedding. Pertuzumab inhibits ligand-dependent HER2 dimerization and signaling,  while also  activating antibody-dependent cellular cytotoxicity. Ado-Trastuzumab-Emtansine (T-DM1): Antibody-Drug Conjugate T-DM1 consists of the trastuzumab antibody as a backbone, a linker,  and a  cytotoxic, a maytansinoid compound that is 20 to 100 times more  potent than  the commonly used vinca alkaloids. Upon binding to HER2, T-DM1 is internalized by the cancer cell,  disrupting  the linker and releasing the cytotoxic agent, which eventually kills  the cancer cell. Encouraging results seen in phase 1 and 2 trials led to the pivotal  EMILIA  phase 3 trial that compared T-DM1 with the combination of  lapatinib plus  capecitabine. T-DM1 was recently approved by the US Food  and Drug  Administration (FDA) for treatment of patients with HER2-positive  metastatic  breast cancer who have received prior treatment with trastuzumab  and taxane  chemotherapy. Phase 3 EMILIA Trial One of the most important outcomes of this study is the duration  of response  to T-DM1, which is double that seen with capecitabine and lapatinib. Substantial improvement was seen in progression-free survival for  all patients  receiving T-DM1, regardless of their geographic location, amount  of prior  therapy received, presence of visceral disease, or estrogen  receptor/progesterone  receptor status. Patients in the T-DM1 arm had a median overall survival exceeding  30 months.  Median overall survival for those in the capecitabine/lapatinib arm  was 25 months,  which compared favorably with the 16 months seen in the original trial of  capecitabine/lapatinib. With regard to nonhematologic toxicities and most other adverse  events, results  strongly favored T-DM1. Investigational T-DM1/Pertuzumab Combination Preliminary data from a phase 1b/2 study showed that subjects  tolerated full doses  of both of these antibodies. Despite the fact that patients had had multiple prior lines of therapy  (up to 14 prior  regimens), more than one-third achieved disease regression or a  durable response  with the dual antibody combination. These data led to a first-line phase 3 trial (BO22589/TDM4788g,  MARIANNE)  in which patients with metastatic breast cancer are randomly assigned  to receive  either a control arm of trastuzumab plus a taxane (either docetaxel or  paclitaxel  at the investigator's choice); the dual antibodies T-DM1 plus pertuzumab;  or only  the targeted therapy, T-DM1. The trial results should be reported next  year and  are expected to help clarify how best to use these antibodies. Other HER2-Targeting Agents Lapatinib is an FDA-approved, orally available dual tyrosine kinase  inhibitor  of HER2 and epidermal growth factor receptor. A study of the  combination  of lapatinib and trastuzumab in patients with metastatic breast cancer  yielded  promising data, and the FDA-approved regimen of lapatinib plus  capecitabine  is an all-oral option for patients who have had disease  progression on  trastuzumab. For patients with estrogen receptor-positive and  HER2+ breast  cancer, a combination of letrozole and lapatinib is another all-oral,  non-cytotoxic  option. Neratinib is an investigational oral, multi-targeted, irreversible  tyrosine kinase  inhibitor. As the clinical development of neratinib moves forward,  several  strategies are being proposed to limit the diarrhea and gastrointestinal  toxicities  associated with this potentially promising agent. Afatinib, another investigational tyrosine kinase inhibitor, is being  studied in a  randomized phase 3 trial that is currently recruiting participants  (ClinicalTrials.gov  Identifier: NCT01125566). Future Developments A number of new treatment combinations and strategies currently  in clinical trials  are expected to result in continued improvements in the treatment  of patients  with HER2-positive breast cancer. Building on the results seen in the metastatic setting, these drugs  may move into  the adjuvant and neoadjuvant settings. Kind regards, Howard A. Burris III, MD Chief Medical Officer Executive Director, Drug Development Program Sarah Cannon Research Institute Nashville, Tennessee Emir Hadzic, PhD Scientific Director Medscape, LLC

Supported by an independent educational grant from Genentech.