Sunday, May 5, 2013

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 
  • 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,
  •  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 
  • (
  •  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.
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