Data from an ongoing phase I clinical trial evaluating SGN-LIV1A for patients with metastatic breast cancer (MBC), with particular focus on metastatic triple-negative breast cancer (mTNBC), shows promising results. The data was at the 39th San Antonio Breast Cancer Symposium (SABCS) held in San Antonio, Texas, December 6-10, 2016.

sabcsThe LIV-1 protein is expressed by most metastatic breast cancers. The protein has also been detected in a number of other cancers, including melanoma, prostate, ovarian, and cervical cancer.

In developing the investigational compound, researchers created an antibody-drug conjugate or ADC which consists of a LIV-1-targeted monoclonal antibody linked to the potent microtubule-disrupting cell-killing agent monomethyl auristatin E or MMAE via a protease-cleavable linker. The drug utilizing the same technology as brentuximab vedotin, a proprietary ADC technology developed by Seattle Genetics. LIV-1 is a protein expressed by most metastatic breast cancers.

The investigational drug is designed to bind to LIV-1 on cancer cells and release the cell-killing agent into target cells upon internalization. SGN-LIV1A may also cause antitumor activity through other mechanisms, including activation of an immune response.

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Aggressive disease
Breast cancer is a cancer which forms in breast tissue. Metastatic breast cancer occurs when the cancer has spread to other parts of the body. While most new diagnoses of breast cancer are made at an early stage, approximately one-third of these patients will eventually develop recurrent or metastatic disease.

Breast cancers are commonly categorized by the expression (or lack thereof) of three key proteins, including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).  These proteins serve are targets for therapeutics.

Triple-negative breast cancer (TNBC) lacks all three proteins and HR+/HER2- breast cancer expresses one or both hormone receptors (HR) but not HER2. This means that the growth of the cancer is not supported by the hormones estrogen and progesterone, nor by the presence of too many HER2 receptors.  As a result, triple-negative breast cancer does not respond to hormonal therapy, such as tamoxifen or aromatase inhibitors, or therapies that target HER2 receptors, such as trastuzumab (Herceptin®; Genentech/Roche).

Triple-negative breast cancer is generally more aggressive than other types of breast cancer.  This diseases tends also to be a higher grade (often grade 3) which means that fewer cancer cells resemble normal, healthy breast cells in their appearance and growth patterns. Finally,  TNBC is often “basal-like.” This means that the cells resemble the basal cells that line the breast ducts. Researchers believe that most triple-negative breast cancers are of the basal-like cell type.

Unmet medical needs
According to the World Health Organization, breast cancer is the second most common cancer in the world and the most frequent cancer among women. The disease also ranks as the fifth cause of death from cancer overall. New treatment approaches are needed to improve outcomes for breast cancer patients, particularly for those with TNBC where there are currently no available targeted therapies.

More than one out of every 10 breast cancers are found to be triple-negative. Hence for patients, doctors and researchers, there is intense interest in finding new medications that can treat this kind of breast cancer. Early studies are trying to find out whether certain medications can interfere with the processes that cause triple-negative breast can

Poor prognosis
“Breast cancer is the most common cancer among women, with an estimated 1.67 million new cases per year worldwide. About 15 to 20 percent of breast cancers are triple negative, which means they lack expression of three breast cancer-associated proteins that serve as key therapeutic targets. Triple-negative breast cancers are more aggressive and generally have poor prognoses,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

Promising early results
“The data presented at SABCS on SGN-LIV1A demonstrate promising early antitumor activity with a 37 percent partial response rate in patients with triple negative metastatic breast cancer, for which there are no available targeted treatments. We are enrolling additional patients with triple negative metastatic breast cancer in our phase 1 study to optimize the dose and inform the next steps for development of SGN-LIV1A in this population with high unmet need,” Drachman further added.

Trial results
Data were reported from 53 patients with LIV-1-expressing MBC who were treated with SGN-LIV1A monotherapy administered every three weeks. Of these patients, 35 had TN MBC. The median age of all patients was 56 years. Patients had received a median of four prior systemic therapies for metastatic disease. Key findings presented by Dr. Andres Forero-Torres, University of Alabama at Birmingham included:

  • Thirty of 47 efficacy-evaluable patients had TN MBC. Among these patients, 11 (37%) achieved a partial response (PR). The disease control rate (DCR), defined as patients achieving a complete response (CR), PR or stable disease (SD), was 67% and the clinical benefit rate (CBR), defined as patients achieving CR or PR of any duration plus patients achieving SD lasting at least 24 weeks, was 47%.
  • At the time of this interim data analysis, the estimated median progression-free survival for metastatic triple-negative breast cancer patients was 12 weeks with seven patients remaining on treatment.
  • The maximum tolerated dose was not reached among doses ranging from 0.5 to 2.8 milligrams per kilogram (mg/kg). Dose escalation is complete and a disease-specific expansion cohort of metastatic triple-negative breast cancer patients is currently enrolling.
  • For all patients in the study, the most common adverse events of any grade occurring in 20 percent or more of patients included fatigue (57%), nausea (53%), alopecia (42%), decreased appetite (34%) and constipation (32%).
  • The incidence of grade 3/4 neutropenia at the 2.5 mg/kg dose was 50%. Two patients (7%) experienced febrile neutropenia, and there was one treatment-related death due to sepsis. Based on these safety data, a separate expansion cohort at 2.0 mg/kg is currently being evaluated.
  • Peripheral neuropathy events occurred in 38% of patients and were generally low grade and manageable.
  • Enrollment continues for patients with metastatic triple-negative breast cancer in the SGN-LIV1A monotherapy part of the study. In addition, enrollment is ongoing for patients with HER2+ breast cancer to evaluate SGN-LIV1A in combination with trastuzumab.

Interim data from the ongoing phase I study of SGN-LIV1A in patients with MBC were previously presented at the 2015 SABCS. The following updated results from this trial describe safety data for all patients and antitumor activity data for patients with metastatic triple-negative breast cancer.

SGN-LIV1A is one of four clinical-stage empowered antibody therapies under development by Seattle Genetics for solid tumors.

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