Data presented today from an ongoing phase I clinical trial evaluating SGN-LIV1A, an antibody-drug conjugate or ADC being developed by Seattle Genetics for the treatment of patients with LIV-1-expressing metastatic breast cancer, at the 38th San Antonio Breast Cancer Symposium (SABCS) taking place in San Antonio, Texas, December 8-12, 2015, shows that the investigational drug demonstrates antitumor activity and has a well-tolerated safety profile in patients with triple negative metastatic breast cancer.
Although there are several therapies available or in development for the treatment of breast cancer, there remains a significant unmet need making it important to identify improved treatment options. Breast cancer is a disease where malignant cells form in the tissue of the breast. Metastatic breast cancer occurs when the cancer has spread to other parts of the body. Excluding non-melanoma skin cancer, breast cancer is the most common cancer and the second leading cause of cancer death in women.
While breast cancer may be referred to as just one disease, there are actually many different types of breast cancer. Understanding these differences helps guide physicians in treatment their patients.
Breast cancer is an intrinsically heterogeneous disease. A characteristic feature of triple negative breast cancer is that it lacks expression of estrogen (ER1-), progesterone (PR-) and human epidermal growth factor receptor-2/neu (HER2/neu) receptors.
Triple negative breast cancer generally to occur more often in younger women and in women who are African-American or Hispanic/Latina. These cancers also tend to grow and spread more quickly than most other types of breast cancer. The aggressive behavior, poor outcome, and absence of targeted therapies makes the management of triple negative a challenge.
About 15 – 20% of all breast cancers are triple negative breast cancer. 
Breast cancer incidence
According to the American Cancer Society more than 234,000 new cases of breast cancer will be diagnosed in the United States in 2015, and more than 40,000 people will die from the disease. 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.
Novel treatment options
SGN-LIV1A consists of a humanized anti-LIV-1 monoclonal antibody (mAb) and the potent microtubule-disrupting agent monomethyl auristatin E (MMAE), utilizing a protease-cleavable linker. When bound to surface-expressed LIV-1 cancer cells, the investigational drug is internalized and traffics to the lysozome. Allowing the selective delivery cytotoxic agents to tumor cells, this approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.
“While there have been important advances in the treatment of breast cancer, there remains a significant unmet medical need for improved therapies, particularly in the metastatic setting where there are no curative therapies and fewer than 25% of patients survive five years,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.
“The data presented at SABCS on SGN-LIV1A demonstrate early anti-tumor activity in heavily pretreated patients, notably among patients with triple negative disease, at generally well-tolerated doses. We are currently enrolling patients with triple negative breast cancer, a subtype for which there are no approved targeted treatments available, to further assess the activity of SGN-LIV1A in a disease-specific cohort,” Drachman continued.
The zinc transporter LIV-1 (SLC39A6) was previously known to be expressed by estrogen receptor-positive breast cancers. Researchers have shown that LIV-1 expression is maintained after hormonal therapy in primary and metastatic sites and is also upregulated in triple-negative breast cancers. 
In the ongoing Phase I trial, LIV-1 is present in 96% of 237 metastatic breast cancer samples screened to date. Moderate-to-high expression was observed in 88% of hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancers and in 79% of triple negative breast cancers. The ongoing phase I, open-label, dose-escalation trial is evaluating the safety, tolerability, antitumor activity, pharmacokinetics and maximum tolerated dose of SGN-LIV1A monotherapy administered every three weeks in patients with LIV1-expressing MBC.
Data were reported from 27 patients with LIV-1-expressing metastatic breast cancer, of whom 18 were HR+/HER2- and nine were TNBC. The median age of patients was 57 years and the median number of prior systemic metastatic cytotoxic therapies was four.
During the SABC meeting, Andres Forero-Torres, MD, from the University of Alabama at Birmingham, presented key findings from the trial. Of the 25 efficacy-evaluable patients, the objective response rate (ORR) was 12%, the disease control rate was 64% and the clinical benefit rate (CBR) was 24%. Disease control rate is defined as patients achieving a complete response (CR), partial response (PR) or stable disease (SD). CBR is defined as patients achieving CR, PR or SD lasting at least six months.
Among the eight patients with triple negative breast cancer, the ORR was 38% and CBR was 63%. At the time of data analysis, early estimates of median progression-free survival (PFS) for all patients was 11 weeks, with an estimated median PFS in triple negative breast cancer patients of 18.4 weeks and an estimated median PFS in HR+/HER2- patients of 11.3 weeks.
The most common of the adverse events (AEs) of any grade occurring in 15% or more of patients included nausea (52%), fatigue (48%), alopecia and peripheral neuropathy (44% each) and decreased appetite and vomiting (33% each). There was a low incidence of myelosuppression, with grade 3 or 4 adverse events of neutropenia in 19% of patients and anemia in 11% of patients. Grade 3 peripheral neuropathy occurred in 11% of patients.
The maximum tolerated dose (MTD) was not reached among doses ranging from 0.5 to 2.8 milligrams per kilogram (mg/kg). Dose escalation is complete. Enrollment in a triple negative breast cancer expansion cohort is ongoing.