The U.S. Food and Drug Administration (FDA) has rejected sacituzumab govitecan also known as IMMU-132, a novel, investigational, antibody-drug conjugate or ADC consisting of SN-38, the active metabolite of irinotecan, conjugated to a humanized monoclonal antibody targeting trophoblastic antigen-2 (Trop2), which is expressed in approximately 80% to 90% of breast cancers.
Triple-negative breast cancer
The investigational drug is designed for the treatment of patients with triple-negative breast cancer (TNBC) who have failed at least 2 prior therapies for metastatic disease.
About 15% of all diagnosed breast cancers is triple-negative breast cancer and, according to the American Cancer Society, the an annual incidence of the disease in the United States alone is estimated to be about 40,000 patients, with 20,000 diagnosed with metastatic TNBC, in the United States alone.
Triple-negative breast cancer does not express estrogen, progesterone or the HER2 receptor. As a result, the disease is insensitive to most of the available targeted therapies for breast cancer treatment, including HER2-directed therapies like trastuzumab (Herceptin®; Genentech/Roche), and endocrine therapies such as tamoxifen or the aromatase inhibitors.
“We believe in sacituzumab govitecan’s potential to be a viable treatment option for these patients,” said Michael Pehl, President and Chief Executive Officer of Immunomedics.
This believe was, in part, based on a Breakthrough Therapy Designation the company received in February 2016 and results from various clinical trials investigating the activity of sacituzumab govitecan in patients with advanced cancers. One of the trials, presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO), showed that sacituzumab govitecan, as a single agent demonstrated, had significant clinical activity in heavily pre-treated patients with HR-positive, HER-2-negative metastatic breast cancer and has a predictable and manageable safety profile.
However, regardless of the results of clinical results, on february 17, 2019 Immunimedics confirmed that it has received a Complete Response Letter from the FDA for the Biologics License Application in which the FDA rejected the drugs.
Although the FDA did not raise concerns about the safety or efficacy of sacituzumab govitecan, the disappointing outcome follows serious manufacturing problems identified in the FDA inspection between August 6 and 14, 2018.
“The issues related to approvability in the Complete Response Letter were exclusively focused on Chemistry, Manufacturing and Control matters and no new clinical or preclinical data need to be generated,” Pehl noted.
This investigation revealed that Immunomedics’s quality control unit at the company’s Morris Plains, New Jersey, drug substance manufacturing facility didn’t have the authority to investigate a February 2018 data integrity breach, which didn’t trigger a deviation. This breach included manipulated bioburden samples, misrepresentation of an integrity test procedure in the batch record, and backdating of batch records, such as dates of analytical results.
According to the FDA, Immunomedics did not give an assurance that samples and batch records from commercial batches it manufactured before the data integrity breach were not impacted by it, and the agency was unable to conduct a proper assessment.
As a result of the problems, the FDA cited Immunomedics for multiple violations. However, according to statements to investors in December 2018 made by the company, the identified problems for which the company has been penalized have been addressed and are now (completely) resolved.
“We are going to request a meeting with the FDA as soon as possible to gain a full understanding of the Agency’s requirements and timelines for approval and we will work closely with the FDA,” Pehl said.
“The goal [is to bring] this important medicine to patients as soon as possible,” he concluded.
Results for Phase I/IIa study confirms that indatuximab ravtansine, also known as BT-062, an antibody-drug conjugate being developed by Biotets, offers good tolerability and signs of efficacy in the treatment of solid tumors and, in pre-clinical studies, very good effectiveness when combined with a chemotherapeutic agent for the treatment of difficult to treat triple-negative breast cancer.
First isolated in 1972 from the bark of the African shrub Maytenus ovatus, maytansinoids represent a class of microtubulin polymerization inhibitors derived from the naturally occurring maytansine, a benzoansamacrolide.[a] Similar to vinca alkaloids, they bind to tubulin at the vinca-binding site, depolymerizing tubulin and, as a result, inducing mitotic block and cell death.
The first and maytansinoid-based ADC, ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche), was approved in 2013 for HER2-positive metastatic breast cancer.
The antibody of the investigational drug binds specifically to the cell surface heparan sulphate proteoglycan CD138 (syndecan-1), a transmembrane protein receptor for the extracellular matrix (ECM) that mediates cell-cell adhesion via interactions with heparan-binding molecules.
CD138, which is over-expressed on multiple myeloma cells and a variety of solid tumors.
Once the conjugate has been internalized into the target cell, the cytotoxic agent DM4 is released from the targeting molecule by lysosomal degradation. As a result, the conjugation of DM4 to the antibody keeps the cytotoxic moiety inactive until it is released within the CD138-expressing target cell. This combination of high efficacy and specificity with low systemic toxicity sets indatuximab ravtansine apart from most therapies currently used to treat malignancies.
Triple-negative breast cancer
In a phase I/IIa trial, funded by the Cluster for Individualized ImmunIntervention (Ci3) Mainz, Germany, researchers examined the safety and anti-tumor activity of indatuximab ravtansine as a monotherapy in patients with triple-negative metastatic breast cancer, a type of cancer in which the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are not expressed, and patients with metastatic bladder cancer.
Both types of tumor are bearing the receptor CD138 on their surface.
To qualify for enrollment in this trial, patients with breast cancer had to have failed at least two treatment regimens. Patients with urinary bladder cancer had to have failed at least one prior treatment regimen. In the phase I part of the trial, the maximum tolerated dose (MTD) of indatuximab ravtansine in solid tumor indications was determined. In the Phase IIa part, indatuximab ravtansine was administered at this dose to further assess its safety and efficacy in the mentioned indications.
The study confirmed a good safety profile of indatuximab ravtansine and showed initial encouraging signs of efficacy in these critically ill patients for whom options for further treatment are largely exhausted.
Furthermore, indatuximab ravtansine in combination with chemotherapy showed very good efficacy in a tumor model for triple-negative breast cancer, a type of tumor that is particularly difficult to treat.
In mice loaded with human tumors, very good efficacy was already shown at low doses of indatuximab ravtansine monotherapy and was further improved when indatuximab ravtansine was given in combination with the cytostatic drug docetaxel.
Preclinical data on the mode of action of indatuximab ravtansine have been published in two full papers.
Underlining the potential
The clinical and preclinical results presented here underline the promising potential and support further development of indatuximab ravtansine as combination therapy for CD138-positive solid tumors.
The combination therapy approach is supported by evidence obtained with
indatuximab ravtansine in the treatment of multiple myeloma, a malignant disease of the bone marrow also involving CD138-positive cells. In this indication a combination of BT-062 with appropriate agents lead to a considerable increase in efficacy:
Safety and efficacy
Safety and early signs of efficacy of indatuximab ravtansine monotherapy were reported in two other clinical trials in patients with relapsed/recurrent or refractory multiple myeloma.
Data from a clinical phase I/IIa trial combining indatuximab ravtansine with lenalidomide or pomalidomide and dexamethasone in multiple myeloma are now available over a period of almost six years. This data show that in this patient population, treatment with indatuximab ravtansine in combination with lenalidomide or pomalidomide and dexamethasone can lead to partial or complete response. The study continues as some patients have been benefitting from the combination treatment for over four years.
These results support that combination therapy with appropriate chemotherapeutic or immune-oncological drugs may further enhance efficacy of indatuximab ravtansine in the solid tumors studied, similar to the effects observed in multiple myeloma.
New business model
Because Biotest is going to focus on the development of plasma products in the future, the company plans to sell off or further develop their portfolio of promising antibody-based drug candidates in a separate company.
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, which is considered advanced-stage cancer and also known as stage IV breast cancer.
According to the National Breast Cancer Foundation (NBCF), symptoms at this stage depend on the degree to which the cancer has spread beyond the breast tissue into other areas of the body. Although there is no cure for metastatic breast cancer, it can be treated. However, proper treatment increases both the quality of life (QoL) and longevity.
Breast cancers are commonly categorized by the expression (or lack thereof) of three key proteins, which serve as targets for therapeutics. These include the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). However, triple-negative breast cancer or TNBC*, as a subtype, lacks all three proteins and HR+/HER2- breast cancer expresses one or both hormone receptors (HR) but not HER2.
“Breast cancer is the most common cancer in women, excluding some forms of skin cancer, in the United States. Of the over 250,000 new cases expected to be diagnosed in the United States this year, about 15 to 20% are triple negative breast cancers. [This subtype of cancer] is very aggressive and associated with poor patient outcomes,” noted Jonathan Drachman, MD, Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.
According to the World Health Organization, breast cancer is the most common cancer in women worldwide with an estimated 1.67 million new cancer cases diagnosed in 2012. In the United States, the disease is the most common noncutaneous cancer in women, with an estimated number of new cases and deaths from breast cancer in 2017 is 252,710 (new cases) and 40,610 (deaths).  Furthermore, the according to the American Cancer Society noted 61,000 cases of in situ disease and 246,660 cases of invasive disease in 2016 
In addition, breast cancer ranks as the fifth cause of death from cancer overall globally.
In the United States, on average, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 71,280 American women will die of lung cancer in 2017. However, depending the type of breast cancer, the disease remains a major unmet medical need and new treatment approaches are needed to improve outcomes for breast cancer patients.
This is particularly so for patients with triple negative breast cancer which is more frequently diagnosed in African American women and younger women, and women who have a BRCA1 gene mutation. This subtype of breast cancer is also more common among Hispanic women compared to white women.
Although triple negative breast cancer can be treated with some chemotherapeutic drugs, radiation therapy and non-HER2 therapies, there are currently no available targeted therapies. Making treatment more difficult is further cause by the fact that triple negative breast cancer often returns after initial treatment and is highly likely to spread.
In addition to being more aggressive than other subtypes of breast cancer, triple-negative breast cancer is also more challenging to treat. Because it lacks all three key proteins and HR+/HER2-, the growth of this cancer is not fueled by hormones. As a result, hormone therapies like tamoxifen (Soltamox®, Midatech Pharma)# and aromatase inhibitors, including anastrozole (Arimidex®; AstraZeneca), exemestane (Aromasin®; Pfizer) and letrozole (Femara®; Novartis), have no therapeutic benefit.
Furthermore, studies have shown that, from a genetic standpoint, most triple-negative breast cancers bear little resemblance to each other. And while this subtype often contains many genetic alterations, only a few – if any – of these alterations are shared across all triple negative breast cancers. However, none of them appear to be primarily responsible for the growth and spread of TNBC, making treatment more complex.
While triple negative breast cancer has a poorer prognosis than ER-positive breast cancer for at least the first 5 years after diagnosis, if a woman survives 5 years without a recurrence, her chances of survival are relatively high.
Potential of a combination therapy
A potentially new approach in the treatment of TNBC may be on the horizon. Earlier this week, Seattle Genetics confirmed two clinical collaboration agreements for the evaluation of SGN-LIV1A for the treatment of patients with triple negative breast cancer.
SGN-LIV1A is an investigational antibody-drug conjugate or ADC being developed by Seattle Genetics that targets the cell surface protein LIV-1, which is expressed on multiple solid tumors including (most) metastatic breast cancers as well as prostate, melanoma, ovarian, and cervical cancers.
The investigational drug consists of a LIV-1-targeted monoclonal antibody linked to a potent microtubule-disrupting agent, monomethyl auristatin E or MMAE by a protease-cleavable linker, using the same technology as brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda). It 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.
The investiational agent will be tested in combination with pembrolizumab (Keytruda®, an anti-PD-1 therapy marketed by Merck**, in a phase Ib/II clinical trial as first line treatment for locally advanced and metastatic triple negative breast cancer or TNBC.
SGN-LIV1A in combination with standard chemotherapy will also be evaluated as neoadjuvant treatment in the phase II I-SPY 2 TRIAL (NCT01042379) for newly diagnosed Stage 2 or 3 human epidermal growth factor receptor 2 (HER2) negative breast cancer, sponsored by Quantum Leap Health Care Collaborative, a nonprofit organization with a mission to speed up transfer of high-impact clinical research and to make novel treatments available to patients as soon as practicable.
This cancer subgroup accounts for up to 85% of breast cancer and includes TNBC.  On average, it takes U.S. $2.5 billion, between 12-15 years, and the involvement of 2,000 to 8,000 patient volunteers to bring a new drug therapy to market. Unfortunately, the high cost and effort does not always guarantee success. According to Quantum Leap Health Care Collaborative, historically, 60-70% of all Phase III oncology trials have either negative results or fail to complete.
To change this outcome, Quantum Leap re-engineered the standard approach to clinical trials. Their goal was to bring the right drug to the right patient at the time the patient is expected to benefit most of the available treatment. In addition, Quantum Leap also wanted to significantly reduce the overall cost, time, and number of patients required to bring new drugs to market. The result was the The I-SPY TRIAL Program which integrates and links Phases I, Phase II, and, eventually, Phase III trials to build a pipeline of novel agents and accelerate the process of identifying the subset of high risk breast cancer patients that will benefit from these new agents, and get the drug to market.
Earlier this year, Rita Nanda, MD, Assistant Professor of Medicine Associate Director, Breast Medical Oncology at the University of Chicago, presented results from the Phase II I-SPY 2 TRIAL investigating pembrolizumab in combination with standard therapy (paclitaxel followed by doxorubicin and cyclophosphamide) as a neoadjuvant treatment for patients with locally advanced triple-negative breast cancer or hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer in an oral presentation during the 2017 annual meeting of American Society of Clinical Oncology (ASCO).
The data showed that the addition of pembrolizumab increased the estimated pathologic complete response (pCR) rate nearly threefold in patients with TNBC (60% vs 20%) and in patients with HR+/HER2- breast cancer (34% vs 13%) compared to standard therapy.
Furthermore, based on Bayesian predictive probability of success in a confirmatory Phase III trial, pembrolizumab graduated from the I-SPY 2 TRIAL for all subtypes in which it was tested, including triple negative breast cancer, all HER2-, and HR+/HER2-.
Earlier lines of treatment
“Our new collaborations expand the clinical investigation of SGN-LIV1A by evaluating [SGN-LIV1A] in earlier lines of treatment for triple negative breast cancer, including the frontline setting in combination with pembrolizumab. In the neoadjuvant setting, SGN-LIV1A has the potential to benefit a broader population of women with breast cancer,” noted Seattle Genetics Jonathan Drachman, MD.
“With four clinical studies underway or planned for SGN-LIV1A in TNBC, we are advancing our goal to improve the health of women with this devastating disease,” Drachman further added.
SGN-LIV1A administered in combination with Merck’s pembrolizumab will be evaluated in a phase Ib/II clinical study in patients with locally advanced or metastatic TNBC. This single arm, open label multicenter study is anticipated to enroll up to 72 patients. Under the terms of the collaboration agreement with Merck, Seattle Genetics will hold the IND for the study and retain global development and commercialization rights to SGN-LIV1A.
SGN-LIV1A in the I-SPY 2 TRIAL
SGN-LIV1A followed by standard chemotherapy (doxorubicin and cyclophosphamide) will be evaluated as a neoadjuvant treatment (prior to surgery) for women with newly diagnosed, locally advanced Stage 2 or 3 HER2-negative breast cancer in the I-SPY 2 TRIAL. This standing phase II randomized, controlled multicenter trial is anticipated to enroll up to 75 patients in the SGN-LIV1A treatment arm.
With TNBC and other aggressive cancers in mind, the I-SPY 2 TRIAL was designed to rapidly screen promising experimental treatments and identify those most effective in specific patient subgroups based on molecular characteristics (biomarker signatures).
The trial is a unique collaborative effort by a consortium that includes the U.S. Food and Drug Administration (FDA), industry, patient advocates, philanthropic sponsors and clinicians from 20 major U.S cancer research centers. Under the terms of the collaboration agreement, Quantum Leap is the trial sponsor and will manage the study operations. Seattle Genetics will retain global development and commercialization rights to SGN-LIV1A.
Four clinical studies are underway or planned for SGN-LIV1A in breast cancer, with a focus on TNBC. In addition to the aforementioned trials, SGN-LIV1A monotherapy is being evaluated in an ongoing phase 1 trial for patients with metastatic breast cancer, including patients heavily pre-treated for TNBC.
A phase Ib/II trial is planned to evaluate SGN-LIV1A as part of a combination regimen as second line treatment for patients with metastatic TNBC who have not been previously treated with immunotherapy.
* Triple Negative Breast Cancer is also called ER-negative PR-negative HER2/neu-negative breast cancer
** Known as MSD outside the United States and Canada
#Nolvadex® (AstraZeneca), another brand of tamoxifen, has been discontinued in the United States.
Keytruda® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, N.J., USA.
The investigational antibody-drug conjugate, sacituzumab govitecan, also know as IMMU-132 (Immunomedics), has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with triple-negative breast cancer or TNBC who have failed at least 2 prior therapies for metastatic disease.
The Breakthrough Therapy Designation was supported by a Phase II study in patients with metastatic TNBC who had received a median of 5 prior therapies (range, 2 – 12).
Triple-negative breast cancer is a serious disease, with an annual incidence estimated to be about 40,000 people, 20,000 for metastatic TNBC, in the United States. As the name implies, TNBC does not express estrogen, progesterone or the HER2 receptor, and is, therefore, insensitive to most of the available targeted therapies for breast cancer treatment, including HER2-directed therapy such as trastuzumab (Herceptin®; Genentech/Roche), and endocrine therapies such as tamoxifen (Nolvadex®; AstraZeneca) or the aromatase inhibitors. The median overall survival is 6-13 months and the median PFS is usually 3-4 months. There is currently no single standard chemotherapy to treat patients with relapsed/refractory metastatic TNBC. Rapid relapse, with visceral and brain metastases, is very common.
Novel treatment option
Sacituzumab govitecan is a first-in-class antibody-drug conjugate designed to deliver a specific payload of a chemotherapeutic directly to the tumor while reducing overall toxic effects that are usually found with conventional administration of these chemotherapeutic agents.
The drug candidate is developed by conjugating the moderately-toxic drug, SN-38, site-specifically and at a high ratio of drug to antibody, to a humanized antibody that targets the Trop-2 receptor expressed by many solid cancers.
SN-38 is the active metabolite of irinotecan (Camptosar), which is used to treat certain solid cancers as a part of combination therapies, so its pharmacology and properties are well- known. The ADC has received Fast Track designation from the FDA for the treatment of patients with triple-negative breast cancer, small-cell and non-small-cell lung cancers, and has also been designated an orphan drug for the treatment of patients with small-cell lung or pancreatic cancer in the U.S., and for the treatment of patients with pancreatic cancer in the European Union.
“We believe Breakthrough Therapy Designation for sacituzumab govitecan further validates this potential therapeutic for patients with TNBC, and we are delighted to receive this important recognition,” noted Cynthia L. Sullivan, President and Chief Executive Officer. “We continue to assess partnering opportunities while completing the scale-up manufacturing and regulatory activities for an international, randomized, controlled, registration trial in TNBC, based on the Special Protocol Assessment agreement that was already granted by the FDA,” she added.
“[Sacituzumab govitecan] is also in Phase II trials in patients with advanced, heavily-pretreated, non-small-cell lung cancer, small-cell lung cancer, and urothelial cancers, where encouraging results have been observed. The Trop-2 receptor targeted by this antibody- drug conjugate has increased expression in a large number of solid cancers. To date, we have enrolled about 300 patients with diverse cancer types,” Sullivan further stated.
Breakthrough Therapy Designation
Breakthrough Therapy Designation was created as part of the 2012 FDA Safety and Innovation Act (FDASIA) to expedite the development and review of a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
In addition to sacituzumab govitecan Immunomedics’ portfolio of investigational products also includes labetuzumab govitecan or IMMU-130, which is in Phase II trials for a number of solid tumors and metastatic colorectal cancer.
Updated results from a Phase II clinical study of sacituzumab govitecan, also known as IMMU-132, in patients with metastatic triple-negative breast cancer who had received a median of 5 (range, 2 – 12) prior lines of therapy were presented earlier this year during the San Antonio Breast Cancer Symposium (SABCS) being held December 8 – 12, 2015, in San Antonio, Texas.
Sacituzumab govitecan is a first-in-class antbdy-drug conjugate or ADC developed by conjugating the moderately-toxic drug, SN-38, site-specifically and at a high ratio of drug to antibody, to a humanized antibody that targets the TROP-2 receptor expressed by many solid cancers. SN-38 is the active metabolite of irinotecan (Camptosar; Pfizer), which is used to treat certain solid cancers as a part of combination therapies, so its pharmacology and properties are well- known.
Despite this late-stage setting, sacituzumab govitecan, as a single agent, produced an interim Objective Response Rate (ORR) of 31% by RECIST 1.1 in 58 evaluable patients, with 78% of these responding patients confirmed with a follow-up computed tomography scan, including 2 patients with a complete response. The investigational antibody-drug conjugate is being developed by Immunomedics, a clinical stage biopharmaceutical company.
A serious disease
Triple-negative breast cancer is a serious disease, with an annual incidence estimated to be about 40,000 people, 20,000 for metastatic triple-negative breast cancer, in the United States. Ths from f cancer is insensitive to most of the available targeted therapies for breast cancer treatment, including HER2-directed therapy such as Herceptin® (trastuzumab; Genentech/Roche), and endocrine therapies (such as tamoxifen or the aromatase inhibitors). The median overall survival is 10-13 months and the median PFS is usually 3-4 months. There is currently no single standard chemotherapy to treat patients with relapsed/refractory mTNBC. Rapid relapse, with visceral and brain metastases are very common.
Among the 60 intent-to-treat patients, the interim median Progression-Free Survival (PFS) was 6.0 months, with 58% of these patients having experienced a PFS event. Importantly, to correlation between PFS and (R=0.62, P<0.001) for the 31 patients whose cancer had progressed after reporting stable disease, partial or complete response as their best response. Median overall survival data were too early to report, with 83% of patients still alive.
Acceptable safety profile
Sacituzumab govitecan has an acceptable interim safety profile in the 60 metastatic triple-negative breast cancer patients reported at the symposium. The major toxicity was Grade 3 or 4 neutropenia in 15% of patients. Severe diarrhea, commonly reported with irinotecan, was rare with only 5% Grade 3/4 incidents. Moreover, repeated doses can be given over months without evoking interfering anti- sacituzumab govitecan antibodies from patients’ own immune system.
“This study provides us with a strong basis for a first pivotal Phase III trial in mTNBC, and we will continue the regulatory and manufacturing activities in calendar year 2016,” noted Cynthia L. Sullivan, President and Chief Executive Officer. “We are fully committed to partnering this important Phase III asset, and that partnership will include the full dedication to progress sacituzumab govitecan not only in triple-negative breast cancer, but simultaneously in other indications.”
Earlier this year, Immunomedics has filed a multicenter, international, randomized, open-label Phase III study of approximately 328 patients with mTNBC who are refractory or relapsing after at least 2 prior chemotherapies that included a taxane for their metastatic disease. In accordance with the Company’s Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration, the primary endpoint of the trial will be PFS, which will be measured by an independent centralized and blinded group of radiology experts who will be assessing tumor response using RECIST 1.1 criteria. Overall survival, Objective Response Rate, duration of response, and time to onset of response will serve as secondary endpoints.
The Phase II study was updated by Aditya Bardia, MD, MPH, Assistant Professor of Medicine at Harvard Medical School, Attending Physician at the Massachusetts General Hospital Cancer Center in Boston, and an investigator in this trial. Steven Jay Isakoff, MD, PhD, as well as Bardia and other colleagues also participated in this multicenter study.
Sacituzumab govitecan has received Fast Track designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with triple-negative breast cancer, small-cell and non-small-cell lung cancers, and has also been designated an orphan drug for the treatment of patients with small-cell lung or pancreatic cancer in the U.S., and for the treatment of patients with pancreatic cancer in the European Union.
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 Societymore 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.