Sacituzumab govitecan, also known as IMMU-132, has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with triple-negative breast cancer (TNBC) who have failed at least 2 prior therapies for metastatic disease. The trial-drug is Immunomedics novel investigational antibody-drug conjugate.

Triple-Negative Breast Cancer or TNBC, is a serious disease. Its includes about 15% of all breast cancer types and according to the American Cancer Society, the an annual incidence is estimated to be about 40,000 people, with 20,000 diagnosed with metastatic TNBC, in the United States alone. [1] As the name implies, Triple-Negative Breast Cancer 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, including  trastuzumab (Herceptin®; Genentech/Roche), and endocrine therapies (such as tamoxifen or the aromatase inhibitors).

TNBC has a particularly aggressive course. Following first-line therapy, the median overall survival is 6-13 months and the median progression-free survival (PFS) is usually 3-4 months. Currently there is no single standard chemotherapy to treat patients with relapsed/refractory metastatic TNBC. Rapid relapse, with visceral and brain metastases, is very common.

Therefore, new treatment strategies are needed. Because Trop-2 is expressed in >90% of TNBC, as measured by immunohistochemical (IHC) assay, researchers conducted a trial to evaluate the safety and efficacy of an anti-Trop-2 monoclonal antibody conjugated to SN-38.[1]

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This novel drug, sacituzumab govitecan, is an investigational and first-in-class antibody-drug conjugate being developed by the clinical-stage biopharmaceutical company Immunomedics, conjugates 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 and may be beneficial for the treatment of patients with TNBC.

SN-38 is a topoisomerase I inhibitor and the active metabolite of the prodrug irinotecan  (Camptosar®, CPT-11; Pfizer), which is used to treat certain solid cancers as a part of combination therapies. SN-38 has a 2-3 logs higher potency than the prodrug.  The pharmacology and properties of the drug are well- known.

Fast Track designation
Sacituzumab govitecan 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.

Breakthrough Therapy
The Breakthrough Therapy Designation received earlier this year was supported by a Phase II study in patients with metastatic TNBC who had received a median of 5 prior therapies, with a minimum of 2 therapies (range, 2 – 12).

The FDA created the Breakthrough Therapy Designation 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.

“We believe Breakthrough Therapy Designation for IMMU-132 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.

Clinical trials
Following the establishment  of the optimal repeated dose in a Phase I trial (, NCT01631552) involving many different solid cancer types, an expanded Phase II was undertaken in a number of cancers, including TNBC.

The primary objective of the multi-center trial was to evaluate the safety and tolerability of sacituzumab govitecan as a single agent administered in 3-week treatment cycles for up to 8 cycles, in previously treated patients with advanced epithelial cancer. The secondary objectives are to obtain initial data concerning pharmacokinetics, immunogenicity, and efficacy with this dosing regimen.

In this trial, patients received 8 or 10 mg/kg sacituzumab govitecan i.v. on days 1 and 8 of 21-day repeated cycles. Assessments of safety and response by RECIST 1.1 were made weekly and bimonthly, respectively. Tumor biopsies (archival, at baseline prior to treatment, and at disease progression) were obtained when safe and feasible.

As of May 10, 2015, 58 patients with Tripple-negative Breast Cancer, with a median of 4 prior therapies (range, 1-11), were treated with sacituzumab govitecan.

Observed grade 3-4 toxicities included neutropenia (26%), febrile neutropenia (2%), diarrhea (2%), anemia (4%), and fatigue (4%).  The participating patients did not developed antibodies to SN-38 or the anti-Trop-2 antibody RS7. Non of the participating patients had to discontinued therapy due to toxicity.

Tumor responses were defined as Objective Response Rate (Complete Response +Partial Response) in 31% of 49 evaluated patients, including 2 with Complete Response (CR), and a clinical benefit ratio (CR+PR+ Stable Disease)>6 months) of 49% (63% with SD>4 months. A total of 23 patients are continuing treatment after 1st assessment.

Trial results
The current median progression-free survival is 7.3 months with 44% maturity in 50 patients treated at the 8 or 10 mg/kg dose level. Overall survival data are still not mature 20 months after enrollment of first patient.

Clinical efficacy correlated to biomarker studies, including Trop-2 expression (target of antibody), topoisomerase-1 expression (target of SN-38), and homologous recombinant deficiency (HRD) assay (marker of DNA repair), is being studied. Immunohistochemistry results in archival specimens currently show 97% positivity of Trop-2 among 34 specimens evaluated, with 79% having high intensity (2+/3+) staining.

The researchers conducting the trial concluded that sacituzumab govitecan shows manageable toxicity, and encouraging anti-tumor activity in relapsed/refractory patients with TNBC. This antibody-drug conjugate appears to have a high therapeutic index in heavily pretreated patients.