Interim data from a 100-patient cohort of cisplatin-eligible patients participating in the TROPHY-U-01, an international, multi-center, open-label, phase II study, in patients with metastatic urothelial cancer (mUC) after failure of a platinum-based chemotherapy regimen or anti-PD-1 /PD-L1 based immunotherapy, shows that sacituzumab govitecan (IMMU-132) produced an overall response rate (ORR) of 29% in 35 patients. 
Sacituzumab govitecan, an antibody-drug conjugate or ADC being developed by Immunomedics, is a novel, first-in-class antibody-drug conjugate. The drug is designed to deliver SN-38, a potent topoisomerase I inhibitor, directly to tumor cells by targeting the Trop-2 antigen expressed by many solid cancers.
Antibody-drug Conjugates are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker. Today, with five approved drugs on the market and many more, such as sacituzumab govitecan in development, ADCs have become a powerful class of therapeutic agents in oncology and hematology.
Based on encouraging Phase I/II results, the U.S. Food and Drug Administration (FDA) has granted sacituzumab govitecan Breakthrough Therapy Designation for the treatment of patients with metastatic triple-negative breast cancer who received at least two prior therapies for metastatic disease.
The interim data was presented during the European Society for Medical Oncology (ESMO) 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2018.
“Patients with metastatic urothelial cancer (mUC) who have cancer progression and relapsed or are refractory after platinum-based and immune checkpoint inhibitors (CPI) therapy have poor outcomes and limited treatment options,” explained Scott T. Tagawa, MD, MS, the Richard A. Stratton Associate Professor in Hematology and Oncology, Associate Professor of Clinical Medicine and of Clinical Urology, member of the Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, who presented the interim results.
“Together with the prior clinical data, I believe the favorable benefit/risk profile of sacituzumab govitecan has the potential to change the treatment landscape of urothelial cancer,” Tagawa added.
The 29% Objective Response Rate (ORR) included two confirmed complete responses, six confirmed partial responses (PRs) and two additional PRs pending confirmation. At the time of data cutoff on August 5, 2019, eight of ten responders have ongoing response. Median time to onset of response was 1.5 months (range, 1.2-2.8). For patients with liver metastases, ORR was 25%.
“These interim results, in a larger number of immune checkpoint inhibitors (CPI-) experienced patients, are consistent with previously reported efficacy of sacituzumab govitecan in mUC, and also show encouraging benefits observed in patients relapsed on enfortumab vedotin,” noted Behzad Aghazadeh, Ph.D, Executive Chairman of Immunomedics.
“Based on these data, we will be exploring registrational pathways with the U.S. Food and Drug Administration (FDA),” Aghazadeh added.
Consistent with the Company’s previous observations, sacituzumab govitecan was well tolerated with a predictable safety profile. Treatment-related Grade 3 and 4 adverse events were mostly hematologic and gastrointestinal related, including neutropenia (54%) and diarrhea (9%). Importantly, there were no grade 2 or above neuropathy or rash, no interstitial lung disease, and no treatment-related deaths.
New Clinical Collaborations
During the ESMO Congress Immunomedics also announced two clinical collaborations that address continuing unmet needs in breast cancer.
A collaboration with Roche will evaluate the safety and efficacy of the combination of atezolizumab (Tecentriq®), a programmed cell death ligand 1 (PD-L1)-blocking checkpoint inhibitor, and sacituzumab govitecan, as a frontline treatment of patients with metastatic or inoperable locally advanced or metastatic Triple Negative Breast Cancer (TNBC).
Triple-negative breast cancer is defined by a lack of tumor-cell expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). The disease accounts for approximately 15% of all invasive breast cancers and is associated with aggressive tumor biology and poor prognosis.
Triple-negative breast cancer is more common in younger women than in older women and in black persons than in persons of other races and ethnic groups, and it is often associated with visceral metastases.
Results from a previous phase I/II clinical trial demonstrated that sacituzumab govitecan was associated with durable objective responses in patients with heavily pretreated metastatic triple-negative breast cancer.  However, while there have been many developments in improving the treatment options for patients with the disease, triple-negative breast cancer represents a major unmet medical need.
“We are pleased to be partnering with Roche, a global leader in breast cancer therapy,” Aghazadeh said.
“With a favorable efficacy and safety profile, we believe sacituzumab govitecan is a strong combination partner and could provide an improved therapeutic option in earlier lines of therapy when combined with immune checkpoint inhibitors,” he added.
The open-label, multicenter, randomized Phase Ib/II study will be conducted as part of MORPHEUS, Roche’s novel cancer immunotherapy development platform. Patients with newly-diagnosed mTNBC will be randomized to receive the combination of atezolizumab and sacituzumab govitecan or nab-paclitaxel plus atezolizumab as standard of care.
MORPHEUS is a Phase Ib/II adaptive platform to develop combinations of cancer immunotherapies more rapidly and efficiently. Roche will be responsible for conducting the randomized trial.
In addition to the clinical colaboration with Roche, Immunomedics has signed ab agreement with GBG Forschungs-GmbH (GBG) in Neu-Isenburg, Germany.
The companies have entered into a collaboration to develop sacituzumab govitecan as a treatment for newly-diagnosed breast cancer patients who do not achieve a pathological complete response (pCR) following standard neoadjuvant therapy.
“While pCR is now widely accepted as a very strong surrogate endpoint for event-free and distant disease-free survival (DDFS) in high-risk breast cancer, for patients who do not achieve a pCR following standard neoadjuvant therapy, the risk for developing metastatic disease is very high,” said Professor Dr. med. Sibylle Loibl, MD, Ph.D, Chief Executive Officer of GBG.
“We are very excited to be the first cooperative group worldwide to evaluate sacituzumab govitecan in this early stage of breast cancer treatment,” Loibl added.
According to the medical literature, depending on the hormone receptor status, about 40% to 70% of HER2-negative breast cancer patients treated with neoadjuvant therapy do not achieve a pCR. 
For these patients, with the exception of those with the HER2-positive subtype, there is currently no approved standard of care, leaving them at high risk of distant relapse of their disease.
“We are extremely pleased to partner with GBG, the world-renowned cooperative group, to launch this exciting study which will introduce sacituzumab govitecan to breast cancer patients at an early stage of their disease,” Aghazadeh commented.
“We look forward to working closely with GBG to study the potential benefits of sacituzumab govitecan in a significantly larger population of breast cancer patients who have few viable alternatives today,” he concluded.
The multinational, post-neoadjuvant Phase III SASCIA study developed by GBG will be conducted under the sponsorship of GBG. Approximately 1,200 high-risk patients with newly-diagnosed HER2-negative breast cancer not achieving a pCR following standard neoadjuvant therapy will be randomized to receive either sacituzumab govitecan or treatment of physician’s choice. Primary endpoint is invasive DFS (iDFS) with overall survival, patient reported outcome/quality of life, circulating tumor DNA clearance, and safety serving as secondary endpoints.
“Given the high level of Trop-2 expression in breast cancer, we are hopeful that sacituzumab govitecan will be established as a new treatment standard for those high-risk patients who failed standard treatment,” remarked Professor Dr. med. Frederik Marmé, MD, PhD, Section Lead for Gynecological Oncology, University Medical Center, Mannheim, Germany, and designated Principal Investigator of the SASCIA trial.
Resubmission BLA Timeline
Based on the remaining activities for compilation of the Biologics License Application (BLA), and preparations for a pre-approval inspection, Immunomedics revised its re-submission guidance from early fourth quarter to the late November or early December timeframe.
Phase II Open Label, Study of IMMU-132 in Metastatic Urothelial Cancer – NCT03547973
Phase I/II Study of IMMU-132 in Patients With Epithelial Cancers – NCT01631552
A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic or Inoperable Locally Advanced Triple-Negative Breast Cancer (Morpheus-TNBC) (Morpheus-TNBC) – NCT03424005
 Initial results from TROPHY-U-01: A Phase 2 open-label study of sacituzumab govitecan in patients (Pts) with metastatic urothelial cancer (mUC) after failure of platinum-based regimens (PLT) or immunotherapy (Tagawa, et al.)Session Title: Proffered Paper 1: Genitourinary Tumors, -Prostate| Presentation #: LBA 55 8:45 a/m. – 9:00 a.m. (Central European Summer Time) | Barcelona Auditorium (Hall 2)
 Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, O’Shaughnessy J,et al Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N.Engl J Med. 2019 Feb 21;380(8):741-751. doi: 10.1056/NEJMoa1814213.
 Untch M, Jackisch C, et al. Nab-Paclitaxel Improves Disease Free Survival in Early Breast Cancer: GBG 69-GeparSepto. J Clin Oncol. 2019 September 1;37:2226-2234