Clinical Phase I Data for ASG-15ME and Enfortumab Vedotin (ASG-22ME) Indicates Anti-tumor Activity in Metastatic Urothelial Cancer

Clinical data for ASG-15ME and Enfortumab vedotin, also known as ASG-22ME and ASG-22M6E,  presented at the American Society of Clinical Oncology‘s (ASCO) 51st Annual Meeting held June 3-7, 2016, in Chicago, IL, shows strong clinical activity of these two novel antibody-drug conjugates (ADCs).[1]

ASG-15ME and Enfortumab vedotin are investigational antibody-drug conjugates (ADCs) that consist of monoclonal antibodies designed to deliver microtubule-disrupting agents selectively to tumor cells. In both drugs, the linker system is designed to be stable in the bloodstream and release the cell-killing agent once inside target cancer 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.

ASCOSLITRK6
ASG-15ME (Product name AGS15E) is a potent, investigational, Monomethyl Auristatin E (MMAE)-based antibody-drug conjugate linked via a protease-cleavable linker to the SLITRK6-specific human gamma 2 antibody (Igγ2).[2]

ADC Bio
MabPlex
Lonza
 

SLITRK6, a proteins that are highly expressed in urothelial cancers, particularly bladder cancer, is a member of the SLITRK family of neuronal transmembrane proteins. It was discovered as tumor antigen expressed in multiple epithelial tumors, including bladder, lung, and breast cancer as well as in glioblastoma. [1][2]

The trial drug is the first and only agent to target SLITRK6, a transmembrane protein identified as an ADC target by researchers at Astellas’ subsidiary Agensys, which is expressed on many solid tumors. Preclinical data demonstrate that ASG-15ME effectively binds to target cells, internalizes and induces cell-killing activity

Nectin-4
Enfortumab vedotin targets Nectin-4, which can be found on multiple solid tumors, including bladder, breast, lung and pancreatic. Nectin-4, which is a valuable serum marker for breast carcinoma, is involved in calcium ions (Ca2+) and play a vital role in the physiology and biochemistry of organisms and the cell.[3]

As a 66-kDa type I transmembrane glycoprotein, Nectin-4, part of the class of embryonic carcino-antigens and belonging to the Nectin family of calcium-independent immunoglobulin (Ig)-superfamily proteins, it is both a homophilic and heterophilic cell adhesion molecule (CAMs).

The Nectin family comprises of a total of five transmembrane glycoproteins (PVR/CD155, Nectin-1/CD111, Nectin-2/CD112, Nectin-3, and Nectin-4), which are all members of the immunoglobulin superfamily.[3]

A soluble form of Nectin-4 (43 kDa) is generated from the membrane protein via the action of the tumor necrosis factor-alpha converting enzyme TACE/ADAM-17, which plays a fundamental role in diverse processes including angiogenesis and cancer through their activities in cell adhesion/fusion, membrane protein shedding, and signal transduction.

As an investigational drug, enfortumab vedotin is composed of an anti-Nectin-4 monoclonal antibody attached, via an enzyme-cleavable linker, to the  microtubule-disrupting agent MMAE. The trial drug, which uses Seattle Genetics’ proprietary linker technology,  is currently in a phase I clinical trial to evaluate the safety and antitumor activity of escalating doses of ASG-22ME in patients with solid tumors.

Enfortumab vedotin is the first and only agent to target Nectin-4, identified as an ADC-target by Agensys’ researchers. Preclinical data demonstrate that enfortumab vedotin effectively binds to target cells, internalizes and induces cell-killing activity.

Common cancer
Bladder cancer begins when cells in the urinary bladder start to grow uncontrollably. Most bladder cancers start in the innermost lining of the bladder, which is called the urothelium or transitional epithelium. Urothelial carcinoma, also known as transitional cell carcinoma (TCC), is the most common type of bladder cancer. Urothelial carcinoma starts in the urothelial cells that line the inside of the bladder.

While patients with early stage bladder cancer are treated with curative intent, outcomes are poor for patients diagnosed with locally advanced or metastatic disease. For the approximately 10 percent of patients with urothelial bladder cancer whose initial diagnoses occur when they have metastatic disease, the average five-year survival is approximately 15%. According to the American Cancer Society, in 2016 approximately 77,000 people will be diagnosed and more than 16,000 will die from urothelial bladder cancer.

“Bladder cancer is the fifth most common cancer in the U.S., and there have been few treatment advances over the past three decades. For metastatic disease, the five-year survival rate is only 15 percent, representing a significant unmet need to identify additional treatment options,” noted Len Reyno, MD, senior vice president and chief medical officer, Agensys, an affiliate of Astellas.

”We are pleased to present these first data for ASG-15ME and ASG-22ME in urothelial cancers, which have a particularly high unmet medical need,” Reyno said.

Heavily pretreated
“The clinical data from the phase I presented at ASCO from the ASG-15ME and enfortumab vedotin programs in heavily pretreated metastatic bladder cancer patients show a manageable safety profile along with objective response rates that are higher than historical rates seen with taxanes,” said Jonathan Drachman, MD, chief medical officer and executive vice president, Research and Development at Seattle Genetics.

“We will continue enrolling patients in the ongoing phase I clinical trials to determine the recommended dose for further development,” Drachman continued.

ASG-15ME-study
During the annual meeting of the American Society of Clinical Oncology data were reported from 49 patients with metastatic urothelial cancer. [4] The median age of patients was 64 years. Of the 49 patients, 48 patients (98%) had undergone treatment with a platinum-based chemotherapy regimen, including 33 patients (67%) with a cisplatin-based regimen, and 14 patients (29%) who had progressed on or after treatment with checkpoint inhibitors.

A total of twenty-nine patients (59%) had received two or more prior systemic therapies. The primary endpoints of the ongoing clinical trial are to evaluate escalating doses, pharmacokinetics and safety of ASG-15ME as a monotherapy. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. In this dose-escalation study, patients received ASG-15ME at 0.1 to 1.25 milligrams per kilogram (mg/kg) weekly for three of every four week cycles.

The researchers found that of the 43 patients evaluable for response, 14 patients (33%) had an objective response (OR), including one patient (2%) who achieved a complete response and 13 patients (30%) who achieved a partial response. While the study is ongoing, preliminary estimates show median duration of response at 16.1 weeks. Disease control was achieved for 27 patients (63%), defined as achieving complete remission (CR), partial remission (PR) or stable disease (SD).

In 16 patients treated at the 1.0 mg/kg dose level, seven patients (44%) had an objective response. In five patients treated at the 1.25 mg/kg dose level, two patients (40%) had an objective response. In the 13 patients whose cancer had metastasized to the liver, four patients (31%) achieved a partial remission. Bladder cancer that metastasizes to the liver typically has a poor prognosis. In the 14 patients who had previously been treated with checkpoint inhibitors, five patients (36%) achieved a partial remission.

Adverse events
The most common treatment-related adverse events of any grade occurring in 15% or more of patients were fatigue (43%) and nausea (20%). Peripheral neuropathy was observed in 10 patients (19%) at Grade 1 and six patients (11%) at Grade 2. No Grade 3 or 4 peripheral neuropathy was reported.

In the study, eight patients developed ocular symptoms with corneal abnormalities. The majority of patients were managed with dose reductions and recovered.

Based on the results, researchers concluded that ASG-15ME targeting SLITRK6 is well tolerated and active,  warranting an ongoing study of ASG-15ME in patients with metastatic urothelial cancer.  Enrollment is ongoing at 1.0 and 1.25 mg/kg to identify a recommended dose for future studies.

Enfortumab vedotin-study
Data were reported from 44 patients with metastatic urothelial cancer. [5] The median age of patients was 66.5 years. Of the 44 patients, 43 patients (98%) had undergone treatment with a platinum-based chemotherapy regimen, including 30 patients (68%) with a cisplatin-based regimen, and 12 patients (27%) who had progressed on or after treatment with checkpoint inhibitors. Twenty-eight patients (64%) had received two or more prior systemic therapies.

The primary endpoints of the ongoing clinical trial are to evaluate escalating doses, pharmacokinetics and safety of enfortumab vedotin as a monotherapy. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. In this dose-escalation study, patients received enfortumab vedotin at 0.5 to 1.25 mg/kg weekly for three of every four week cycles.

The researchers found that of the 36 patients evaluable for response, 10 patients (28%) achieved a partial response (PR). While the study is ongoing, preliminary estimates show median duration of response at 16.1 weeks. Disease control was achieved for 25 patients (69%), defined as achieving complete remission, partial remission or stable disease.

In eight patients treated at the 1.25 mg/kg dose level, four patients (50%) had an objective response. In the 10 patients whose cancer had metastasized to the liver, four patients (40%) achieved a partial remission. Bladder cancer that metastasizes to the liver typically has a poor prognosis. In the 12 patients who had previously been treated with checkpoint inhibitors, three patients (25%) achieved a partial remission.

The most common treatment-related adverse events of any grade occurring in 15 percent or more of patients were pruritis and nausea (30% each), fatigue (25%), diarrhea (21%) and rash (18%). Peripheral neuropathy was observed in 11 patients (19%) at Grade 1 and three patients (5%) at Grade 2. No Grade 3 or 4 peripheral neuropathy was reported. In this study, two patients developed ocular symptoms with corneal abnormalities. The patients were managed with dose reductions and/or steroid eye drops.

These results warrant ongoing study of ASG-22ME.  Hence, enrollment is ongoing at 1.0 and 1.25 mg/kg to identify a recommended dose for future studies.

Ongoing studies
The ASG-15ME and enfortumab vedotin phase I clinical trials are ongoing to identify a recommended dose for future clinical evaluation.

Futher collaboration
Agensys (subsequently acquired by Astellas) and Seattle Genetics, the companies developing ASG-15ME and Enfortumab vedotin, entered into the ADC collaboration in January 2007 and expanded it in November 2009.

Under the collaboration and following regulatory approval, the companies are co-developing and plan to globally co-commercialize the two investigational drugs.