The annual congress of the European Society of Medical Oncology (ESMO), this year held in Copenhagen, Denmark (October 7 – 11, 2016) is the premier scientific platform to present the latest oncology research and as such, the ultimate learning experience for congress attendees.

Among the latest news presented during this year’s meeting are exciting results confirming a 59% Objective Response Rate (ORR) for Enfortumab Vedotin, also known as ASG-22ME (Seattle Genetics and Agensys/Astellas) in patients with metastatic urothelial cancer, at recommended phase II dose of 1.25 mg/kg, supporting advancement of the clinical development program.

esmo_2016_logoThis news is important because the clinical data for both agents continue to demonstrate encouraging overall response rates in patients with metastatic urothelial cancer, including those treated with checkpoint inhibitors. Furthermore, safety and recommended Phase II doses were presented for both programs. Seattle Genetics and Astellas are co-developing the drug, and plan to co-commercialize globally for ASG-15ME and enfortumab vedotin.

MabPlex
 

Novel, investigational drugs
Enfortumab vedotin is an investigational antibody-drug conjugate or ADC composed of an anti-Nectin-4 monoclonal antibody attached to monomethyl auristatin E, a microtubule-disrupting agent also known as MMAE. The novel drug is using Seattle Genetics proprietary technology.

Enfortumab vedotin is the first and only agent to target Nectin-4, a cell adhesion molecule identified as an ADC target by Agensys (now Astellas), which is expressed on many solid tumors. Preclinical data demonstrate that enfortumab vedotin effectively binds to target cells, internalizes and induces cell-killing activity.

ASG-15ME, the other investigational antibody-drug conjugate included in presentations during the annual ESMO congress, is composed of an anti-SLITRK6 monoclonal antibody attached to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), using Seattle Genetics proprietary, industry-leading linker technology. ASG-15ME is the first and only agent to target SLITRK6, a transmembrane protein identified as an ADC target by 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 and SLITRK6 are highly expressed in urothelial cancers, particularly bladder cancer but also include carcinomas of the ureter, and renal pelvis, which occur at a ratio of 50:3:1, respectively. Most bladder cancers start in the innermost lining of the bladder, which is called the urothelium or transitional epithelium. Urothelial cancer begins when urothelial cells in the urinary bladder, ureter, or renal pelvis start to grow uncontrollably.

Why important
Patients with metastatic urothelial cancer are in dire need of improved treatment options. While patients with early stage urothelial cancer are treated with curative intent, the prognosis for any patients diagnosed with locally advanced or metastatic disease is grim.

For the approximately 10% of patients with urothelial cancer whose initial diagnoses occur when they have metastatic disease, the average five-year survival is approximately 15%, hence new treatment options are urgently needed.

This news is emphasized by a report from the American Cancer Society, in 2016 approximately 77,000 people will be diagnosed and more than 16,000 will die from urothelial bladder cancer.

Trial results
Interim clinical data for enfortumab vedotin (ASG-22ME) and ASG-15ME in patients with metastatic urothelial cancer were presented at the ESMO Congress during poster sessions on Sunday, October 9, 2016.  Enfortumab vedotin and ASG-15ME are investigational antibody-drug conjugates (ADCs) that target the cell surface proteins Nectin-4 and SLITRK6, respectively.

The clinical data for both agents continue to demonstrate overall response rates in patients with previously treated metastatic urothelial cancer, including those with prior checkpoint inhibitors. Safety and recommended phase II doses were also presented for both programs. While both phase 1 studies will continue to enroll patients, the companies plan to advance enfortumab vedotin and discuss next steps with regulatory agencies. Evaluation of next developmental steps for ASG-15ME is ongoing.

Commenting on the trial results, Jonathan Drachman, M.D., chief medical officer and executive vice president, Research and Development at Seattle Genetics, said: “We are pleased to advance the enfortumab vedotin development program for patients with metastatic urothelial cancer. These patients are in dire need of new treatment options as their prognosis is grim, with a five-year survival rate of about 15%.”

“The antitumor activity and safety profile of enfortumab vedotin in heavily pretreated metastatic patients is encouraging, particularly in those patients who have failed both platinum-based chemotherapy and checkpoint inhibitors. We look forward to discussions with regulatory agencies,” Drachman added.

“Both enfortumab vedotin and ASG-15ME hold potential promise for metastatic urothelial cancer patients,” noted Steven Benner, M.D., senior vice president, therapeutic area head for oncology development, Astellas.

“As we consider our next steps in these two development programs, we also pause to thank the patients, caregivers and clinical investigators who participate in these clinical trials for the important role they play in advancing the science of cancer care,” he added.

Interim data
The respective clinical trial data showed that each agent had antitumor activity in patients previously treated with platinum-based chemotherapy, checkpoint inhibitors, taxanes and those with liver metastases. Enfortumab vedotin and ASG-15ME were generally well-tolerated, and phase 1 enrollment is ongoing with both agents, with an increased focus on checkpoint-inhibitor treated patients to further understand safety and activity in this population.

Analysis of phase I Dose Escalation Trial of ASG-22CE/ASG-22ME
The interim data showed that from 58 patients with metastatic urothelial cancer having a median age of 67 years. Of these patients, 56 patients (97%) had undergone treatment with a platinum-based chemotherapy regimen and 20 patients (35%) had progressed on or after treatment with checkpoint inhibitors. Thirty-six patients (62%) had received two or more prior systemic therapies. The primary endpoints of the ongoing clinical trial are to evaluate pharmacokinetics and safety of enfortumab vedotin as a monotherapy at escalating doses of 0.5 to 1.25 milligrams per kilogram (mg/kg) weekly for three of every four week cycles. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. Key findings include:

  • Of the 49 patients evaluable for response, 18 patients (37%) had an objective response, including one patient (2%) who achieved a complete response and 17 patients (35%) who achieved a partial response. The preliminary estimate of median progression-free survival is 16.6 weeks.
  • The recommended phase II dose is 1.25 mg/kg. In 17 patients treated at the 1.25 mg/kg dose level, 10 patients (59%) had a partial response. Disease control was achieved for 14 patients (82%), defined as achieving complete response, partial response or stable disease.
  • In the 16 patients across dose levels who had previously been treated with checkpoint inhibitors, six patients (38%) achieved a partial response. At the recommended phase II dose, four out of seven patients (57%) previously treated with checkpoint inhibitors achieved a partial response.
  • In the 12 patients whose cancer had metastasized to the liver, which typically has a poor prognosis, five patients (42%) achieved an objective response. Of 20 patients previously treated with taxanes, eight (40%) achieved an objective response.
  • The most common treatment related adverse events of any grade occurring in 20 percent or more of patients were pruritis (31%), fatigue (30%), diarrhea (29%), nausea (28%), rash (26%) and alopecia (21%).
  • Eight of 19 patients (42%) experienced a rash at the recommended phase II dose and none of these patients required dose modification or discontinued therapy as a result.

Analysis of AGS15E (ASG-15ME) in Metastatic Urothelial Cancer
Data were reported from 54 patients with metastatic urothelial cancer having a median age of 64 years. Of these patients, 52 patients (96 percent) had previously undergone treatment with a platinum-based chemotherapy regimen and 17 patients (32%) had progressed on or after treatment with checkpoint inhibitors. Thirty patients (56%) had received two or more prior systemic therapies. The primary endpoints of the ongoing clinical trial are to evaluate the pharmacokinetics and safety of ASG-15ME as a monotherapy at escalating doses of 0.1 to 1.25 mg/kg weekly for three of every four week cycles. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. Key findings include:

  • Of the 48 patients evaluable for response, 18 patients (38%) had an objective response, including one patient (2%) who achieved a complete response and 17 patients (35%) who achieved a partial response. The preliminary estimate of median progression-free survival is 16.1 weeks.
  • The recommended phase II dose is 1.0 mg/kg. In 20 patients treated at the 1.0 mg/kg dose level, 10 patients (50%) had an objective response, including one patient (five percent) who achieved a complete response and nine patients (45%) who achieved a partial response. Disease control was achieved for 14 patients (70%), defined as achieving complete response, partial response or stable disease.
  • Of the 14 patients across dose levels who had previously been treated with checkpoint inhibitors, six patients (43%) achieved a partial response. At the recommended phase II dose, three out of seven patients (43%) previously treated with checkpoint inhibitors achieved a partial response.
  • In the 13 patients whose cancer had metastasized to the liver, which typically has a poor prognosis, six patients (46%) achieved an objective response. Of 22 patients previously treated with taxanes, nine (41%) achieved an objective response.
  • The most common treatment related adverse events of any grade occurring in 20 percent or more of patients were fatigue (44%), nausea (22%) and decreased appetite (20%).
  • Fourteen patients (26%) experienced ocular adverse events and six patients (11%) developed ocular symptoms with corneal abnormalities at the recommended phase II dose. All events resolved with appropriate management.

Ongoing development
Both agents demonstrated encouraging anti-tumor activity and safety in these patient groups, and these data support the advancement to later stage development.

Enrollment is ongoing for Enfortumab Vedotin (ASG-22ME)  at 1.25 mg/kg. The study has been amended to include a checkpoint inhibitor-treated cohort to further understand safety and activity in this population. For AGS15E (ASG-15ME) enrollment is ongoing at 1.0 mg/kg and the study has been amended to include a checkpoint inhibitor-treated cohort to further understand safety and activity in this population.