Promising Immunotherapy Tested in Two Large Trials of Urothelial Cancer

After a dearth of advances in the treatment of bladder cancer in recent years, two trials are underway at Cleveland Clinic that are designed to test promising results from earlier trials on immunotherapy, and the immunotherapeutic agent pembrolizumab, specifically.

“There have been no major advances in the systemic therapy for bladder cancer in almost 25 years,” says Petros Grivas, MD, PhD, of the Department of Hematology and Oncology at Cleveland Clinic. “There is an urgent need for new therapies validated with well-designed clinical trials.” Dr. Grivas’ focus is on new therapeutic approaches to bladder cancer.

Bladder cancer is the fourth most common cancer in men, and one of the most common cancers in the Western world. This year, an estimated 74,000 new patients will be diagnosed, and about 16,000 will die from bladder cancer in the United States alone. More than half a million Americans are bladder cancer survivors. The chance of a man getting bladder cancer during his lifetime is now about 1 in 26, and for a woman it is about 1 in 90. The most common type is urothelial, which can also arise from other parts of the urinary tract (e.g., renal pelvis, ureter, urethra).

Current first-line therapy for metastatic urothelial cancer is chemotherapy for those who are fit, and no standard second-line treatment has been shown to prolong survival. However, immunotherapy shows promise, Dr. Grivas says.

“Results from early clinical trials in urothelial cancer are very encouraging,” he says. “They show rapid and durable response rates in a proportion of patients and delay of cancer growth with very promising one-year overall survival rates.” Cleveland Clinic is currently involved with several trials of immunotherapeutic agents and strategies.

The two trials underway aim to validate encouraging preliminary results in a larger patient population.

“These two trials may help answer the question of who may benefit more from the immunotherapeutic approach, which could inform patient selection in the future,” says Dr. Grivas. Since neither trial requires a certain degree of expression of a particular biological marker (e.g., PDL1), they are available to a larger number of patients.

Trial MRK1814

Trial MRK1814 is for patients with metastatic, recurrent or locally advanced (unresectable) urothelial cancer who have received one or two prior chemotherapies. (For the purposes of eligibility, primary chemoradiation for bladder preservation is not considered to be a prior line of systemic therapy.).

“The design (of MRK1814) is simple: It compares immunotherapy to chemotherapy. There is no placebo; everyone gets active treatment,” says Dr. Grivas.

The trial’s primary objective is to evaluate the overall survival of patients with metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy. Patients are treated with the immunotherapeutic agent pembrolizumab (MK-3475) or chemotherapy (paclitaxel or docetaxel), given every three weeks. The trial does not require a new biopsy; it uses patient tissue from prior surgery or prior biopsy to determine eligibility. Investigators expect to complete accrual in the next few months.

Trial MRK2184

A second trial, MRK2814, is an opportunity for patients with metastatic, recurrent or unresectable urothelial cancer who are not candidates to receive cisplatin-based chemotherapy. It has some similarities with MRK1814 and uses the same immunotherapeutic agent, pembrolizumab (MK-3475), and there is no placebo; everyone gets immunotherapy every three weeks. Patients may have had recurrence more than a year after completion of peri-operative (neo-adjuvant or adjuvant) chemotherapy. Patients do not require a new biopsy as long as no interval treatment has occurred between prior tissue acquisition and trial screening.

Both trials allow Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2, and require adequate organ function and measurable disease, according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria.

“In the future, we anticipate better ways to select patients, as well as more information about the optimal combinations and/or sequencing of immunotherapy with other cancer treatments,” says Dr. Grivas.

Both trials are multi-centered, and Cleveland Clinic is one of the sites.

Cleveland Clinic is only a few weeks from opening another immunotherapy study in the adjuvant (i.e., after cystectomy) setting in patients with urothelial bladder cancer, with or without prior neoadjuvant chemotherapy. Researchers also are working toward opening a trial of immunotherapy in patients with BCG-refractory, high-risk, non-muscle-invasive bladder cancer who either refuse or cannot tolerate cystectomy.

“We have a great infrastructure for conducting trials with tight regulatory oversight, and we have a multidisciplinary team with high expertise and experience in clinical trials,” says Dr. Grivas.

To Refer Candidates

If you have patients who might be candidates for any of these clinical trials, please contact one of our research nurses: Allison Tyler, RN,BSN, at 216.445.0861 or tylera2@ccf.org; or Pam Profusek, RN, MS, at 216.445.1690 or profusp@ccf.org.