Investigational Therapy Shows Promise in Advanced Bladder Cancer

Patients with advanced urothelial carcinoma — the most common type of bladder cancer — could soon have new hope in an investigational therapy currently being studied in clinical trial.

Enfortumab vedotin, an antibody-drug conjugate being manufactured by Astellas and Seattle Genetics, is being examined for its efficacy in treating patients with locally advanced or metastatic disease who have already received platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor. “There is an antibody that helps direct a drug to cancers, particularly those that express Nectin-4 (a cell surface protein), and urothelial cancers are one that are very high expressers of Nectin-4,” Andrew P. Krivoshik, M.D., Ph.D., senior vice president and oncology therapeutic area head at Astellas, said in an interview with CURE. “The antibody conjugate goes to the part of the body that has the target so that the drug is delivered very selectively to those areas.”

A phase 2 trial of enfortumab vedotin split patients into two groups — the second group is still enrolling patients for participation. In the first set, comprised of 128 patients, researchers saw a 44% objective response rate, meaning the cancer shrunk or disappeared in these patients — all of whom received an anti–PD-1/PD-L1 drug and platinum-containing chemotherapy. The second group will include patients who were treated with a PD-1/PD-L1 inhibitor but not with platinum-based chemotherapy.

“Historically, in that patient population, relative to chemotherapy, the response rate has only been 10% to 13%,” Krivoshik said. “The fact that there is such a large percentage that are seen as responsive in this patient population that is seen as a highly unmet medical need is very exciting.”

A phase 1 version of the trial showed a similar response to enfortumab vedotin, which led to a breakthrough therapy designation by the Food and Drug Administration (FDA) in March 2018. Seattle Genetics and Astellas plan to submit a biologics license application to the FDA by the end of this year to try to make enfortumab vedotin available to patients sooner.

“As the landscape of treatment paradigms is sort of evolving, it’s not clear in terms of will those patients have different response rates. Will they have different safety profiles?” Krivoshik said. “So that second cohort really helps confirm our understanding of the overall patient population that may potentially benefit from enfortumab vedotin.”

Similarly, a global phase 3 clinical trial of enfortumab vedotin is ongoing and enrolling patients to serve as a confirmatory trial. Researchers hope to enroll an estimated 550 patients and examine overall survival. Patients who want to learn more can visit clinicaltrials.gov and speak with their physician to see if a clinical trial is right for them.

The most common treatment-related side effects experienced by patients on the phase 2 trial included fatigue, alopecia, decreased appetite, rash and peripheral neuropathy.

“Despite some of the recent approvals, particularly with the checkpoint inhibitors for immunotherapy for locally advanced or metastatic urothelial cancer, there is still a high unmet need, particularly upon those patients who have progressed after initial therapy,” Krivoshik said. “What this 44% response rate sort of helps to put into context is that we have a drug, enfortumab vedotin, that may be able to help patients whose cancer progresses following the treatment of standard chemotherapy or immunotherapy.”