Check, Please! Checkpoint Inhibitors Show Promise in Bladder Cancer

Immunotherapies known as checkpoint inhibitors are so promising in bladder cancer that many patients want them as first treatments — before they’ve been proven in that setting.
BY ARLENE WEINTRAUB
PUBLISHED: SEPTEMBER 13, 2017
That presents a challenge, because it was not clear whether there was a survival benefit with immuno-oncology drugs compared with chemotherapy in second-line treatment until the results of the Keytruda trial came in, says Joaquim Bellmunt, M.D., Ph.D., associate professor at Harvard Medical School and director of the bladder cancer center at Dana-Farber Cancer Institute. Some disappointment came when the Keytruda and Tecentriq trials arrived at opposite conclusions on survival.

“Why one trial is positive and the other is negative is a big question,” Bellmunt says. Ongoing analyses are trying to determine whether trial design and patient selection are the reasons behind this lack of benefit for Tecentriq in the phase 3 trial. Another possibility is that drugs that block PD-1 versus PD-L1 may have different levels of effectiveness. 

EYEING COMBINATION STRATEGIES 

That’s not the only area of research when it comes to the best use of the newer treatments for bladder cancer. Several trials are underway, not only comparing immuno-oncology treatments with chemotherapy for firstline treatment, but also testing whether giving the two treatments together might be more effective than either by itself. Combining Keytruda with chemotherapy is already approved for treating lung cancer, for example, and the drug is now being combined with gemcitabine and cisplatin in a trial of bladder cancer patients who have not undergone previous systemic chemotherapy. 

A trial of Imfinzi combined with radiation therapy in bladder cancer patients is being planned, and a similar study will be conducted that combines Keytruda and radiotherapy. In addition, that and another upcoming trial are combining Imfinzi with tremelimumab, an experimental immunotherapy that blocks a different checkpoint called CTLA-4. This combination recently produced disappointing results in a lung cancer trial, failing to improve progression-free survival when compared with chemotherapy, but oncologists who treat patients with bladder cancer still hold out hope for such immuno-oncology cocktails. “We’re looking to improve outcomes by combining immunotherapeutic agents,” Bellmunt says. 
One closely watched trial combines Keytruda with the targeted drug epacadostat, an experimental compound that blocks an enzyme called IDO1. The enzyme suppresses the immune system by blocking the activation of certain T cells, which in turn allows tumor growth. A small trial presented at a meeting in June showed that, in 40 patients, the Keytruda/epacadostat combination produced an objective response rate of 35 percent. The study is ongoing, and a phase 3 trial is also planned. 

“There’s a keen interest in combining checkpoint inhibitors with something else to help the immune system work better,” Plimack says. Combination approaches could help two categories of patients: those who haven’t yet been treated with immunotherapy, and those who have but who have become resistant to it. Imfinzi is now being tested in combination with several different types of drugs, including Lynparza (olaparib), which inhibits a tumor-promoting enzyme called PARP, and AZD4547, an experimental compound that inhibits the activity of fibroblast growth factor receptor (FGFR) proteins that would otherwise help drive bladder cancer. 


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