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Groundbreaking Trial Results Expand Treatment Options for Some People with Bladder Cancer

, by Shana Spindler

A female patient wearing a headscarf sits next to a female physician. The physician is showing the patient a wireless tablet.

Credit: iStock

UPDATE: On December 15, 2023, the Food and Drug Administration (FDA) approved enfortumab vedotin (Padcev) in combination with pembrolizumab (Keytruda) for people with bladder cancer that has spread to other parts of the body or cannot be removed surgically.

The approval was based on the results of the EV-302 trial, which showed that the enfortumab-pembrolizumab combination doubled how long people with advanced bladder cancer survived compared with people treated with standard chemotherapy. Details on the trial results are discussed in the story below.

For the first time in decades, people with advanced bladder cancer have more effective treatment options, according to results of two large clinical trials. One treatment—the combination of enfortumab vedotin (Padcev) and the immunotherapy drug pembrolizumab (Keytruda)—proved to be particularly powerful.

The findings mark a pivotal moment following years of little progress, according to several leading bladder cancer experts. Both studies included people whose bladder cancer had spread to other parts of the body or could not be removed by surgery, and both studies involved immunotherapy drugs.

In the first trial, known as CheckMate-901, patients received standard chemotherapy for advanced bladder cancer, either alone or in combination with the immunotherapy drug nivolumab (Opdivo), as initial treatment for advanced bladder cancer.

The second trial, called EV-302, compared the enfortumabpembrolizumab combination with a standard chemotherapy regimen. Enfortumab is a type of treatment known as an antibodydrug conjugate.

In both trials, people treated with the new combination treatment lived longer than those who received chemotherapy—a never-before-seen improvement over the standard initial treatments for advanced bladder cancer.

Researchers reported the results of both trials on October 22 at the European Society for Medical Oncology (ESMO) annual meeting in Madrid.

It was the improvement in survival in people treated with the enfortumab and pembrolizumab combo—a doubling compared with chemotherapy—that received the greatest praise, even drawing a standing ovation during the presentation of the results at the ESMO meeting.

Discovering two treatments that improve survival for people with advanced bladder cancer “is monumental in our field,” said Andrea Apolo, M.D., of NCI’s Genitourinary Malignancies Branch.

After many failed attempts to improve upon chemotherapy, Dr. Apolo said, with the results of both trials “the future looks bright for our patients.”

Long-awaited improvements in bladder cancer treatment

Despite the advent of many new immunotherapies and targeted drugs for cancer in the last decade, chemotherapy regimens that include platinum drugs (e.g., cisplatin) have been the standard initial treatment for people diagnosed with advanced bladder cancer for decades. However, most patients experience a worsening of their cancer during or soon after treatment.

Recently, evidence has begun to suggest that immunotherapy may have a role in treating this disease. In 2020, for example, researchers reported that giving avelumab (Bavencio) right after chemotherapy improved overall survival and has become the new standard treatment for bladder cancer.

And a few years before that, the Food and Drug Administration (FDA) granted accelerated approval to nivolumab for treating advanced bladder cancer that had worsened following treatment with chemotherapy.

But, despite multiple efforts to improve the initial treatments for advanced disease, no treatments tested in previous clinical trials have increased how long patients lived compared with chemotherapy alone, said Michiel S. van der Heijden, M.D., Ph.D., of the Netherlands Cancer Institute, who led CheckMate-901 and participated as an investigator in the EV-302 trial.

In those previous trials, researchers compared an array of immunotherapy combinations with several different drugs with chemotherapy alone, but none proved to be more effective.

Now, with the EV-302 and CheckMate-901 trials, researchers used some of the lessons learned from those earlier studies in the hope of finding the right drug combination to help their patients live longer.

Antibody combination doubles survival without chemotherapy

“It’s a big day for us in bladder cancer,” said EV-302 lead investigator Thomas Powles, M.D., of the Barts Cancer Institute Queen Mary University of London, as he began his ESMO presentation of the trial’s results.

Enfortumab, a targeted therapy that uses an antibody to carry a deadly payload into bladder cancer cells, received FDA accelerated approval in 2019 to treat bladder cancer that has worsened despite treatment with other therapies. In 2023, another accelerated approval of the drug was granted for treatment of patients with advanced bladder cancer who are unable to receive cisplatin-containing chemotherapy.

Both approvals were based on early-phase clinical trials showing that cancers stopped growing or disappeared entirely in some people who received enfortumab.

In the EV-302 trial, funded by Astellas Pharma and Seagen, nearly 900 people with advanced bladder cancer were randomly assigned to receive enfortumab plus pembrolizumab or chemotherapy as an initial treatment. People in the chemotherapy group received a maximum of six infusions of chemotherapy. About a third of those patients also received avelumab, but it was not required as part of the trial.

Overall, tumors shrank or stopped growing in about 67% of participants treated with enfortumab plus pembrolizumab, compared with 44% of those who received platinum-based chemotherapy.

In addition, the cancer disappeared entirely, known as a complete response, in almost 30% of participants in the enfortumab-plus-pembrolizumab group compared with about 12% in the chemotherapy group.

Having a complete response in nearly one-third of patients “is not something we’ve seen before,” Dr. Powles noted.

Most patients in each group experienced treatment-related side effects. The most common side effects in the enfortumab-plus-pembrolizumab group included skin reactions and pain or numbness in the hands and feet. Fatigue, nausea, and a decrease in red and white blood cells were more common in those who received chemotherapy.

After following participants for a median of about a year and a half, Dr. Powles and his colleagues found that patients in the enfortumab-plus-pembrolizumab group lived nearly twice as long as those in the chemotherapy group: a median of 31 months versus 16 months.

Enough patients continued to respond to the new combination on the EV-302 trial that the median length of response could not be determined. At the longest assessment reported, more than 30 months out, about 40% of patients who received enfortumab plus pembrolizumab continued to respond to treatment. However, the patients will need to be followed longer, Dr. Apolo noted.

Before the EV-302 trial, no therapy had ever increased patient survival compared with chemotherapy as the initial treatment, Dr. Powles said.

“This is the first time we’ve achieved that goal,” he continued—at which point the ESMO audience erupted in applause.  

With nivolumab, improved survival, long remissions

In the CheckMate-901 study—funded by Bristol-Myers Squibb, the manufacturer of nivolumab—about 600 patients were randomly assigned to receive nivolumab plus chemotherapy (cisplatin and gemcitabine) or chemotherapy alone, as their initial treatment.

The addition of nivolumab extended the median amount of time participants lived to about 22 months, compared with 19 months in people treated with chemotherapy alone. Results from this trial were also published in the New England Journal of Medicine.

The median length of complete remission was about 3 years, triple the length of remission in those who received chemotherapy alone. And about one-fifth of those who received nivolumab remained in remission at the last assessment reported, nearly 5 years after beginning treatment.

A new standard of care raises important questions

Dr. Apolo called enfortumab plus pembrolizumab the new standard of care as the initial treatment of patients with advanced bladder cancer.

The combination led to the highest percentage of patients whose cancers shrank or stopped growing, she noted, and gave patients the best chance at living longer.

Enfortumab plus pembrolizumab “takes first place” as the best up-front treatment for the disease, she said.

“But,” Dr. Apolo added, “with new standards of care come questions and challenges.”

For example, she wondered what the order of treatments should be if a patient’s cancer stops responding to the enfortumabpembrolizumab combination and if there is a role for additional immunotherapy once people have completed treatment with enfortumab and pembrolizumab. Additional studies are needed to address these critical questions, Dr. Apolo said.

She also emphasized the importance of understanding why enfortumab and pembrolizumab work together so well in people with advanced bladder cancer, noting that a deeper knowledge about the biology could bring new advances and reveal ways to prevent resistance to treatment. 

And “we must discuss the cost,” Dr. Apolo said. Enfortumab and pembrolizumab are expensive, so it will be important to ensure that people who need the treatment can access it, she continued.

Nevertheless, she said, the results of these trials—particularly EV-302—have set a new standard. Enfortumab plus pembrolizumab “has raised the bar.”

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