Evolution and Revolution in Bladder Cancer Treatment

Stacey Reeves’ cancer journey only began a few years ago, but it has been filled with twists and turns.

A 54-year-old South Carolina resident and a social worker for the U.S. Department of Veterans Affairs, Reeves was diagnosed with bladder cancer three years ago. After experiencing disease recurrence following treatment via surgery, chemotherapy and immunotherapy, she has had no evidence of disease (NED) for more than a year since beginning treatment with Padcev (enfortumab vedotin-ejfv), an antibody-drug conjugate that has been making waves in the oncology world.

“Since probably March 2023, every other week, I do my Padcev infusion,” she says. “I had my first PET [positron emission tomography] scan in April 2023 with Padcev, and I had a total response, nothing lit up in the PET scan. [I] did my next PET scan, [and there] was no evidence of disease. And then I just had my third one to mark my 12-month anniversary of [having] NED.”

“[Padcev] really made an evolution, if you will, in the urothelial or bladder cancer world,” Dr. Yousef Zakharia, co-leader of the Genitourinary Oncology Program at the University of Iowa in Iowa City, says.

Attendees at the European Society for Medical Oncology Congress 2023 in Madrid gave a standing ovation to the results of the EV-302 clinical trial comparing the safety and efficacy of Padcev and Keytruda (pembrolizumab) among patients with previously untreated locally advanced or meta- static urothelial carcinoma versus chemotherapy, which had been the standard of care for approximately 30 years, Zakharia says.

Trial results later published in The New England Journal of Medicine showed the median overall survival (the time a patient lives regardless of disease status) via treatment with Padcev and Keytruda, an immunotherapy (which helps the body’s immune system fight cancer cells), to be 31.5 months, nearly double that of the 16.1-month overall survival conferred by chemotherapy.

The median progression- free survival (the time a patient lives without their disease worsening) was 12.5 months among patients treated with Padcev and Keytruda versus 6.3 months among those treated with chemotherapy, and the overall response rate (patients whose disease responded partially or completely to treatment) was 67.7% with Padcev and Keytruda and 44.4% with chemotherapy, with complete response (NED) rates of 29.1% and 12.5%, respectively.

“This drug is so effective compared with chemotherapy that we used to have before,” Dr. Bamidele Adesunloye, medical oncologist at City of Hope Atlanta in Newnan, Georgia, says. “Our gold standard used to be cisplatin [platinum-based chemotherapy]. And when you look at the antibody-drug conjugates, specifically when you combine it with immunotherapy, which is Keytruda, [in] first-line [treatment of] bladder cancer, you get almost 70% response rates.”

The Food and Drug Administration (FDA) approved the combination of Padcev and Keytruda for patients with locally advanced or metastatic bladder cancer in December 2023, less than a year after the agency granted the drug combination accelerated approval for the treatment of patients who were ineligible for treatment with cisplatin-based chemotherapy.

“It was a eureka moment for me,” Adesunloye says of the addition of this treatment to providers’ tool kits. “Because you look at the fact that most of these patients, when they present to us, are very, very sick. They have multiple metastatic sites of their disease, and bladder cancer is an aggressive cancer that can progress rapidly. Most of the time, your first- line therapy may be your last line of therapy. So you had better make sure you have a very good drug as your first line, because if you don’t have a good drug to control the disease, you may never have another option again. … This really revolutionized the way we … look at bladder cancer.”

The FDA previously granted accelerated approval to Padcev in 2019 for the treatment of patients with locally advanced or metastatic urothelial cancer who received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant (presurgical)/adjuvant (postsurgical) locally advanced or metastatic setting based on the results of a phase 2 trial.

The drug then received a full approval in 2021 for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin-containing chemotherapy and had received at least one prior line of therapy.

A Targeted Chemotherapy

In traditional chemotherapy, “you put an IV [line] in the vein of the patient, you give the drug, and the platinum goes all over the body and kills cancer cells,” Dr. Terence Friedlander explains. Friedlander is a professor of medicine and Robert and Virginia O’Reilly Family Endowed Chair as well as chief of the Zuckerberg San Francisco General Hospital Division of Hematology/Oncology at the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco.

“While yes, it works in some patients — for example, patients who are about to have their bladder removed — giving platinum saves lives. It prevents recurrences that would otherwise happen, and in the metastatic setting, it can slow down the disease even if it doesn’t cure people. The big problem with platinum, beyond that it wasn’t a cure for every- body, was that it’s toxic, and the platinum deposits in multiple tissues in the body,” Friedlander says. “So what that means is people can get hearing loss from the platinum. They can get ringing in the ears: tinnitus. They can get taste changes; they can taste the metal molecules. It can damage the kidneys. It can damage the nerves, so the peripheral nerves can get numbness or tingling too.

“So it causes a lot of other shorter-term side effects like severe nausea. People feel ill when they take it. It runs them down; they have a lot of fatigue. They can have electrolyte problems; the salts in their blood can get out of whack. So it’s a really unsatisfying treatment, even though it works and has value.”

Antibody-drug conjugates such as Padcev or Trodelvy (sacituzumab govitecan), which received accelerated approval from the FDA in 2021 for the treatment of locally advanced and metastatic urothelial cancer, are described by Zakharia as forms of “targeted chemotherapy.”

“It is an antibody that is directed toward certain receptors on the cancer cells,” he says. “In bladder cancer more specifically, we have NECTIN4 and TROP2. Both of them have antibody-drug conjugates manufactured toward those and are specific toward those receptors. And basically, this antibody is attached to a payload, which is a very effective chemotherapy.

“And the way it works [is that] it takes that chemotherapy, carries it directly to the cancer cells, and it gets internalized within the cancer cells. And basically that payload or chemotherapy gets integrated within the microtubules and starts disrupting the cell growth, and that results in cell killing. In other words, it is basically carrying the cytotoxic material directly and specifically to the cancer cells with the hope to save the normal cells from the toxic side effects associated with that if they do not have that specific receptor expressed.”

The targeted nature of antibody- drug conjugates is “refreshing” to Patricia Gilleland, 77, who lives in Georgia and received a diagnosis of bladder cancer in April 2022, joining a number of other issues she is faced with.

“I’ve got a tumor in my brain, which is an acoustic neuroma that is benign. I have a little spot on my lung, which right now is stable. I have a prolapsed vagina, which gives me hell, but you know, I’m thankful every day I get up,” she says. “I’m grateful.”

Gilleland, who walks with the assistance of a cane and has experienced hearing loss, underwent surgery in 2022 to remove her bladder and uterus as well as part of her vagina and began treatment with Padcev about a month after her surgery.

“I don’t want to do any more damage to the rest of my body and cells,” she says. “I try not to read a lot of articles about the side effects and what’s going to happen later on. You know, I just live in the moment. I like that. I want [the treatment] to help the good cells and destroy the bad cells.”

A patient of Adesunloye’s at City of Hope Atlanta, she says the only side effect she’s experienced is fatigue.

“When I go to the cancer center, I forget I’m sick,” she says. “I feel better. I feel well. And I feel like a lot of it has to do with my medication.”

‘I Knew Something Was Wrong’

Reeves received a diagnosis of stage 3 high-grade urothelial cancer in June 2021 after questions about blood in her urine led to the discovery of a mass in her left ureter tube. Surgery removed the tumor, but there were soon signs of trouble.

“I went in for my three-month cystoscopy for follow-up, and I would say probably a month before that, I knew something was wrong,” Reeves says. “I had called my surgeon, asked for some other scan or something, and it just didn’t feel right. [I] felt like I had when I had been diagnosed with cancer.”

A new tumor was found in her bladder, and Reeves underwent four months of treatment with the commonly used chemotherapy pair of cisplatin and gemcitabine.

“I had a lot of side effects from that [and] struggled a lot through that chemotherapy,” she says. “All your typical [side effects], like what you see in the movies and TV: losing hair, getting sick, vomiting, weight loss, fatigue, all those sorts of things.”

Surgery followed in June 2022. What physicians had thought was a thickening of her bladder wall turned out to be a tumor that had spread to her pelvic wall, vaginal wall and uterus, with a growth also found in her appendix, necessitating a total hysterectomy as well as removal of much of the vaginal and pelvic walls, bladder and appendix.

Reeves began treatment with the immunotherapy Opdivo (nivolumab) in August 2022. Following an infusion in November, she began experiencing severe diarrhea due to a case of colitis. She stopped her treatment with Opdivo, and a PET scan to assess her colitis showed that her cancer had metastasized again, this time to her lymph nodes.

She started treatment with Padcev, and after initially experiencing severe side effects — “I don’t think I got out of bed for five days. I could not stop throwing up,” she says — she is now on a modified dosing schedule and has become a self-described “huge fan” of the treatment.

‘We Are Far Away From Curing Everybody’

Research continues into antibody-drug conjugates for the treatment of bladder cancer, with Zakharia saying that the Padcev-Keytruda combination is currently being studied in the neoadjuvant setting, and Friedlander saying phase 3 trial data are expected that could convert Trodelvy’s accelerated approval to a full approval. Meanwhile, HER2 receptor-targeting antibody-drug conjugates Enhertu (trastuzumab deruxtecan) and disitamab vedotin are also being studied in bladder cancer.

Despite recent advancements, unmet needs persist.

“Certainly, there are a significant number of patients who [were] not responding,” Zakharia says. “[For] about 30%, 40% of patients, we’re not shrinking their tumors, at least based on the reported clinical trial [findings, and so] … there is an unmet need of curing every patient. Certainly we are heading [in] that direction, but we are far away from curing everybody.”

Side effects of antibody-drug conjugates, Adesunloye said, can include motor and sensory neuropathy, hyper- glycemia, dry eye, blurry vision and rash.

Reeves lost her hair during her time on Padcev and has experienced severe dry eye and inflammation of the corneas, in addition to cataracts, which she attributed to treatment with steroids, as well as fatigue, rash and crepey skin.

“But it’s better than having metastatic cancer and all the side effects that I’ve had from the other stuff,” she says. “It’s manageable, it’s tolerable. But [if you experience side effects], let your care team know what’s going on.”

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