A new combination of cancer medications appears to extend overall survival in patients with advanced bladder cancer more than the chemotherapies currently used as the standard of care.
The research, being presented Sunday at this year’s European Society for Medical Oncology Congress in Madrid, suggests that a combination of the antibody drug enfortumab vedotin and the immunotherapy pembrolizumab, administered through IV infusions, cut the risk of disease progression or death by 55% in patients with advanced bladder cancer who hadn’t been treated before and whose cancer spread to other parts of the body — extending overall survival by a median of 31.5 months versus 16.1 months with standard chemotherapy.
This is one of several new studies exploring ways to improve how bladder cancer is treated.
“The problem with chemotherapy is although it works quite well initially, resistance occurs quickly, and the median survival for metastatic bladder cancer has been about a year,” said Dr. Thomas Powles, a professor of urology cancer at the University of London and director of the Barts Cancer Centre in the United Kingdom, who presented the research this weekend.
“What this study showed is, we did a big, randomized Phase 3 study where we compared a new treatment — two new drugs — with standard chemotherapy,” Powles said. “And in this randomized trial, when you gave those two drugs together, you reduced the risk of death for this cancer by over 50%. So, you’ve doubled survival, with patients living twice as long, and we’ve got long-term durable remission.”
Globally, bladder cancer is the sixth most common cancer in men and the disease kills about 200,000 people every year, many of whom die from advanced disease that has spread beyond the bladder. Treatment options typically depend on the stage of disease but may include surgery or common chemotherapy drugs, such as carboplatin or cisplatin.
And the new research findings — funded by the US drugmakers Seagen, Inc., Astellas Pharma and Merck & Co. — come at a time when the United States is experiencing a significant shortage of platinum-based chemotherapy drugs, including carboplatin and cisplatin.
The Phase 3 trial included 886 patients who were randomly assigned to receive either three-week cycles of the enfortumab vedotin and pembrolizumab combination, administered as IV infusions, or a chemotherapy treatment called gemcitabine with cisplatin or carboplatin.
The trial found that the new drug combination had a similar safety profile as the chemotherapies, with adverse reactions such as skin rashes or hyperglycemia occurring in 55.9% of patients taking the combination compared with 69.5% of those taking platinum chemotherapy.
“We only got the data three weeks ago, so it’s happening just very, very quickly,” Powles said, adding the next step for the research team is to submit their data to the US Food and Drug Administration and other agencies around the world. The data has not yet been published in a peer-reviewed journal.
“Because it’s so conclusive, we don’t need to do a larger study. We now need to transform this into patients quickly, so we need to go to the agencies — the FDA in the United States, the EMA in Europe and around the world,” he said. “We need to get this approved quickly.”
The research findings by Powles and his colleagues have the potential to change the standard of care for advanced bladder cancer, said Dr. Toni Choueiri, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, who was not involved in the new paper but is attending the ESMO Congress in Madrid.
“Ever since I was in med school, a metastatic bladder cancer treatment was gemcitabine and platinum. Gemcis or GemCarbo, we called it. Since the late ’90s, nothing beat that in frontline. But now, the combination of pembrolizumab, an immunotherapy checkpoint blocker, and enfortumab vedotin, an antibody-drug conjugate, beat — hands down — the old regimen that we have had since the late 1990s,” Choueiri said. “I think this is going to become a new standard.”
Some other new studies have evaluated new ways to treat a different set of advanced bladder cancer patients — those whose disease continued to progress after trying one or two previous treatments.
Another Phase 3 trial found that a targeted therapy was effective for patients with advanced or metastatic urothelial cancer who had specific gene mutations. Urothelial cancer is a type of bladder cancer that begins in the urothelial cells, which line the inside of the bladder. Almost all bladder cancers are urothelial carcinomas.
The study, published Saturday in the New England Journal of Medicine, compared overall survival among 136 patients who were given the anti-cancer medication erdafitinib as an oral pill versus 130 who were given standard chemotherapy. The patients, whose cancer had previously been treated with other types of therapy, were followed for a median of 15.9 months.
“Cisplatin-based chemotherapy is the standard treatment for newly diagnosed advanced and metastatic urothelial cancer. However, more than 50% of patients with metastatic urothelial carcinoma are ineligible for cisplatin treatment, and those who receive chemotherapy typically have progression within a few months,” the researchers, from the University of Texas MD Anderson Cancer Center and other US institutions, wrote in the study. The Phase 3 study was funded by drugmaker Janssen.
“Erdafitinib therapy resulted in significantly longer median overall survival than chemotherapy among patients with advanced or metastatic urothelial carcinoma,” the researchers wrote, finding that median overall survival was 12.1 months among patients taking erdafitinib therapy versus 7.8 months among those taking chemotherapy.
In 2019, the US Food and Drug Administration granted accelerated approval to erdafitinib for patients with locally advanced or metastatic bladder cancer who have specific gene mutations and have seen their cancer progress during or following chemotherapy. The drug became the first therapy targeting a genetic alteration to be approved by the FDA to treat patients with the most common type of bladder cancer, metastatic urothelial cancer.
Erdafitinib, a kinase inhibitor drug, works by blocking the action of the protein that signals cancer cells to multiply, essentially slowing or halting the spread of cancer cells, according to the National Library of Medicine. The incidence of treatment-related adverse events in the Phase 3 trial was similar among patients taking erdafitinib versus those taking chemotherapy, but events that led to death were less common with erdafitinib than with chemotherapy, occurring in 0.7% of erdafitinib patients versus 5.4% of chemotherapy patients.
‘A new standard approach’
Another study, published Sunday in the New England Journal of Medicine and being presented at the ESMO Congress, found that using chemotherapy in combination with immunotherapy drugs resulted in improved survival among patients with previously untreated advanced bladder cancer, compared with just chemotherapy alone.
That Phase 3 trial was conducted among 608 patients with advanced bladder cancer that’s spreading or not able to be surgically removed and hadn’t been treated before. Half of them were given intravenous infusions of the immunotherapy drug nivolumab plus the chemotherapies gemcitabine and cisplatin every three weeks for up to six cycles, followed by nivolumab every four weeks for a maximum of two years. The other half were given gemcitabine-cisplatin alone every three weeks for up to six cycles. The researchers found that grade 3 or higher adverse events — such as anemia or urinary tract infections seen in a Phase 2 trial — occurred in 61.8% of patients receiving the nivolumab combination versus 51.7% of those taking chemotherapy.
The researchers, from Mount Sinai and other international institutions, found that overall survival was a median of 21.7 months with the nivolumab combination therapy compared with 18.9 months with gemcitabine-cisplatin alone. The trial was funded by drugmaker Bristol Myers Squibb in collaboration with Ono Pharmaceutical Company.
“No new agent when added to first-line standard-of-care cisplatin-based chemotherapy has improved overall survival in metastatic urothelial carcinoma until now,” study author Dr. Matthew Galsky, co-director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute at Mount Sinai, said in a news release. “These results support nivolumab plus cisplatin-based chemo as a new standard approach for the treatment of metastatic urothelial cancer.”