MINNEAPOLIS -- A new era of systemic treatment for bladder cancer has arrived, a US Department of Veterans Affairs (VA) hematologist/oncologist told colleagues, and more changes await on the horizon.
“After a historically long dry spell, you're seeing novel drugs and combinations under investigation,” said Elizabeth Henry, MD, of Edward Hines, Jr. VA Hospital and Loyola University Medical Center in Chicago, Illinois, in a presentation at the annual meeting of the Association of VA Hematology/Oncology. “Our treatment paradigm will almost certainly continue to change.”
There’s a major need for new approaches in bladder cancer, Dr. Henry said. While the median survival for patients with metastatic disease treated has risen, it remains low at about 15 months. And, she said, the 5-year survival rate is about 15% with modern treatments.
Platinum-based chemotherapy is still the first-line treatment, she said, and cisplatin-based combos remain the standard. However, many patients are not eligible to take cisplatin because of factors such as reduced performance status, impaired renal function, peripheral neuropathy, hearing loss and heart failure. “Many patients have renal insufficiency and are platinum ineligible from the get-go,” Dr. Henry said.
In these patients, immune checkpoint inhibitors are an option, but research suggests they may lead to poorer survival in those with PDL1-low tumors. In 2018, the US Food and Drug Administration (FDA) advised their use as first-line treatment only in PDL1-high, cisplatin-ineligible patients or those who can’t undergo chemotherapy, she said.
As second-line therapy after platinum treatment, Dr. Henry said, several drugs targeting the PD1/PDL1 pathway are now FDA-approved with response rates at 15% to 25%; only 1 (pembrolizumab) has level 1 evidence from a phase 3 randomized clinical trial.
Single-agent chemotherapy is an option for patients who have worsened or cannot undergo treatment with immune checkpoint inhibitors. However, according to Dr. Henry, response rates are low (about 10%-15%) and there's no prospective or randomized control trial data showing a survival benefit.
What now? Targeted approaches are entering the picture. For example, fibroblast growth factor receptor inhibitors, which target a pathway that often mutates in bladder cancer. One drug, erdafitinib (Balversa), received FDA approval earlier this year based on a phase 2 trial data that showed an objective response rate (ORR) of 40%. Dr. Henry cautioned that unusual adverse effects can occur, including hyperphosphatemia (a disorder that boosts phosphate levels), ocular toxicity (which can lead to retinal detachment), and toxicity of the skin and hair.
“Patients need to be closely followed if they're starting this as a targeted drug,” Dr. Henry said.
Anti-Nectin-4 antibody drug conjugate, which targets urothelial carcinomas with uniformly high expression of the Nectin-4 cell surface marker, also is showing promise. Recent research suggests a “remarkable” ORR of 42% and nearly 8 months duration of response, she said.
Adverse effects include rash, peripheral neuropathy, and hyperglycemia. “Overall, this is thought to be a relatively well-tolerated therapy,” she said.
In terms of other advances, “we are moving closer to an era of molecular subtype-specific therapeutic strategies,” Dr. Henry said, and the National Comprehensive Cancer Network recommends early molecular testing in stage IIIB/IV urothelial cancer. “It can help facilitate treatment decisions and prevent delays in later lines of therapy, although we're still limited by development of individualized biomarker assays for specific drugs.”
