As EV + Pembrolizumab Moves Earlier In Bladder Cancer, New Questions Emerge About When To Stop Treatment

The success of enfortumab vedotin plus pembrolizumab in muscle-invasive bladder cancer (MIBC) is beginning to shift the conversation about how much treatment patients ultimately need.

“One important controversy that comes from the improvements and outcomes we’re seeing with enfortumab vedotin in the perioperative setting is the question of, how much treatment do people need to have?” Dr. Elizabeth Wulff, a medical oncologist at the University of Kansas Health System, notes.

As the antibody-drug conjugate and checkpoint inhibitor combination moves earlier into the treatment of muscle-invasive disease, physicians are beginning to face a new set of clinical decisions, including how much therapy to give, how long to continue it, and whether some patients may ultimately need less treatment than initially planned.

Strong Responses Raise New Questions

Results from the phase III KEYNOTE-B15/EV-304 trial suggest perioperative enfortumab vedotin plus pembrolizumab significantly improves outcomes compared with standard gemcitabine plus cisplatin followed by radical cystectomy, including improvements in event-free survival, overall survival, and pathologic complete response rates.

The strength of these responses has been striking. In many cases, the combination appears to produce deep tumor responses prior to surgery, reinforcing the powerful activity of the ADC-immunotherapy combination.

But with stronger therapeutic options comes the new dilemma about when to stop treatment. Investigators have observed that many patients in perioperative trials do not complete the entire postoperative portion of therapy, yet outcomes remain strong.

“We know that … many patients don’t complete the entire adjuvant or post-operative portion of this treatment,” Dr. Wulff says. “And that suggests that, even in spite of the finding that many patients don’t complete the postoperative portion, we have seen these beautiful improvements in outcomes.”

For now, clinicians are encouraged to follow the treatment approach used in the clinical trials. But the experience is prompting new discussions about whether future studies might explore ways to reduce treatment exposure while maintaining the same benefit.

“Important work is going to need to be done in determining — either on a molecular basis, or even on just a toxicity basis — how we might be able to expose patients to less of these treatments and still get the same outcome,” Dr. Wulff adds.

Such research could eventually help oncologists tailor therapy more precisely, identifying patients who may benefit from shorter treatment durations or fewer doses once an adequate response has been achieved.

A Shifting Treatment Approach For MIBC

For decades, treatment strategies in MIBC have focused on improving outcomes by intensifying therapy. Now, the focus could shift to maintaining outcomes while minimizing unnecessary treatment.

Historically, radical cystectomy has remained the cornerstone of curative therapy for MIBC. But if targeted therapy continues to produce strong responses earlier in the disease course, investigators may begin exploring whether some patients could ultimately avoid bladder removal altogether.

“Patients on these trials largely did get to radical cystectomy as intended — it was essentially equal in both arms,” Dr. Wulff says.

Yet the long-term goal, she notes, may extend beyond simply curing the cancer. “When they are hopefully left without disease after this perioperative treatment and surgery, then what is the quality of their survivorship? How are they living? … Now that we have demonstrated benefit from enfortumab vedotin and pembrolizumab, then who really needs to have cystectomy. Who can keep their bladder? Those are some of the most important questions,” Dr. Wulff adds.

Additionally, while this regimen is one that could be used for a range of patients, Dr. Wulff points out that some, such as those with severe neuropathy or significant autoimmune disease, may not be appropriate candidates for the combination.