Looking Toward Combination Therapies in Metastatic Bladder Cancer

Patients with metastatic bladder cancer have more treatment options than ever before. In the past few years, the approvals of immunotherapies and targeted therapies have contributed to new research and better response rates, explained Dr. Daniel P. Petrylak.

Researchers now want to see how well these therapies work in combination with one another. One of those promising combinations is a regimen of Padcev (enfortumab vedotin-ejfv), a type of targeted therapy called an antibody-drug conjugate, with Keytruda (pembrolizumab), a type of immunotherapy. In a clinical trial, the combination helped shrink tumors in 90% of patients.

“This is an exciting combination, but the data are still evolving,” Petrylak, a professor of medicine and urology at Yale Cancer Center, said in an interview with OncLive®, a sister publication of CURE®. “Certainly, this response rate with a high CR (complete response) rate of about 14% is impressive. We need a clinical trial in order to identify whether this is going to be equivalent to or better than cisplatin-based chemotherapy.”

Padcev, which targets Nectin-4, a protein expressed in more than 80% of bladder cancers, received accelerated approval from the Food and Drug Administration (FDA) in December 2019. The medication is meant to be used for the treatment of adult patients with locally advanced or metastatic bladder cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy.

Immunotherapy medications that can be used as initial treatment options for patients not eligible to receive cisplatin-based chemotherapy and who are PD-L1-positive include Keytruda and Tecentriq (atezolizumab). “As frontline therapy, atezolizumab was shown to be better than chemotherapy in (a) randomized trial. Now, that is our standard first-line treatment,” he said.

If disease progresses after initial treatment, patients with metastatic disease can turn to medications called checkpoint inhibitors as a second-line therapy. In addition to Keytruda and Tecentriq, three other checkpoint inhibitors are FDA-approved — Imfinzi (durvalumab), Opdivo (nivolumab) and Bavencio (avelumab). “There is no way to distinguish between these except for the fact that only pembrolizumab has positive phase 3 data,” Petrylak said.

Balversa (erdafitinib) is another approved targeted medication, which targets FGFR3/FGFR2 gene mutations. FGFR genes are mutated in 20% to 60% of urothelial carcinomas — the most common bladder cancers.

Petrylak advised that patients receive next generation sequencing early in their metastatic disease course to check for mutations which can help guide treatment regimens. “We have multiple options which can be used, but the question is what is the optimal sequence? Of course, should we start thinking about erdafitinib combined with enfortumab vedotin in an FGFR-positive patient,” he said.

However, he added, “We’ve got a lot of work to do as we have yet to hit the ball out of the park.”