Treatment with the FGFR inhibitor erdafitinib in patients with metastatic bladder cancers marked by mutations in the FGFR3 gene resulted in a 40 percent overall response rate (ORR) and was well-tolerated, according to an international Phase II trial led by The University of Texas MD Anderson Cancer Center.

The trial results, published in the New England Journal of Medicine, led to approval of erdafitinib in April by the Food and Drug Administration (FDA), making it the first targeted therapy approved for treating patients with advanced bladder cancer.

The oral targeted therapy also achieved a 59 percent ORR in patients for whom immunotherapy had previously failed, indicating this may be a viable option for these patients in need of alternative treatments.

"Patients have been in desperate need for alternative strategies, especially when a large number of patients cannot tolerate the current standards of care," said principal investigator, Prof Arlene Siefker-Radtke. "We were very gratified to see a 40 percent response rate in patients treated on this clinical trial. Not only did it work well in patients with lymph node metastases, but also in patients with high volume and very aggressive disease."

"Standard of care for these cancers is cisplatin-based chemotherapy, an aggressive regimen with significant side effects, and this has largely remained unchanged for several decades," explained Prof Siefker-Radtke. "Recently, immune checkpoint inhibitors have been approved for the treatment of advanced bladder cancer, but only 15 to 20 percent of patients see any benefit from these therapies."

"I noticed that I wasn't seeing a great response to immune checkpoint inhibitors in my patients with FGFR3 mutations, which led me to wonder whether this would reflect a group of patients with an unmet need," said Prof Siefker-Radtke. "When we heard about novel agents targeting this pathway, I became quite interested in exploring them in our bladder cancer patients."

Mutations in FGFR3 are present in approximately 15 to 20 percent of patients with metastatic bladder cancer and up to 35 percent of patients with other urothelial cancers, such as those of the renal pelvis and ureter.

The international trial enrolled 99 patients with metastatic or surgically unresectable urothelial cancer and verified alterations in the FGFR3 gene.

Three patients in the trial had complete responses, or tumour disappearance, and 39 percent had stable disease.

Median PFS was 5.5 months and median OS was 13.8 months.

Among 22 patients previously treated with immunotherapy, 59 percent (13) had a partial or complete response.

"With a response rate of over 50 percent in patients previously treated with immunotherapy, the data suggest treatment with erdafitinib may be preferential for patients with FGFR3 mutations. However, this is preliminary evidence, so we need additional data to confirm this finding," said Prof Siefker-Radtke.

All patients on the trial reported side effects from the therapy, with 21 percent discontinuing treatment due to adverse events and 67 percent reporting grade 3 or 4 adverse events.

The most common treatment-related side effects were stomatitis (9 percent), nail dystrophy (6 percent), and hand-foot syndrome (5 percent).

Based on the results of the trial, the FDA granted a breakthrough therapy designation to erdafitinib in 2018 and approved the drug in April 2019 for treating patients with locally advanced or metastatic urothelial cancers with mutations in the FGFR2 or FGFR3 genes.

"With the recent approval of erdafitinib for the treatment of patients with FGFR3-mutant urothelial cancers, we now have an additional agent to add to our armamentarium," stated Prof Siefker-Radtke. "My hope is we will be able to add this to our treatment strategy, learn how it combines with immunotherapy and how we can use the effects of this drug to improve the survival for all of our bladder cancer patients."

A Phase III trial currently is underway to evaluate the efficacy of erdafitinib relative to chemotherapy or the checkpoint blockade inhibitor pembrolizumab in patients with metastatic urothelial cancer and FGFR3 mutations.

Source: University of Texas MD Anderson Cancer Center