Patients with advanced or metastatic urothelial carcinoma are showing some benefit from a tyrosine kinase inhibitor named after Erda, the Norse goddess of the Earth. Erdafitinib is a fibroblast growth factor receptor (FGFR) inhibitor that the FDA approved in April 2019 for the treatment of urothelial carcinoma marked by mutations in the FGFR3 gene and FGFR3-FGFR2 fusions. Results from an open-label, phase II study were taken into consideration for a fast-track approval of the drug and were recently published in the New England Journal of Medicine (2019 ;381(4):338-348). The clinical trial found a 40 percent response rate among patients with FGFR mutations
"It's the first fibroblast growth factor (FGF) inhibitor approved for the treatment of any cancer. It's the first oral agent in bladder cancer, and it's the first personalized therapy for bladder cancer to target an FGFR-altered tumor," said Arlene Siefker-Radtke, MD, Professor of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center and a coauthor of the study.
Genetic studies have suggested that urothelial carcinoma can be classified into several subtypes, with each having distinct prognoses and responding differently to chemotherapy or immunotherapy. The NCI reports there are close to 80,000 new cases of urothelial carcinoma in 2019 and it accounts for about 17,600 deaths.
FGFR3 mutations may contribute to higher rates of cancer cell proliferation in the urothelial lining. The mutations occur in 15-20 percent of metastatic bladder cancers and about 35 percent of upper tract cancers which include renal, pelvis and ureter, Siefker-Radtke noted.
Examining Therapies
Generally, the standard first-line treatment for patients with urothelial carcinoma is with cis-platinum. However, patients are more likely to be over age 70 with comorbidities and frail. They "have medical issues that limit their ability to tolerate an aggressive treatment. There are limited treatment options," she told Oncology News in an interview.
Patients with advanced disease receive second-line therapy with immune checkpoint inhibitors (ICI). Following immunotherapy, treatment with taxanes are a possibility, and in Europe, vinflunine.
Previously published studies suggest only 15-20 percent of bladder cancers respond to ICIs, and patients whose disease doesn't respond to chemotherapy or immunotherapy have few options. Siefker-Radtke noticed in her own practice that patients with mutations in the FGFR3 gene weren't responding to ICIs. She noted that some studies suggest only one in 22 of these patients respond to ICIs.
One recent meta-analysis found that second-line therapies for metastatic urothelial cancer generally offer "no survival benefit, poor response rate, and significant treatment related-toxicity" (Front Oncol 2019; doi: 10.3389/fonc.2019.00679).
For the multi-center study, patients were enrolled if they had had locally advanced and unresectable or metastatic urothelial carcinoma with the FGFR3 gene mutation or FGFR2/3 fusions. All had undergone at least one course of chemotherapy. People who had prior immunotherapy were also enrolled. All had disease progression during, or after, at least one course of previous systemic chemotherapy or within 12 months after receiving neoadjuvant or adjuvant chemotherapy.
Initially, 111 eligible participants were randomized to receive either an intermittent schedule of erdafitinib 10 mg daily for 7 days on and 7 days off (33 patients), or to a continuous daily schedule of 6 mg of the drug (78 patients). Of the patients, 43 percent had received at least 2 previous courses of treatment and 79 percent had visceral metastases.
But after an interim analysis of 99 patients still in the study, the continuous dose was selected for everyone based on toxicity and encouraging potential clinical activity. Researchers found the continuous dose could be increased to 8 mg/day to optimize inhibition of FGF; 41 patients who had no adverse events from the drug were increased to 9 mg/day.
"At the start, nobody knew if we could give these drugs in a continuous fashion," Siefker-Radtke said.
The rate of confirmed objective tumor response to erdafitinib therapy was 40 percent-3 percent had a complete response and 37 percent a partial response. Encouragingly, among the 22 patients who had previous immunotherapy, the response rate was 59 percent.
Of the 97 patients who underwent at least one disease evaluation after baseline, 48 (49%) had tumor reductions of 30-100 percent. Response rates were similar regardless of previous treatment regimens or other factors.
All patients reported having adverse events (AEs) during treatment with 67 percent being grade 3 or 4. Of these, 46 percent were determined to be treatment-related. Common AEs included hyponatremia, stomatitis, and asthenia. Serious AEs were reported in 39 patients.
Thirteen patients stopped the treatment because of AEs, including retinal detachment, hand-foot syndrome, dry mouth, and skin or nail curling. Sixty-two patients stopped because of disease progression and 55 patients had a dose reduction.
The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related AEs grade 3 or higher, usually managed adjusting the dose, were reported in 46 percent of the patients, though 13 percent discontinued treatment.
The study concluded that "the 40 percent response rate to erdafitinib compares favorably with data from phase I and II studies of other FGFR inhibitors (which reported response rates of 0-25%)."
"The efficacy is encouraging," said Srikala Sridhar, MD, MSc, FRCPC, Associate Professor of Oncology at the University of Toronto, who was not a part of the study. "I would say this a relatively well-tolerated oral drug, and being oral versus IV is an advantage for our patients. Toxicity of these drugs is likely less than chemotherapy, but different in nature. We will need to build experience with managing the side effects."
Pippa Wysong is a contributing writer.