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CHICAGO -- Patients with FGFR-mutated advanced urothelial cancer that progressed after anti-PD-1/L1 therapy lived significantly longer if they received the selective FGFR inhibitor erdafitinib (Balversa) instead of chemotherapy, a randomized trial showed.

Median overall survival (OS) increased from 7.8 months with physician's choice of chemotherapy to 12.1 months with the targeted agent. Progression-free survival (PFS) doubled from 2.7 to 5.6 months with erdafitinib, which induced objective responses four times as often as chemotherapy.

The safety profile was consistent with erdafitinib clinical experience, and fewer patients discontinued because of adverse events (AEs) versus patients treated with chemotherapy, reported Yohann Loriot, MD, of Gustave Roussy Institute in Villejuif, France, at the American Society of Clinical Oncology (ASCO) annual meeting.

"Erdafitinib significantly extended overall survival in patients with advanced or metastatic urothelial cell carcinoma with FGFR alterations, after prior treatment with immune checkpoint inhibitors, with a median overall survival of more than one year," said Loriot. "The overall survival benefits were consistent across clinically relevant subgroups."

"Overall, the phase III study supports the clinical efficacy of erdafitinib as the standard-of-care option for patients with metastatic carcinoma and FGFR alterations, after prior immune checkpoint inhibitor treatment," he added. "The overall survival benefit also supports molecular testing for FGFR alterations in all patients with metastatic urothelial carcinoma."

Erdafitinib is part of an "explosion of new agents" for advanced urothelial cancer over the past 10 years, said ASCO invited discussant Daniel Petrylak, MD, of Yale Cancer Center in New Haven, Connecticut. Cisplatin-containing chemotherapy remains the standard first-line therapy for cisplatin-eligible patients. Gemcitabine/carboplatin followed by avelumab (Bavencio) maintenance has been standard for cisplatin-ineligible patients, and more recently enfortumab vedotin (Padcev)/pembrolizumab (Keytruda).

Pembrolizumab, avelumab, and nivolumab (Opdivo) are all approved as second-line therapy. Third-line options consist of enfortumab, sacituzumab govitecan (Trodelvy), and erdafitinib, Petrylak continued.

"Unfortunately, despite these riches, about one quarter of urothelial cancer patients in the United States do not receive first-line treatment, and two thirds of these patients do not receive second-line treatment, despite the fact that immune checkpoint inhibitors have a favorable safety profile," he said. "We need to do a better job of getting our patients on treatment and to understand the reasons why these patients are not being treated."

Use of biomarker testing also has been disappointing, Petrylak noted, as only a minority of patients with advanced urothelial cancer undergo testing as part of their treatment planning.

"So, I think the most important take-home message from today is that all patients with metastatic urothelial carcinoma need to be tested for FGFR3 or FGFR2 alterations," he stated.

Future studies should focus on determining a rational approach to sequencing erdafitinib enfortumab, and sacituzumab, said Petrylak. Additionally, better understanding of resistance pathways to erdafitinib is essential to development of effective combination therapy.

The key objective of THOR was to determine safety and efficacy of erdafitinib in the post-immune checkpoint inhibitor setting of locally advanced/metastatic urothelial cancer. Loriot pointed out that checkpoint inhibitors are used in first- and second-line treatment, and about 30% of patients respond to the agents. Treatment options are limited for disease that progresses during or after immune checkpoint inhibition.

"In the real-world setting, only about 30% of patients receive subsequent anticancer treatment after anti-PD-1/L1 discontinuation," said Loriot. "No large, randomized studies have demonstrated a survival benefit in biomarker-selected populations after anti-PD-1/L1 treatment."

About 20% of advanced/metastatic urothelial cancers have FGFR alterations, which may function as oncogenic drivers. Erdafitinib has accelerated approval in the U.S. and approval in 17 other countries for FGFR3/2-altered locally advanced/metastatic urothelial cancer following progression of platinum-based chemotherapy.

In a , erdafitinib produced a 40% objective response rate (ORR), which was associated with a median PFS of 5.5 months and median OS of 11.3 months in patients with FGFR-altered advanced urothelial cancer. The THOR trial was designed to confirm those results.

Investigators in the multicenter study enrolled patients with FGFR3/2-altered disease who had received one or two prior lines of therapy (including an immune checkpoint inhibitor) and had confirmed progressive disease. Patients were randomized to erdafitinib or to physician's choice of chemotherapy (docetaxel or vinflunine). The primary endpoint was OS.

Data analysis included 266 patients, most of whom were Asian or white. About 70% of patients had received two prior lines of therapy, and about 90% had low PD-L1 expression (combined positive score <10).

The primary analysis showed that erdafitinib reduced the survival hazard by 36% versus chemotherapy (95% CI 0.47-0.88, P=0.005). Subgroup analysis showed a consistent benefit irrespective of type of FGFR alteration, number of prior lines of therapy, presence or absence of visceral metastases, location in the upper or lower tract, and choice of chemotherapy comparator.

Patients randomized to erdafitinib had a 42% reduction in the hazard for disease progression or death (95% CI 0.44-0.78, P=0.0002).

Erdafitinib led to an ORR of 45.6%, including nine (6.6%) complete responses, as compared with 11.5% with chemotherapy (one CR).

AEs were consistent with those observed in the phase II trial. Serious AEs occurred in 18 patients randomized to erdafitinib and 27 assigned to chemotherapy. One treatment-related death occurred in the erdafitinib group versus six in the chemotherapy arm.

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