Erdafitinib, Enfortimab Vedotin Offer New Treatments for Metastatic Urothelial Carcinoma

Urothelial carcinoma is the sixth most common cancer diagnosis in the United States, with an estimated 81,400 new diagnoses in 2020 and 17,980 deaths.

Patients with metastatic urothelial carcinoma have new, much-needed options in second- and third-line treatments with the recent FDA approvals of erdafitinib and enfortumab vedotin, according to a presentation at the Hematology/Oncology Pharmacy Association virtual 2021 conference.

Urothelial carcinoma is the sixth most common cancer diagnosis in the United States, with an estimated 81,400 new diagnoses in 2020 and 17,980 deaths. It largely impacts older adults, with a median age of 73 years, and men are much more impacted than women.

Presenter Renee McAlister, PharmD, BCOP, a clinical pharmacy specialist at Vanderbilt University Medical Center, said that approximately 90% of urothelial carcinomas arise in the bladder, although approximately 10% arise in the upper tract.

Traditional second-line treatments include immunotherapy and single agent chemotherapy, such as docetaxel, paclitaxel, and gemcitabine. These treatments all have relatively low response rates, however, with approximately 13.3% of patients responding to docetaxel and 9.5% responding to paclitaxel.

Single agent chemotherapy is traditionally the only option for third-line treatment. With the approval of erdafitinib in both the second and third lines and enfortumab vedotin in the third line, however, these options have been expanded.

Erdafitinib is a fibroblast growth factor (FGFR) inhibitor that was approved in April 2019 for metastatic urothelial carcinoma with a susceptible FGFR3 or FGFR2 genetic alteration that has progressed during or following platinum-containing chemotherapy. FGFR3 mutations and FGFR2/3 fusions are most common in bladder cancers, McAlister said, occurring in up to 20% of metastatic urothelial carcinomas.

The BLC2001 study evaluated erdafitinib in patients with a median age of 68 years, most of whom had progressed following prior chemotherapy and 22% of whom had progressed following prior immunotherapy.

According to McAlister’s presentation, investigators found a confirmed response rate of 40%, with 3% of patients exhibiting a complete response and 37% exhibiting a partial response. Furthermore, 49% of patients with a FGFR3 mutation responded and 16% of patients with FGFR2/3 fusions responded. The overall median duration of response was 5.6 months, and the median progression-free survival (PFS) was 5.5 months. Finally, the median overall survival (OS) was 13.8 months.

Treatment-related adverse events (TRAEs) included hyperphosphatemia, stomatitis, diarrhea, dry mouth, decreased appetite, dysgeusia, alopecia, hand foot syndrome, and nail changes. McAlister noted that hyperphosphatemia is a biomarker for efficacy and can be managed by restricting dietary intake to 600 to 800 grams per day or by initiating a phosphate binder for levels greater than 7 mg/dL. Patients should also avoid vitamin D and antacids.

Next, McAlister discussed the approval of enfortimab vedotin in both the second- and third-line settings. Enfortimab, a nectin-4 monoclonal antibody, was approved in December 2019 for the treatment of locally advanced or metastatic urothelial carcinoma after platinum-based chemotherapy and a programmed cell death protein 1 (PD-1) or programmed death cell ligand 1 (PD-L1) inhibitor. The approval was based on the phase 2 EV-201 study and the phase 3 EV-301, the results of which were published about a month ago, McAlister said.

The phase 3, open-label, multicenter study consisted of mostly men (79.1%), with a median age of 68 years. About 18% of participants had a history of diabetes, 87% had received 1 to 2 previous systemic therapies, and about 70% wee non-responders to immunotherapy. According to the study results, the median OS was 12.8 months in the enfortimab group versus 8.97 months in the chemotherapy arm. Similarly, PFS was 5.5 months in the enfortimab group and 3.71 months in the chemotherapy group.

TRAEs included alopecia, peripheral sensory neuropathy, pruritus, fatigue, decreased appetite, diarrhea, ocular toxicity, anemia, and hyperglycemia. McAlister said recommended dosing is 1.25 mg/kg intravenously on days 1, 8, and 15 of a 28-day cycle. She also noted that it has a low emetic risk and added that testing for nectin-4 expression is not required.

“These approvals really have changed the landscape for metastatic bladder cancer,” McAlister concluded.


McAlister R. Targeted Therapy in Metastatic Urothelial Carcinoma. Presented at: Hematology/Oncology Pharmacy Association 2021 virtual conference; April 15, 2021. Accessed April 15, 2021.