Targeted Therapies Improve Response Rates in Patients with Metastatic Urothelial Cancer

Although standard chemotherapy is often effective in the first-line treatment of locally invasive urothelial carcinoma, until recently, there have been few second- or third-line treatment options for patients with advanced or metastatic disease. During the 2021 Hematology/Oncology Pharmacy Association Annual Conference, Renee K. McAlister, PharmD, BCOP, Oncology Clinical Pharmacy Specialist, Melanoma/Genitourinary Oncology Clinics, Vanderbilt University Medical Center, Nashville, TN, discussed promising results from clinical trials evaluating the use of erdafitinib (Balversa) and enfortumab vedotin (Padcev), 2 FDA-approved drugs that are changing the therapeutic landscape for metastatic urothelial cancer.

“Prior to these approvals, we had response rates in the second- and third-line setting of approximately 10% to 15%,” said Dr McAlister. “Now, we’re having response rates as high as 40% in patients who have been heavily pretreated.”

Erdafitinib

Erdafitinib is an FGFR inhibitor that was approved by the FDA in April 2019 for patients with metastatic urothelial carcinoma with a susceptible FGFR3 or FGFR2 genetic alteration that has progressed during or following platinum-containing chemotherapy. According to Dr McAlister, FGFR3 mutations and FGFR2/3 fusions are most common in bladder cancers, and occur in up to 20% of metastatic urothelial carcinomas.

The approval of erdafitinib was based on the phase 2 BLC2001 trial, which included 99 patients with locally advanced or metastatic urothelial carcinoma with an FGFR3 mutation or an FGFR2/3 fusion. Patients who had disease progression after ≥1 previous courses of therapy (unless cisplatin-ineligible), with an Eastern Cooperative Oncology Group performance status of 0-2, an adequate baseline organ function, and no uncontrolled cardiovascular disease, elevated phosphate despite medical treatment, or brain metastases were eligible for enrollment.

Dr McAlister reported that 43% of patients in the study had received ≥2 previous lines of therapy, and 78% had visceral metastases. Nevertheless, data showed an overall response rate of 40%, with 3% of patients exhibiting a complete response and 37% exhibiting a partial response. The median duration of response was 5.6 months, median progression-free survival (PFS) was 5.5 months, and median overall survival was 13.8 months.

“It’s important to mention that 59% of patients who had received prior immunotherapy had a confirmed response rate,” she said. “As we think about our lines of therapy, erdafitinib can come before or after immunotherapy.”

Treatment-related adverse events included hyperphosphatemia, stomatitis, diarrhea, dry mouth, decreased appetite, dry skin, alopecia, hand−foot syndrome, dry eye, and nail changes. Dr McAlister noted that hyperphosphatemia, which is a biomarker for treatment efficacy, can be managed by restricting dietary phosphate intake to 600 to 800 g/day or by initiating a phosphate binder for levels >7 mg/dL.

Enfortumab Vedotin

Enfortumab vedotin is an antibody–drug conjugate that was approved by the FDA in December 2019 for the treatment of locally advanced or metastatic urothelial carcinoma after platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

The approval of enfortumab vedotin was based on results of the phase 2 EV-201 trial and the phase 3 EV-301 trial.

The EV-301 trial enrolled patients with metastatic urothelial carcinoma who had disease progression on or after receiving a PD-1 or PD-L1 inhibitor and had received 1 previous platinum-containing chemotherapy regimen. In addition to being heavily pretreated 80% of patients in each group had visceral metastases. More importantly, said Dr McAlister, nearly 70% of patients in each group were nonresponders to immunotherapy.

Results showed a statistically significant improvement in median overall survival in the enfortumab vedotin arm compared with the chemotherapy arm (12.88 months vs 8.97 months, respectively). PFS was also significantly longer with enfortumab vedotin compared with chemotherapy (5.55 months vs 3.71 months, respectively. In addition, the overall response rate more than doubled from 17.9% with chemotherapy to 40.6% with enfortumab vedotin.

The most common treatment-related adverse events were alopecia, peripheral sensory neuropathy, pruritus, fatigue, decreased appetite, diarrhea, dysgeusia, nausea, ocular toxicity, and maculopapular rash.

“It’s important to remember that this antibody–drug conjugate is ultimately releasing cytotoxic chemotherapy, so you can expect myelosuppression and hyperglycemia,” said Dr McAlister.

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