Treatment options for patients with urothelial cancer are rapidly expanding. In just one month, the US Food and Drug Administration (FDA) has granted three accelerated approvals for immune checkpoint inhibitors targeting the programmed death receptor 1 ligand (PD-L1) for use in advanced urothelial cancer.
- On 17 April 2017, the indication of atezolizumab (TECENTRIQ®, Genentech) was extended to include treatment-naïve patients who have locally advanced or metastatic urothelial cancer and who are ineligible for cisplatin-based therapy. This decision was based on results in 119 treatment-naïve patients enrolled on the phase II IMvigor210 trial. In these patients, treatment with atezolizumab resulted in an overall response rate (ORR) of 23.5%, with 6.7% complete response (CR). The median duration of response (DoR) has not been reached. No new safety signals were seen in the first-line setting. Atezolizumab is the first immunotherapy to be approved for first-line use in urothelial cancer and the confirmatory phase III IMvigor130 study in this setting is ongoing. Atezolizumab has previously gained accelerated approval for patients with advanced urothelial cancer who had progressed on first-line platinum-based therapy. Surprisingly, per a company press release regarding the phase III IMvigor211 study, atezolizumab did not improve overall survival, which was a primary endpoint, compared to chemotherapy in platinum-pretreated patients. More information on these unexpected results is eagerly awaited.
- On 1 May 2017, durvalumab (IMFINZI™, AstraZeneca UK Limited) was granted accelerated approval for treatment of patients with advanced urothelial cancer who have progressed during or following platinum-based chemotherapy. Approval was based on evidence of rapid and durable responses in 182 patients included in the single arm phase I/II Study 1108. The ORR was 17.0% (including 5 CR) in all patients and 26.3% in patients with PD-L1 high-expressing tumors. The median DoR has not been reached. Among responding patients, 45% had responses of 6 months or longer and 16% had responses of 12 months or longer. Adverse events (AEs) were consistent with the known safety profile of durvalumab. Serious AEs occurred in 46% of patients, and eight (4.4%) patients died. Full approval of durvalumab is contingent upon confirmation of benefit in advanced clinical trials. Durvalumab was approved regardless of PD-L1 status in urothelial carcinoma tissue. However, a complementary diagnostic for PD-L1 expression testing in urothelial carcinoma tissue (VENTANA-PD-L1 [SP263] Assay, Ventana Medical Systems, Inc.) was simultaneously approved as a tool that may help guide clinicians in their treatment decisions.
- On 9 May 2017, a third PD-L1 inhibitor, avelumab (BAVENCIO®, EMD Serono, Inc.) was approved for patients with advanced urothelial cancer with disease progression during or following platinum-containing chemotherapy. This approval was based on results in 242 patients with advanced, progressive urothelial cancer enrolled in the multicenter, single-arm phase II JAVELIN Solid Tumor Trial. Confirmed ORR was 13.3% in patients who had been followed for at least 13 weeks, and 16.1% in patients who had been followed for at least 6 months. The median DoR had not been reached in either group. The most common AEs that occurred in at least 20% of patients were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection. Serious AEs were reported in 41% of patients and 6% died due to AEs. Patients being treated with avelumab should receive premedication with an antihistamine and acetaminophen prior to each administration.
In addition to the above PD-L1 inhibitors, the PD-1 inhibitor nivolumab is also approved for second-line use in urothelial cancer. Approval of pembrolizumab in this patient population is also expected based on results from the phase III KEYNOTE-045 trial, which is the only trial to demonstrate a significant survival benefit compared to second-line chemotherapy.