The PD-L1 inhibitor atezolizumab has gained priority review status from the FDA as a treatment for patients with locally advanced or metastatic urothelial carcinoma (mUC).
According to a statement from developer Genentech, the review will be based on data from the phase II IMvigor 210 study,1,2where atezolizumab had an overall response rate (ORR) of 15% in patients with locally advanced or mUC, regardless of PD-L1 expression. Among patients with PD-L1 expression ≥5%, ORR was 26%.
Atezolizumab previously received an FDA breakthrough therapy designation for patients with PD-L1positive metastatic bladder cancer. Under the expedited priority review program, the FDA will make its approval decision for atezolizumab by September 12, 2016.
“Atezolizumab was granted priority review designation based on results of the IMvigor 210 study, which showed the medicine shrank tumors in a type of advanced bladder cancer, and the majority responding to treatment continued to respond after nearly a year of follow up,” said Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech. “The treatment options available for advanced bladder cancer are very limited, and we are committed to working with the FDA to bring the first anti-PDL1 cancer immunotherapy to people with this disease as quickly as possible.”
IMvigor 210 enrolled an all-comer population of 316 patients with with inoperable locally advanced or mUC. Data from 311 patients were evaluable; the mean patient age was 66 years, 78% were male, and 62% of patients had ECOG PS 1. The site of primary tumor was the bladder for 75% of patients with metastasis to viscera reported for 78% of patients and to the liver in 31% of patients.
All patients had progressed during or following platinum-based chemotherapy. The patients had been heavily pretreated, with 40% of patients undergoing 2 or more prior systemic regimens in the metastatic setting and 74% of patients receiving previous cisplatin-based chemotherapy.
Tumor tissue was prospectively assessed centrally for PD-L1 expression using the SP142 immunohistochemistry assay. PD-L1 status was assessed on tumor cells and immune cells using an SP142 antibody-based immunohistochemistry assay; however, both the patients and investigators were blinded as to PD-L1 status.
Atezolizumab was administered at 1200 mg intravenously on the first day of each 21-day cycle until no further clinical benefit was demonstrated. Median treatment duration was 12 weeks (range, 0-46 weeks). The coprimary study endpoints were ORR, as assessed by central review and the investigators, both by modified RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety.
When results were evaluated according to the degree of PD-L1 expression on immune cells and on all comers, significant ORR improvements across all groups were seen that increased with higher PD-L1 expression. For the primary analysis, ORR by RECIST 1.1 was 15% (P = .0058) in all comers, 18% (P = .0004) at the IC1/2/3 level (any PD-L1 expression), and 27% (P = .0001) in the IC2/3 subgroup with PD-L1 expression ≥5%. The median DoR had not been reached at the time of cutoff.
At an updated analysis with 11.7 months’ follow-up, ORR was 26% (95% CI, 18-36) in the IC2/3 group, 18% (95% CI 13-24) in the IC1/2/3 group, and 15% (95% CI, 11-19) in the overall population. Among 45 responders, 84% (n = 38) had ongoing responses at the updated follow-up.
Treatment-related adverse events (AEs) of any grade occurred in 66% of patients, with 15% of patients experiencing grades 3/4 treatment-related AEs.
The most common grade 3/4 treatment-related AEs were fatigue (2%), followed by decreased appetite, pyrexia, anemia, ALT and AST increase, arthralgia, dyspnea, pneumonitis, colitis, and hypertension and hypotension (all 1%). There were no treatment-related deaths.
An ongoing confirmatory phase III study, IMvigor 211 (NCT02302807), is comparing atezolizumab to chemotherapy in patients with locally advanced or metastatic urothelial bladder cancer who have progressed on at least one prior platinum-containing regimen.