On May 18, 2016, the U. S. Food and Drug Administration gave accelerated approval to atezolizumab injection (Tecentriq, Genentech, Inc.) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody.
The approval was based on a multicenter, single-arm trial in 310 patients with locally advanced or metastatic urothelial carcinoma. Patients entering this trial had disease progression during or following a platinum-containing chemotherapy regimen or within 12 months of treatment with a neoadjuvant or adjuvant platinum-containing regimen. The study excluded patients who had a history of autoimmune disease or required systemic immunosuppressive medications. Tumor specimens were required in all patients. All patients received an intravenous infusion of atezolizumab, 1200 mg, every 3 weeks. Major efficacy outcome measures included confirmed objective response rate (ORR) as assessed by independent review facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and duration of response (DoR).
Visceral metastases were present in 78% of patients and 40% of patients had received greater than or equal to 2 prior regimens in the metastatic setting. Nineteen percent (19%) of patients had progressed following neoadjuvant or adjuvant therapy.
The confirmed ORR by independent review was 14.8% (95% CI: 11.1, 19.3) in all treated patients. Median DoR was not reached and response duration ranged from 2.1+ to 13.8+ months. Of the 46 responders, 37 patients had an ongoing response for greater than orequal to 6 months and 6 for greater than or equal to12 months. Tumor specimens were evaluated using the Ventana PD-L1 (SP142) Assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Patients were considered PD-L1 positive if PD-L1 stained tumor-infiltrating immune cells occupied greater than or equal to 5% of the tumor area. Of the 310 patients, 32% were classified as having PD-L1 expression of greater than or equal to 5% (defined as PD-L1 stained tumor-infiltrating immune cells [ICs] covering greater than or equal to 5% of the tumor area). The remaining 68% of patients were classified as having PD-L1 expression of less than 5% (PD-L1 stained tumor-infiltrating ICs covering less than 5% of the tumor area). The confirmed ORR was 26.0% (95% CI: 17.7, 35.7) in 100 patients whose specimens had PD-L1 expression of greater than or equal to 5% and 9.5% (95% CI: 5.9, 14.3) in 210 patients whose specimens had PD-L1 expression of less than 5%. Response durations in these subgroups were similar to those noted above in all treated patients.
The most common adverse reactions of atezolizumab (greater than or equal to 20% of patients) were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation. Grade 3-4 adverse events were seen in 50% of patients. Infection and immune-related adverse events such as pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, diabetes, pancreatitis, and dermatitis/rash were also seen with atezolizumab.
The recommended dose of atezolizumab is 1200 mg administered as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. Testing of PD-L1 expression in tumor specimens is not required for the use of atezolizumab, but may guide in patient selection. The Ventana PD-L1 (SP142) Assay is approved for PD-L1 testing on tumor-infiltrating immune cells.
This application was approved before the Prescription Drug User Fee Act (PDUFA) goal date of September 12, 2016. Atezolizumab received Breakthrough Therapy Designation for this indication and the application was granted Priority Review. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Full prescribing information is available at:
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).