FDA Grants Accelerated Approval to Atezolizumab for Urothelial Carcinoma

Sandra Horning, MD

The FDA has granted an accelerated approval to the PD-L1 inhibitor atezolizumab (Tecentriq) as a treatment for patients with locally advanced or metastatic urothelial carcinoma (mUC) following a platinum-based chemotherapy, based on improvements in objective response rates (ORR) from a phase II study.

In the trial, which was labeled IMvigor 210, atezolizumab had an ORR of 14.8% in patients with locally advanced or mUC, regardless of PD-L1 expression. Among patients with PD-L1 expression ≥5%, the ORR was 26%. To aid in the detection of the biomarker, the FDA has also approved the Ventana PD-L1 (SP142) assay as a companion diagnostic.

“Tecentriq is a new medicine that can work with the immune system to treat people with a type of bladder cancer that progressed after platinum-based chemotherapy,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, the manufacturer of atezolizumab, said in a statement. "We thank the scientists, doctors, patients, and their families who made it possible to bring Tecentriq to patients with advanced urothelial carcinoma.”

IMvigor 210 enrolled an all-comer population of 316 patients with inoperable locally advanced or mUC. Data from 310 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, progression-free survival, overall survival and safety.

At a median follow-up of 14.4 months, ORR was 14.8% (95% CI, 11.1-19.3; n = 46/310) in all comers, 26% (95% CI, 17.7-35.7; n = 26/100)&nbsp;in patients with&nbsp;PD-L1 expression &ge;5%, and 9.5% (95% CI, 5.9-14.3; n = 20/210) in those with PD-L1 expression <5%. In a subgroup of 59 patients from the IMvigor 210 study who progressed after neoadjuvant or adjuvant platinum-based chemotherapy, the ORR was 22% (95% CI, 12.3-34.7).&nbsp;

Complete response rates in the overall, higher—PD-L1, and lower&ndash;PD-L1 groups were 5.5%, 12%, and 2.4%, respectively. Partial response rates were 9.4%, 14%, and 7.1%, respectively. The median duration of response was 12.7 months (range, 2.1+ to 12.7) in the higher PD-L1 population, and had not yet been reached in either the overall group or the lower PD-L1 cohort. &nbsp;

Overall, 10 patients discontinued atezolizumab due to adverse events (AEs). The most common grade 3/4 adverse events included&nbsp;urinary tract infection (9%), anemia (8%), fatigue (6%),&nbsp;dyspnea (4%), and&nbsp;hematuria (3%). There were 3 patient deaths, which were related to&nbsp;sepsis, pneumonitis or intestinal obstruction.

&ldquo;Tecentriq provides these patients with a new therapy targeting the PD-L1 pathway,&rdquo; Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA&rsquo;s Center for Drug Evaluation and Research, said in a statement. &ldquo;Products that block PD-1/PD-L1 interactions are part of an evolving story about the relationship between the body&rsquo;s immune system and its interaction with cancer cells.&rdquo;

Atezolizumab previously received a breakthrough therapy designation from the FDA for the treatment of patients with PD-L1—positive metastatic bladder cancer. The accelerated approval is contingent on results from an ongoing confirmatory phase III study, IMvigor 211 (NCT02302807), which is comparing atezolizumab with chemotherapy in patients with locally advanced or metastatic urothelial bladder cancer who have progressed on at least 1 prior platinum-containing regimen.