The FDA has granted an accelerated approval to atezolizumab as a frontline treatment for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma.
Sandra Horning, MD
The FDA has granted an accelerated approval to atezolizumab (Tecentriq) as a frontline treatment for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (mUC), according to Genentech, the manufacturer of the PD-L1 inhibitor.
The approval is based on data from the single-arm phase II IMvigor210 trial. In a study cohort of 119 cisplatin-ineligible, treatment-naive patients, the objective response rate (ORR) with atezolizumab was 23.5% (n = 28; 95% CI, 16.2-32.2), including a complete response (CR) rate of 6.7%.1
Based on a separate cohort from the IMvigor210 trial, atezolizumab previously received an accelerated approval as a treatment for patients with locally advanced or mUC whose disease progressed during or after platinum-based chemotherapy, or <12 months of receiving platinum-containing chemotherapy, either before or after surgery.
“We are pleased that Tecentriq will now be available to more people with advanced bladder cancer, including those who are unable to receive initial treatment with cisplatin chemotherapy,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a statement. “Tecentriq was the first cancer immunotherapy approved by the FDA for people with advanced bladder cancer and has become a standard of care in those whose disease has progressed after receiving other medicines, either before or after surgery, or after their disease has spread.”
Among the 123 patients, 119 received at least 1 dose of atezolizumab. There was an association between tumor mutation load and response. The median PFS and OS were 2.7 months (95% CI, 2.1-4.2) and 15.9 months (95% CI, 10.4 to not estimable), respectively.
The median duration of response was not yet reached. Among patients with PD-L1 expression ≥5% (n = 32), the ORR was 28.1% (95% CI, 13.8-46.8), including a CR rate of 6.3%. In patients with PD-L1 expression <5%, the corresponding rates were 21.8% (95% CI, 13.7-32.0) and 6.9%, respectively.
The most common grade 3/4 adverse events (AEs) included fatigue (8%), urinary tract infection (5%), anemia (7%), diarrhea (5%), increase in the level of creatinine in the blood (5%), increase of the liver enzyme alanine transaminase (4%), hyponatremia (15%), decreased appetite (3%), and back/neck pain (3%).
AEs led to 5 patients discontinuing treatment. Five patients died, due to sepsis, cardiac arrest, myocardial infarction, respiratory failure, and respiratory distress. An additional patient had inflammation of the brain due to the herpes simplex virus and disease progression at the time of death.
The IMvigor 210 cohort on which the previous accelerated approval of atezolizumab was based included an all-comer population of 316 patients with inoperable locally advanced or mUC who progressed after receiving platinum-based chemotherapy.2 Data from 310 patients were evaluable. 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.
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, PFS, OS, 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) in patients with PD-L1 expression ≥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).
Complete response rates in the overall, higher—PD-L1, and lower–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.
Overall, 10 patients discontinued atezolizumab due to adverse events (AEs). The most common grade 3/4 adverse events included urinary tract infection (9%), anemia (8%), fatigue (6%), dyspnea (4%), and hematuria (3%). There were 3 patient deaths, which were related to sepsis, pneumonitis or intestinal obstruction.
The accelerated approvals of atezolizumab are 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 in the frontline setting and after progression on at least 1 prior platinum-containing regimen.
The treatment-naive IMvigor210 cohort enrolled 123 patients with cisplatin-ineligible locally advanced or mUC at 47 locations in North America and Europe between June 9, 2014, and March 30, 2015. Patients received 1200 mg of atezolizumab IV every 3 weeks until progression. The primary endpoint was ORR, with secondary outcomes measures including progression-free survival (PFS) and overall survival (OS).