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The FDA has granted a priority review to a supplemental new drug application for the use of the PD-L1 inhibitor atezolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma as a frontline therapy or following progression occurring ≥12 months after neoadjuvant or adjuvant chemotherapy.
Sandra Horning, MD
The FDA has granted a priority review to a supplemental new drug application (sNDA) for the use of the PD-L1 inhibitor atezolizumab (Tecentriq) in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (mUC) as a frontline therapy or following progression occurring ≥12 months after neoadjuvant or adjuvant chemotherapy.
The sNDA 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 at a median follow-up of 17.2 months was 23% (n = 27; 95% CI, 16-31), including a complete response rate of 9% (n = 11).1 Under the expedited review, the FDA is scheduled to make a final decision on the sNDA by April 30, 2017.
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.
“In May 2016, Tecentriq became the first treatment approved by the FDA for people with previously treated advanced bladder cancer in more than 30 years,” said Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, the developer of atezolizumab, said in a statement. “We are committed to continue working with the FDA to make Tecentriq available to more people with this type of advanced bladder cancer, specifically those who are unable to tolerate cisplatin-based chemotherapy as an initial treatment.”
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).
Among the 123 patients, 119 received at least 1 dose of atezolizumab. Responses occurred regardless of PD-L1 status and across poor prognostic factor subgroups. The median duration of response was not reached. 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 most common treatment-related adverse events included fatigue (n = 36; 30%), diarrhea (n = 14; 12%), and pruritus (n = 13; 11%). Fourteen (12%) patients had immune-mediated events. Adverse events led to treatment discontinuation in 9 patients (8%). There was 1 treatment-related to death due to sepsis.
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 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.
The IMvigor 210 cohort on which the 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.