Atezolizumab Achieves Primary Endpoint in Pivotal Phase II Bladder Cancer Study

Sandra Horning, MD

Second-line treatment with atezolizumab (MPDL3280A) has met the primary endpoint of a pivotal phase II study by effectively shrinking tumors in patients with locally advanced or metastatic urothelial bladder cancer (UBC), according to a statement from the PD-L1 inhibitors developer, Genentech.

Data from the open-label phase II study, known as IMvigor 210, were not yet made publicly available. However, in a statement the developer noted that PD-L1 status coincided with responses to atezolizumab and that adverse events (AEs) were consistent with previous experiences.

Based on phase I findings in heavily pretreated patients with metastatic UBC, atezolizumab received a breakthrough therapy designation from the FDA in late May 2014. As part of this designation, Genentech has entered into discussions with the FDA regarding a potential regulatory filing of the phase II IMvigor 210 data.

“We are encouraged by the number of people who responded to atezolizumab and maintained their response during the study because minimal progress has been made in advanced bladder cancer for nearly 30 years,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Roche Genentech, said in a statement. “We plan to present results at an upcoming medical meeting and will discuss next steps with health authorities to bring a new treatment option to patients as soon as possible.”

In the IMvigor 210 study, atezolizumab was administered at 1200 mg intravenously on the first day of each 21-day cycle. The trial consisted of two cohorts: Cohort 1 enrolled patients with untreated UBC and Cohort 2 recruited those who had progressed on prior treatment with a platinum-based regimen. Data from Cohort 1 were not yet available, according to the company.

The primary endpoint of the study was objective response rate (ORR), with secondary outcome measures focused on duration of response (DoR), overall survival (OS), progression-free survival (PFS), and other endpoints. PD-L1 status was assessed on tumor cells and immune cells (IC) using an SP142 antibody-based immunohistochemistry assay developed by Roche Diagnostics.

In a preceding phase Ia study, 92 patients were treated with atezolizumab every 3 weeks at 15 mg/kg or a 1200 mg flat dose. The median age of patients was 66 years and the majority were male (75%). Visceral metastases were seen in 79% of patients at baseline and 94% of patients had received a prior platinum-based chemotherapy (≥2 prior therapies in 72%).

According to updated findings presented at the 2015 ASCO Annual Meeting, in patients with the highest level of PD-L1 expression (IC2/3) the ORR was 50%. This consisted of 9 complete responses (CR) and 14 partial responses (PR). Of those with visceral metastases at baseline (n = 32), the ORR was 38%.

In the IC3 group alone (n = 12), the ORR was 67% (95% CI, 35-90), with a CR rate of 33%. In the IC2 group (n = 34), the ORR was 44% (95% CI, 27-62). The CR rate was 15%. In patients with lower levels of PD-L1 expression (IC0/1), the ORR was 17% (95% CI, 7-32).

The median DoR had not been reached at the time of the December 2014 cutoff, with 67% of responses ongoing. Ten patients were treated for over 1 year.

The median PFS in the IC2/3 group (n = 48) was 6 months, with a 1-year rate of 39%. At a 14-month follow-up, the median OS in this group had not been reached, with a 1-year rate of 57%. In the IC0/1 group, the median PFS was 1 month and the median OS was 7.6 months. The 1-year PFS and OS rates were 10% and 38%, respectively.

"Metastatic urothelial bladder cancer is associated with poor outcome. There are currently no FDA-approved therapies for patients who relapse after platinum-based therapy, and the overall survival is 5 to 7 months," lead investigator Daniel P. Petrylak, MD, co-director of the Signal Transduction Research Program at Yale Cancer Center, said during his presentation at ASCO. "Atezolizumab has demonstrated promising clinical activity in a heavily pretreated metastatic urothelial bladder cohort with encouraging survival and clinically meaningful response data."

The most frequently observed all-grade AEs with atezolizumab were fatigue (16%), asthenia (13%), nausea (11%), decreased appetite (10%), pruritus (10%), rash (8%), pyrexia (7%), diarrhea (5%), and increased AST (2%). There were no treatment-related deaths and only 1 patient discontinued therapy due to an adverse event.

Five percent of patients had a grade 3/4 immune-related AE, including increased AST (n = 3), increased ALT (n = 2), increased blood bilirubin (n = 1), and hypophysitis (n = 1). Overall, 40% of patients had a grade 3/4 AE of any cause.

"Atezolizumab has been well tolerated with manageable side effects. No treatment-related deaths were noted, and grade 3/4 immune-mediated AEs were only seen in 5%," Petrylak added.

In addition to the IMvigor 210 study, two phase III studies are also assessing atezolizumab for patients with bladder cancer. In the phase III IMvigor 211 study, atezolizumab is being compared with chemotherapy in patients with relapsed UBC. Additionally, the phase III IMvigor 010 study will assess adjuvant atezolizumab versus observation in patients with early-stage muscle-invasive bladder cancer based on PD-L1 status.

In addition to bladder cancer, atezolizumab has been explored across a variety of solid tumors. Earlier this year, atezolizumab received a breakthrough therapy designation in non—small cell lung cancer. The therapy has also demonstrated efficacy in a phase I study for patients with triple-negative breast cancer. Based on these findings, pivotal studies are underway for both of these indications.

Petrylak DP, Powles T, Bellmunt J, et al. A phase Ia study of MPDL3280A (anti-PDL1): Updated response and survival data in urothelial bladder cancer (UBC). J Clin Oncol. 2015;33 (suppl; abstr 4501).