Jean H. Hoffman-Censits, MD
Second-line treatment with atezolizumab (MPDL3280A) led to a median overall survival (OS) of 11.4 months in patients with locally advanced or metastatic urothelial carcinoma (mUC) who had high PD-L1 levels, according to updated data from the pivotal phase II IMvigor 210 study. Regardless of PD-L1 status, 38 of 45 patients (84%) who responded to the anti–PD-L1 agent had ongoing responses.
“This primary analysis of IMvigor 210 demonstrated that atezolizumab has the potential to change the standard of care for metastatic urothelial cancers,” lead study author Jean H. Hoffman-Censits, MD, director, Multidisciplinary Genitourinary Oncology Center, Kimmel Cancer Center, Thomas Jefferson University Hospital, said when presenting the data at the 2016 Genitourinary Cancers Symposium.
In the open-label, single-arm, multicenter IMvigor 210 study, atezolizumab was administered at 1200 mg intravenously on the first day of each 21-day cycle. The trial consisted of 2 cohorts: Cohort 1 enrolled patients with untreated mUC and Cohort 2 recruited those who had progressed on prior treatment with a platinum-based regimen. Data from Cohort 2 were presented at the GU Symposium, while results from Cohort 1 are not yet mature.
The Cohort 2 population included 316 pretreated patients, 40% of whom had received at least 2 systemic regimens for metastatic disease. Of the 316 patients, 311 were evaluable (median page, 66 years).
The primary endpoint of the study was objective response rate (ORR) by RECIST v1.1, with secondary outcome measures focused on duration of response (DoR), OS, progression-free survival (PFS), and safety. PD-L1 status was assessed on tumor cells and immune cells using an SP142 antibody-based immunohistochemistry assay developed by Roche Diagnostics. The median treatment duration was 12 weeks (range, 0-46).
The ORR results were stratified by level of PD-L1 expression as measured by PD-L1 tumor-infiltrating immune cell (IC) status: IC 2/3 (medium and high expression; n = 100), IC 1/2/3 (any expression; n = 208), and all patients (n = 310).
At a median follow-up of 11.7 months (range, 0.2+ months to 15.2 months), ORR was 26% at the IC 2/3 level, 18% for the IC 1/2/3 subgroup, and 15% in all patients (P
<.01 for all groups). Complete response rates were 11%, 6%, and 5%, respectively.
Responses were also observed in several subgroups with poor prognostic factors, including visceral metastases (n = 243; ORR = 10%), liver metastases (n = 97; ORR = 6%), ECOG performance status of 1 (n = 193; ORR = 10%), and Hb <10 g/dL (n = 68; ORR = 9%).
The median duration of response has not yet been reached.
The median PFS was 2.1 months, regardless of PD-L1 status. The 6-month PFS rate was 30%, 23%, and 21% in the high–PD-L1 subgroup, low–PD-L1 cohort, and total population, respectively.
Median OS was 11.4 months, 8.8 months, and 7.9 months, in the IC 2/3, IC 1/2/3, and overall populations, respectively, with 12-month OS rates of 48%, 39%, and 36%.
Atezolizumab is an engineered monoclonal antibody that binds to the ligand PD-L1, preventing the activation of PD-1. The antibody is modified to prevent the induction of antibody-dependent cytotoxicity or complement-dependent cytotoxicity. This design is meant to reduce toxicity seen with the agent.
In IMvigor 210, “Atezolizumab was well tolerated with no treatment-related deaths, a low rate of treatment-related grade 3/4 toxicities, and no treatment related renal toxicity,” the manufacturer of the anti–PD-L1 antibody, Roche, reported in a statement.
Sixty-nine percent of patients experienced an adverse event (AE) of any grade. Grade 3/4 treatment-related AEs occurred in 16% of patients and grade 3/4 immune-related AEs occurred in 5% of patients. The most frequently occurring grade 3/4 AEs were fatigue at 2% and decreased appetite, anemia, pneumonitis, hypertension, hypotension, colitis, arthralgia, dyspnea, and ALT increase at 1% each. There were no deaths associated with treatment.
Based on phase I data, atezolizumab received a breakthrough therapy designation from the FDA in 2014 for patients with mUC whose tumors express PD-L1. Roche is planning to submit results from the IMvigor 210 trial to the FDA under this designation.
“It is encouraging to see that the majority of people with advanced bladder cancer who responded to atezolizumab maintained their response with longer follow up,” said Sandra Horning, MD, chief medical officer and Head of Global Product Development of Roche, said in a statement. “We are looking forward to sharing these results with the FDA and other health authorities in the hope that we may bring atezolizumab to treating physicians and their patients as soon as possible.