Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response.

— Jonathan E. Rosenberg, MD, and colleagues

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In a phase II trial reported in The Lancet, Jonathan E. Rosenberg, MD, of Memorial Sloan Kettering Cancer Center, and colleagues found that the anti–PD-L1 (programmed cell death ligand 1) antibody atezolizumab produced durable responses in a marked proportion of patients with previously treated locally advanced or metastatic urothelial carcinoma, with a higher response rate being associated with higher expression of PD-L1 (programmed cell death ligand 1) on infiltrating immune cells (ICs).¹ It was also found that response was associated with The Cancer Genome Atlas (TCGA) bladder cancer intrinsic molecular subtypes and mutation load.

Study Details

In the study, 310 patients from 70 academic medical centers and community oncology practices in Europe and North America were enrolled between May 2014 and November 2014 and received atezolizumab intravenously (IV) at 1,200 mg every 3 weeks. Patients had inoperable locally advanced or metastatic urothelial carcinoma progressing after platinum-based chemotherapy.

Formalin-fixed paraffin-embedded tumor specimens were obtained from patients before enrollment. PD-L1 expression on tumor-infiltrating immune cells was assessed prospectively by immunohistochemistry, with categories defined by percentage of PD-L1–positive cells: IC0 (< 1%), IC1 (≥ 1% but < 5%), and IC2/3 (≥ 5%). The co-primary endpoints were objective response rate on independent review according to RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 and investigator-assessed objective response rate according to immune-modified RECIST in the intention-to-treat population.

Overall, 33% of patients were in the IC0 group, 35% were in the IC1 group, and 32% were in the IC2/3 group, with baseline characteristics among the groups being similar. In total, patients had a median age of 66 years, 78% were male, 91% were white, 78% had visceral metastases, and 82% had received at least one systemic regimen in the metastatic setting.

Response Rates

The primary analysis (data cutoff in May 2015) showed that compared with a response rate of 10% in historical controls, atezolizumab treatment resulted in a significantly improved objective response rate for each prespecified immune cell group, with rates of 27% in IC2/3 (P < .0001), 18% in IC1/2/3 (P = .0004), and 15% in all patients (P = .0058). With longer follow-up (data cutoff in September 2015), objective response rates on independent review were 26% in the IC2/3 group, 18% in the IC1/2/3 group, and 15% overall. On investigator assessment, response rates were 27% in the IC2/3 group, 22% in the IC1/2/3 group, and 19% among all patients. After a median follow-up of 11.7 months, 38 (84%) of 45 responders had an ongoing response.

Intrinsic Subtype and Mutation Load

In exploratory analyses, 195 patients were classified into luminal cluster I (n = 72) and II (n = 50) and basal cluster III (n = 38) and IV (n = 35) intrinsic TCGA subtypes. PD-L1 immune cell prevalence was greater in the basal subtype (60% vs 23%, P < .0001). Response to atezolizumab occurred in all TCGA subtypes but was significantly higher in the luminal cluster II subtype (34%, P = .0017) than in subtypes I (10%), III (16%), and IV (20%).

Estimation of mutation load in 150 patients using a panel of 350 cancer-related genes showed that median mutation load was significantly higher in responders (12.4 vs 6.4 per megabase, P < .0001). The association between mutation load and response was not related to TCGA subtype (P = .2200) or immune cell subgroup.

Adverse Events

Grade 3 or 4 treatment-related adverse events occurred in 16% of patients, with fatigue (2%) being the most common. Grade 3 or 4 immune-related adverse events occurred in 5%, with pneumonitis, increased aspartate transaminase, increased alanine transaminase, rash, and dyspnea being the most common. Treatment-related serious adverse events occurred in 11%; no treatment-related deaths were observed. Overall, adverse events led to dose interruption in 30%, treatment withdrawal in 4%, and systemic steroid use in 22%.

The investigators concluded:

“Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma.” ■

Disclosure: The study was funded by F. Hoffmann-La Roche Ltd. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet. March 4, 2016 (early release online).