Elsevier

The Lancet

Volume 387, Issue 10031, 7–13 May 2016, Pages 1909-1920
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(16)00561-4Get rights and content

Summary

Background

Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population.

Methods

For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov, number NCT02108652.

Findings

Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19–37], p<0·0001; IC1/2/3: 18% [13–24], p=0·0004) and in all patients (15% [11–20], p=0·0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18–36) in the IC2/3 group, 18% (13–24) in the IC1/2/3 group, and 15% (11–19) overall in all 310 patients. With a median follow-up of 11·7 months (95% CI 11·4–12·2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3–4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3–4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study.

Interpretation

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.

Funding

F Hoffmann-La Roche Ltd.

Introduction

Urothelial carcinoma kills more than 165 000 patients annually worldwide and is the ninth most common cancer overall worldwide.1, 2 The efficacy of immunotherapy in non-muscle-invasive urothelial carcinoma of the bladder was first established in 1976 with BCG, but no immunotherapy has been approved for the treatment of advanced disease.3 Platinum-based chemotherapy is the standard of care in previously untreated patients with metastatic urothelial carcinoma, and is associated with an overall survival of around 9–15 months.4, 5 The prognosis for patients who relapse after platinum-based chemotherapy is poor, with median survival ranging from 5 to 7 months and no known life-prolonging treatments available.6 New approaches are needed to break this therapeutic stalemate.

Programmed death ligand 1 (PD-L1) is an immune checkpoint that negatively regulates T-cell function by binding to its receptors programmed death 1 (PD-1) or B7-1 on activated T lymphocytes and other immune cells. Because T lymphocytes have a central role in mediating acquired anti-tumour immunity, expression of PD-L1 in the tumour microenvironment endows tumours with a mechanism to evade eradication by the host immune system.7, 8, 9 PD-L1 is broadly expressed across a wide range of malignancies, including urothelial carcinoma, and blockade of the PD-L1–PD-1 pathway has been shown to produce overall survival benefits in non-small-cell lung cancer, melanoma, and renal cell carcinoma.7, 10, 11, 12, 13, 14, 15

Recent data have suggested that immune checkpoint inhibitors are more active in tumours with high mutation rates than in those with lower mutation rates.11, 16, 17, 18, 19, 20, 21, 22 Emerging data from The Cancer Genome Atlas (TCGA) suggest that urothelial carcinoma carries the third highest mutation rate of all studied cancers and that gene expression signatures could be used to separate the disease into luminal and basal subtypes.23, 24 Additional mechanisms, such as increased prevalence of non-synonymous mutations, higher neoantigen load, higher antigen binding affinity, and some T-effector signatures, have all been identified as factors that might predict for a durable clinical benefit in patients treated with immune checkpoint inhibitors, which is consistent with the hypothesis that mutations might create neoantigens that are recognised by anti-tumour T cells.25, 26, 27, 28, 29 Taken together, these observations provide a rationale for the clinical investigation of anti-PD-L1 immunotherapy in metastatic urothelial cancer.

Atezolizumab is an engineered humanised monoclonal immunoglobulin G1 antibody that binds selectively to PD-L1 and prevents its interaction with PD-1 and B7-1, while sparing the interaction between PD-L2 and PD-1.30, 31 Atezolizumab has shown durable responses in a cohort of patients with metastatic bladder cancer in a phase 1 study, with higher response rates recorded in patients with higher levels of PD-L1 expression on tumour-infiltrating immune cells than in those with lower PD-L1 expression.32

To confirm the anti-tumour activity of atezolizumab in patients with advanced urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy, we conducted a phase 2, global, multicentre, single-arm trial to assess the efficacy and safety of atezolizumab. Prospective assessment of the association of PD-L1 expression with response was a co-primary endpoint. Additionally, exploratory translational studies were done to address the scientific hypotheses associated with checkpoint inhibition in metastatic urothelial carcinoma.

Section snippets

Study design and participants

For this phase 2, global, multicentre, single-arm two-cohort trial (appendix p 9), patients aged 18 years or older were eligible for enrolment into either cohort 1 or 2 if they had histologically or cytologically documented locally advanced (on the TNM staging system, T4b and any N; or any T and N2–3) or metastatic (M1, stage IV) urothelial carcinoma (including of the renal pelvis, ureter, urinary bladder, or urethra). Cohort 1 comprised patients who had not received previous treatment in the

Results

Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 eligible patients were enrolled into the study in cohort 2 (figure 1 and appendix p 9). 310 patients received at least one dose of atezolizumab and were evaluable for efficacy and safety, whereas the other five enrolled patients later did not meet eligibility criteria and were not dosed with study drug. At the time of the data cutoff on Sept 14, 2015, 202 (65%) of 310 patients had discontinued treatment, of whom 193

Discussion

Since the development of combination treatment with methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy 30 years ago, no major improvements have been made in treatment outcomes for patients with urothelial carcinoma.44 The results of this large single-arm phase 2 study show that atezolizumab induced durable anti-tumour responses in patients with advanced urothelial carcinoma whose tumours have progressed during or after treatment with platinum-based chemotherapy. This trial

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