Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial

Summary

Background

Few options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population.

Methods

We conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged ≥18 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m², paclitaxel 175 mg/m², or 75 mg/m² docetaxel) intravenously every 3 weeks. Randomisation was stratified by PD-L1 expression (expression on <1% [IC0] or 1% to <5% [IC1] of tumour-infiltrating immune cells vs ≥5% of tumour-infiltrating immune cells [IC2/3]), chemotherapy type (vinflunine vs taxanes), liver metastases (yes vs no), and number of prognostic factors (none vs one, two, or three). Patients and investigators were aware of group allocation. Patients, investigators, and the sponsor were masked to PD-L1 expression status. The primary endpoint of overall survival was tested hierarchically in prespecified populations: IC2/3, followed by IC1/2/3, followed by the intention-to-treat population. This study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT02302807.

Findings

Between Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11·1 months [95% CI 8·6–15·5; n=116] vs 10·6 months [8·4–12·2; n=118]; stratified hazard ratio [HR] 0·87, 95% CI 0·63–1·21; p=0·41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15·9 months [95% CI 10·4 to not estimable] vs 8·3 months [5·6–13·2]; HR 0·57, 95% CI 0·26–1·26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3–4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients).

Interpretation

Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting.

Funding

F Hoffmann-La Roche, Genentech.

Introduction

Advanced urothelial carcinoma has a poor prognosis, with few patients surviving more than 5 years after diagnosis.¹ First-line cisplatin-based chemotherapy can improve overall survival,2, 3 but most patients have disease progression. Treatment patterns for locally advanced or metastatic urothelial carcinoma following platinum-containing chemotherapy vary globally. Vinflunine (approved only in the European Union [EU]) and taxanes are commonly used,4, 5 with prospective clinical data for these drugs showing a modest median overall survival of 6–7 months in this setting.6, 7 In the past few years, checkpoint inhibitors have changed the treatment of metastatic urothelial carcinoma.⁸ In a randomised phase 3 trial,⁹ patients with metastatic urothelial carcinoma given pembrolizumab, an anti-programmed death-1 (PD-1) drug, had longer survival than did those given chemotherapy. Additionally, atezolizumab—a monoclonal antibody that inhibits programmed death-ligand 1 (PD-L1) while leaving the PD-L2–PD-1 interaction intact10, 11—is active and well tolerated across multiple cancers, including metastatic urothelial carcinoma.11, 12, 13, 14, 15, 16

Research in context

Evidence before this study

Between Jan 1, 2005, and Sep 5, 2014, we searched PubMed and international congress presentations pertaining to phase 3 studies of platinum-treated urothelial carcinoma. We searched PubMed for articles published in English with medical subject heading search terms ”advanced” AND “bladder cancer”, “urothelial carcinoma”, “transitional cell carcinoma”. Before the present study (IMvigor211), vinflunine was the only drug approved by a health authority (in Europe) for the treatment of advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy based on phase 3 data. Vinflunine and taxanes were commonly used drugs globally, but no standard appeared to predominate, and these drugs were associated with poor overall survival and toxicity. Because cancer immunotherapies had provided breakthroughs in numerous tumour types, and because urothelial carcinomas might be especially immunogenic on the basis of high somatic mutation burden, checkpoint inhibitor drugs targeting the programmed death-ligand 1 (PD-L1)–anti-programmed death-1 pathway warranted investigation in this setting. Single-arm phase 1 and 2 data with atezolizumab from 2014–17 have demonstrated safety and activity in this setting of previously treated metastatic urothelial carcinoma.

Added value of this study

To our knowledge, IMvigor211 is the first phase 3 randomised trial to report results for an anti-PD-L1 antibody in patients with metastatic urothelial carcinoma. Atezolizumab did not prolong overall survival in the predefined population of patients with PD-L1 expression on 5% or more of tumour-infiltrating immune cells, which precluded further statistical analysis. The PD-L1 biomarker enriched for responses in both the chemotherapy and the atezolizumab groups, which was unexpected and partly accounted for the negative result of the trial. Atezolizumab was associated with well tolerated, durable remissions in both the PD-L1-selected and intention-to-treat populations—a finding that was consistent with previous phase 2 data and that is uncommon with chemotherapy. Exploratory analysis showed differential overall survival benefit within the control group, based on chemotherapy choice, which could have accounted for some of the findings. Our results additionally show promise for alternative biomarkers beyond PD-L1 expression, such as tumour mutation burden. The data suggest that the risk–benefit profile for atezolizumab could be acceptable in patients with platinum-treated advanced urothelial carcinoma.

Implications of all the available evidence

Five immune checkpoint inhibitors have been approved in at least one country for patients with platinum-treated metastatic urothelial carcinoma. Data from randomised phase 3 trials exist for only atezolizumab and pembrolizumab. These checkpoint inhibitors appear attractive compared with chemotherapy in unselected patients in this setting and have potential to change the standard of care.

US approval of atezolizumab in patients with platinum-treated metastatic urothelial carcinoma was based on findings from phase 1 and 2 studies showing durable responses with long-term clinical benefit.12, 16 Although atezolizumab has shown activity in patients with all levels of PD-L1 expression, response rates were notably higher in patients with higher PD-L1 expression on tumour-infiltrating immune cells.12, 16 We therefore designed the IMvigor211 study to compare overall survival with atezolizumab to that with chemotherapy by PD-L1 expression in patients with platinum-treated metastatic urothelial carcinoma. To increase our understanding of the biology of metastatic urothelial carcinoma, we also explored the relevance of tumour mutation burden to overall survival. Here, we report results of the primary and exploratory analyses.