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

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.

Lancet. 2018 Feb 24;391(10122):748-757. doi: 10.1016/S0140-6736(17)33297-X. Epub 2017 Dec 18.

Powles T1, Durán I2, van der Heijden MS3, Loriot Y4, Vogelzang NJ5, De Giorgi U6, Oudard S7, Retz MM8, Castellano D9, Bamias A10, Fléchon A11, Gravis G12, Hussain S13, Takano T14, Leng N15, Kadel EE 3rd15, Banchereau R15, Hegde PS15, Mariathasan S15, Cui N15, Shen X15, Derleth CL15, Green MC15, Ravaud A16.

1Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St Bartholomew's Hospital, London, UK. 
2Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain; Institute of Biomedicine of Seville, Seville, Spain.
3Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
4Département de Médecine Oncologique, Université Paris-Saclay, Gustave Roussy, Villejuif, France.
5US Oncology Research, Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
6Istituto Scientifico Romagnolo per lo studio e la Cura dei Tumori IRST IRCCS, Meldola, Italy.
7Oncology Department, European Georges Pompidou Hospital, René Descartes University, Paris, France.
8Department of Urology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
9University Hospital 12 de Octubre, Medical Oncology Department CIBER-ONC, Madrid, Spain.
10National and Kapodistrian University of Athens Alexandra Hospital, Athens, Greece.
11Centre Léon Bérard, Lyon, France.
12Department of Cancer Medicine, Institut Paoli Calmette, Marseille, France.
13Plymouth University, Peninsula Schools of Medicine and Dentistry, Plymouth University Hospitals NHS Trust, Plymouth, UK.
14Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan.
15Genentech, South San Francisco, CA, USA.
16Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France.
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