Elsevier

The Lancet

Volume 393, Issue 10189, 15–21 June 2019, Pages 2404-2415
The Lancet

Articles
Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial

https://doi.org/10.1016/S0140-6736(19)30723-8Get rights and content

Summary

Background

A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma.

Methods

In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821.

Findings

Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57–0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76–1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3–4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation.

Interpretation

Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma.

Funding

F Hoffmann–La Roche Ltd and Genentech Inc.

Introduction

In patients with locally advanced or metastatic renal cell carcinoma, tyrosine kinase inhibitors targeting vascular endothelial growth factor (VEGF), such as sunitinib, have been the first-line standard of care for the past decade.1, 2, 3 However, many patients have disease that is inherently resistant to these approaches, and almost all patients acquire resistance over time.4 Efficacy is particularly low in some patient subgroups, including cases with a sarcomatoid differentiation5 and disease expressing programmed death-ligand 1 (PD-L1).6, 7, 8 Additionally, the use of these drugs can be limited by adverse events, such as diarrhoea, fatigue, palmar-plantar erythrodysaesthesia, and mucositis, which impair patients' quality of life,9, 10 underscoring a need for new therapeutic targets and drug combinations for patients with metastatic renal cell carcinoma. Treatment with checkpoint inhibitors, including the anti-PD-L1 antibody atezolizumab, has resulted in durable responses and improvements in overall survival in pre-treated patients with metastatic renal cell carcinoma.7, 11, 12

Research in context

Evidence before this study

We searched PubMed and international congress presentations pertaining to studies in metastatic renal cell carcinoma between May 1, 2010, and May 1, 2015, for articles published in English with MeSH search terms “metastatic” AND “kidney cancer”, “renal cell carcinoma”, “programmed cell death 1”, “PD-1”, “programmed cell death ligand 1”, and “PD-L1”. We identified an unmet clinical need for effective and tolerable approaches to the treatment of patients with metastatic renal cell carcinoma. Approved therapies in the first-line metastatic setting included tyrosine kinase inhibitors, such as sunitinib and pazopanib, and the combination of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab with interferon alfa-2a; however, these therapies are associated with considerable morbidity due to adverse events and do not result in a sustained, durable clinical benefit. Additionally, elevated programmed death-ligand 1 (PD-L1) expression on tumour-infiltrating immune cells is often associated with a worse prognosis in renal cell carcinoma. Checkpoint inhibitors, such as atezolizumab, nivolumab, and pembrolizumab, target the PD-L1 or programmed cell death protein 1 (PD-1) pathway and represent an attractive strategy to reinvigorate tumour-specific T-cell immunity. Despite numerous advancements, metastatic renal cell carcinoma remains a largely incurable disease because a substantial majority of patients develop resistance to standard therapies, including VEGF-directed drugs or immunotherapy. Therefore, an ongoing need exists for more-efficacious and better-tolerated treatments. Collectively, the role of VEGF in the immune response and its crucial role in renal cell carcinoma pathogenesis provide a compelling rationale to test whether dual inhibition of the PD-L1–PD-1 and VEGF pathways will result in improved clinical benefit for patients with metastatic renal cell carcinoma.

Added value of this study

The IMmotion151 trial met its coprimary endpoint, showing improved investigator-assessed progression-free survival with atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma whose disease expressed PD-L1. Clinical efficacy is further supported by higher objective response rates, especially complete response rates, with atezolizumab plus bevacizumab versus sunitinib treatment. Overall survival did not cross the significance boundary, and longer-term follow-up is necessary to establish whether a survival benefit will emerge. Patients given atezolizumab plus bevacizumab had improved progression-free survival regardless of the clinical risk group examined, including patients with previous nephrectomy, sarcomatoid histology, and established prognostic risk scores, including patients with favourable prognostic risk. The combination of atezolizumab plus bevacizumab was shown to have a tolerable safety profile consistent with previous studies and was associated with fewer high-grade treatment-related adverse events and a lower regimen discontinuation rate versus sunitinib, and low corticosteroid use. Additionally, patients reported a delay in symptom interference with daily living when given atezolizumab plus bevacizumab versus sunitinib. Results support the clinical activity of checkpoint inhibitor-based combinations in first-line metastatic renal cell carcinoma.

Implications of all the available evidence

Given that both the VEGF and PD-L1 pathways are important in renal cell carcinoma pathogenesis, concomitant inhibition of VEGF signalling might enhance the efficacy of immunotherapy in the front-line treatment of patients with metastatic renal cell carcinoma. Results from this study and others support this hypothesis.

Bevacizumab binds to VEGF and is approved in combination with interferon alfa for metastatic renal cell carcinoma.13 In addition to its antiangiogenic effects,14 VEGF blockade by bevacizumab modulates the immune environment, including enhancing T-cell priming and activation via promotion of dendritic cell maturation,15, 16 increasing T-cell tumour infiltration by normalising tumour vasculature,17, 18 and establishing an immune-permissive tumour microenvironment by decreasing myeloid-derived suppressor-cell and regulatory T-cell populations.18, 19 Therefore, T-cell-mediated cancer-cell killing by atezolizumab could be enhanced through reversal of VEGF-mediated immunosuppression mechanisms by the addition of bevacizumab.20

Objective responses for atezolizumab plus bevacizumab were first observed in a phase 1b study18 in metastatic renal cell carcinoma. Subsequently, a phase 2 study11 assessed atezolizumab alone and in combination with bevacizumab versus sunitinib. Atezolizumab plus bevacizumab improved progression-free survival and the proportion of patients who achieved an objective response versus sunitinib in the subgroup of patients with disease expressing PD-L1. Atezolizumab also showed antitumour activity when administered as a single drug, supporting complementary activity of bevacizumab plus atezolizumab in patients with metastatic renal cell carcinoma.

We report the primary analysis of the efficacy and safety of atezolizumab plus bevacizumab versus sunitinib in the IMmotion151 study, the first randomised, phase 3 trial combining an anti-PD-L1–PD-1 antibody with an anti-VEGF drug as treatment for patients with metastatic renal cell carcinoma.

Section snippets

Study design and participants

We did a multicentre, open-label, phase 3, randomised controlled trial at 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region (Australia, Bosnia and Herzegovina, Brazil, Canada, Czech Republic, Denmark, France, Germany, Italy, Japan, South Korea, Mexico, Poland, Russia, Singapore, Spain, Taiwan, Thailand, Turkey, UK, and USA; appendix). Eligible patients were aged 18 years or older with unresectable locally

Results

The study enrolled 915 patients in the ITT population between May 20, 2015, and Oct 12, 2016, at 152 sites across 21 countries; 454 patients were randomly assigned to receive atezolizumab plus bevacizumab and 461 patients to receive sunitinib (figure 1). A total of 362 (40%) of 915 patients had PD-L1 positive tumours. Baseline characteristics were well balanced between study groups and between the PD-L1 positive and ITT populations (table 1). Overall, 142 (16%) patients had tumours with a

Discussion

This phase 3 study met its co-primary endpoint by showing improved progression-free survival with atezolizumab plus bevacizumab over sunitinib in patients with metastatic renal cell carcinoma whose disease expressed PD-L1. Clinical efficacy is supported by a higher proportion of patients in the atezolizumab plus bevacizumab group achieving an objective response than those in the sunitinib group, most notably the proportion achieving a complete response. The observed progression-free survival

Data sharing

Qualified researchers can request access to individual patient-level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here: https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx. For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here //www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm

References (29)

  • RJ Motzer et al.

    Pazopanib versus sunitinib in renal cancer

    N Engl J Med

    (2013)
  • S Patel et al.

    Phase 2 study of intravenous TZT-1027 in patients with advanced or metastatic soft-tissue sarcomas with prior exposure to anthracycline-based chemotherapy

    Cancer

    (2006)
  • DF McDermott et al.

    Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma

    Nat Med

    (2018)
  • RJ Motzer et al.

    Nivolumab for metastatic renal cell carcinoma: results of a randomized phase 2 trial

    J Clin Oncol

    (2015)
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    Investigators listed in the appendix

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