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.