Research in context
Evidence before this study
We searched PubMed with the terms “metastatic urothelial carcinoma”, “surgically unresectable urothelial carcinoma”, “relapsed urothelial carcinoma”, “clinical trials”, “platinum based chemotherapy”, “immune response”, “immune checkpoint blockade”, “immunotherapy”, and “PD-L1 expression” for articles published in English between Sept 1, 2000, and Aug 31, 2016 (the date of our final search). The findings of this search suggested that patients with metastatic or surgically unresectable urothelial carcinoma have a poor prognosis, that first-line treatment with cisplatin-based chemotherapy has a response in only 50% of patients, and that this response is of short duration but is associated with considerable toxicities. Furthermore, patients whose disease progresses on cisplatin-based therapy have few treatment options. Objective responses to second-line single-agent chemotherapy are uncommon: they occur in approximately 10% of patients. No standard of care second-line therapy is available for these patients. Evidence suggests that urothelial carcinoma is an immunogenic disease, with high expression of PD-L1, and the presence of tumour-infiltrating lymphocytes in urothelial carcinoma specimens has been correlated with improved clinical outcomes. Immune checkpoint blockade is a promising new approach to activating therapeutic tumour immunity, as shown by the regulatory approval of an anti-PD-L1 agent to treat metastatic urothelial carcinoma in patients whose disease progressed during or after platinum-based chemotherapy. Furthermore, in an open-label, multicentre phase 1 and 2 expansion cohort study in patients with metastatic urothelial carcinoma, the PD-1 inhibitor nivolumab elicited a response in 24·4% of patients irrespective of tumour PD-L1 expression and with an acceptable safety profile, in patients who had received one or more previous lines of chemotherapy. These findings provided the rationale for further investigation of nivolumab in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed during or after platinum-based chemotherapy.
Added value of this study
No second-line treatments for metastatic urothelial carcinoma were approved until 2016. Our study is the largest to date to report the activity and safety of nivolumab, a PD-1 immune checkpoint inhibitor, in the second-line (or later) setting for the treatment of metastatic or surgically unresectable urothelial carcinoma. Nivolumab monotherapy provided a confirmed objective response and overall survival that was clinically meaningful, irrespective of tumour PD-L1 expression. These findings, taken together with those of a phase 2 study of atezolizumab (which has anti-PD-L1 activity), provide significant data showing that blockade of the PD-1–PD-L1 immune inhibitory pathway can elicit meaningful clinical responses in patients with metastatic urothelial carcinoma.
Implications of all the available evidence
Patients with metastatic or surgically unresectable locally advanced urothelial carcinoma that has progressed during or after one or more previous platinum-containing regimens have a poor prognosis, with few treatment options. Immune checkpoint inhibitors such as nivolumab have elicited significant improvements in outcomes across several tumour types, and increasing evidence suggests that these drugs could be an effective treatment option for patients with metastatic urothelial carcinoma. Findings from our study support further investigation of nivolumab in this setting.