Nearly three decades have passed since the first ground-breaking treatments were developed for patients with metastatic urothelial carcinoma. The combination chemotherapy regimen methotrexate, vinblastine, doxorubicin, and cisplatin has not been surpassed in terms of response and survival.1 In 2000, gemcitabine plus cisplatin was tested as a less toxic alternative, but 37% of patients could not tolerate the treatment regimen.2 Decades of research exploring cytotoxic frontline chemotherapies followed,3 but no treatments were able to exceed the therapeutic outcomes achieved with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin. About 25–50% of patients with metastatic urothelial carcinoma are unable to receive cisplatin-based chemotherapy because of renal impairment.4 Nonetheless, platinum-based combination chemotherapy remains the standard first-line treatment for patients with metastatic urothelial carcinoma.4 In the second-line setting, many drugs have been tested, but none have become established as a standard of care because of a low frequency of response (10% of patients or less). The most intensively studied regimen in the second-line setting—vinflunine plus best supportive care—did not significantly improve overall survival compared with best supportive care in a phase 3 trial (hazard ratio 0·9, 95% CI 0·7–1·1; intention-to-treat population),5 although an increase in median overall survival of 2·6 months was noted with vinflunine in a subsequent analysis of the eligible population that excluded patients with protocol violations at baseline (hazard ratio 0·8, 95% CI 0·6–1·0; p=0·023).
Immune checkpoint treatment, consisting of blockade of immune inhibitory pathways, has led to substantial advances in the treatment of cancer. The potential for this approach in the treatment of urothelial carcinoma is suggested by the effectiveness of immunotherapy with BCG; given intravesically, BCG induces an immune response against tumour cells and is indicated as adjuvant treatment after surgical resection in patients with high-grade non-muscle-invasive urothelial carcinoma.6 The immune checkpoint inhibitor ipilimumab, which blocks CTLA-4, enhanced immune responses and tumour regression in studies of patients with localised urothelial carcinoma.7, 8
Research in context
Evidence before this study
We searched PubMed from Dec 1, 1994, to May 31, 2014, using the search terms “metastatic urothelial carcinoma”, “relapsed urothelial carcinoma”, “clinical trials”, “immune response”, “immune checkpoint blockade”, and “immunotherapy”. Studies identified from the search revealed poor outcomes for patients with recurrent or relapsed urothelial carcinoma, with few treatment options to improve survival. A few papers reported findings from studies investigating immunotherapy in advanced urothelial carcinoma, including BCG treatment. The immune system is a target for treatment in urothelial carcinoma; immunotherapy with BCG is standard treatment for superficial urothelial carcinoma, reducing the risk of local recurrence by about 60% and leading to 5-year survival of about 90% in patients with unifocal disease. Additionally, CD8+ tumour-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma; patients with advanced urothelial cancer and higher numbers of CD8+ tumour-infiltrating lymphocytes within the tumour (≥8 cells) seem to have better disease-free and overall survival than those with similar-staged urothelial carcinoma and fewer intra-tumoural CD8+ tumour-infiltrating lymphocytes. Together with the promising anti-PD-L1 data reported in advanced urothelial carcinoma, these findings provided the rationale for further investigation of immune checkpoint blockade with the PD-1 inhibitor nivolumab for recurrent metastatic urothelial carcinoma.
Added value of this study
This study includes, to our knowledge, the largest datasets for an anti-PD-1 immune checkpoint inhibitor in second-line (and beyond) urothelial carcinoma, a disease for which few treatment options exist. The proportion of patients with an objective response, the duration of responses, and the overall survival reported might signify greater clinical activity than other available options.
Implications of all the available evidence
Patients with recurrent metastatic urothelial carcinoma have poor clinical prospects because of the scarcity of effective treatments. A growing body of evidence suggests that immune checkpoint inhibition can offer effective treatment for patients with urothelial carcinoma, as in other tumour types. The results presented here support further development of PD-1 checkpoint inhibition in larger trials of this disease.
A promising target for immunotherapy is the PD-1/PD-L1 immune checkpoint. PD-1 is expressed on T cells and can inhibit T-cell responses on interaction with its ligands, PD-L1 and PD-L2; high PD-L1 expression has been found in bladder tumour cells.9, 10 In a clinical trial with atezolizumab,11 an antibody that blocks PD-L1, 15% of patients with metastatic or surgically unresectable urothelial carcinoma who were previously treated with platinum-based chemotherapy responded to treatment, leading to US Food and Drug Administration approval of this drug for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or after platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Treatment with nivolumab, a fully human monoclonal IgG4 antibody that blocks PD-1, has proven effective in several solid tumours. Compared with comparator treatments (eg, dacarbazine, docetaxel, or everolimus), nivolumab improved overall survival in melanoma,12 non-small-cell lung cancer,13, 14 renal-cell carcinoma,15 and head and neck cancer,16 and studies have shown promising clinical activity in several additional malignancies including Hodgkin’s lymphoma17 and microsatellite-unstable colorectal cancer.18
Nivolumab is being investigated in an ongoing multicentre, open-label, phase 1/2 clinical study of several advanced or metastatic solid tumour types (CheckMate 032).19, 20 We report the activity and safety of nivolumab monotherapy in a cohort of patients from this study who had locally advanced or metastatic urothelial carcinoma (unselected for PD-L1 expression) and were previously treated with platinum-based chemotherapy.