Research in context
Evidence before this study
We searched PubMed and major international oncology and urology congresses for articles published in English pertaining to metastatic urothelial carcinoma between June 1, 2011, and June 1, 2016, with MeSH search terms “metastatic” AND “bladder cancer”, “urothelial carcinoma”, “urothelial cancer”, “programmed cell death 1”, “PD-1”, “programmed cell death ligand 1”, and “PD-L1”. This search identified an unmet clinical need for effective and tolerable therapies for metastatic urothelial carcinoma based on the paucity of positive data from randomised phase 3 studies. Platinum-based combination chemotherapy has been the preferred regimen in the first-line setting and single-agent chemotherapy is typically reserved for the second-line setting. However, 40–50% of patients with metastatic urothelial carcinoma are ineligible for cisplatin because of poor performance status, comorbidities, or impaired renal function, and these patients generally receive carboplatin-based regimens, an inferior option. Although tolerability has improved with new treatments over the past 30 years, efficacy has not. Checkpoint inhibitors that target programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) are the first new systemic therapies for metastatic urothelial carcinoma, both for first-line treatment of cisplatin-ineligible patients and for patients with disease progression despite platinum-based chemotherapy.
Added value of this study
To our knowledge, IMvigor130 is the first phase 3, randomised trial to report results for platinum-based chemotherapy plus PD-L1 or PD-1 blockade, or PD-L1 blockade alone or PD-1 blockade alone, versus standard platinum-based chemotherapy plus placebo as a first-line treatment for metastatic urothelial carcinoma. IMvigor130 met its co-primary progression-free survival endpoint, showing a significant improvement when atezolizumab was added to platinum-based chemotherapy versus platinum-based chemotherapy alone. At the interim analysis, the result for the co-primary endpoint of overall survival did not cross the interim efficacy boundary. The combination of atezolizumab plus platinum-based chemotherapy had a safety profile consistent with previous studies and with the safety profiles of each individual agent.
Implications of all the available evidence
The results of IMvigor130, to our knowledge the largest phase 3 trial reporting results from first-line treatment for metastatic urothelial cancer, included both cisplatin-eligible and cisplatin-ineligible patients. Preliminary results have already impacted clinical practice; recommendations from the US Food and Drug Administration and European Medicines Agency based on an unplanned early analysis by independent data monitoring committees of IMvigor130 led to revision of the prescribing label for atezolizumab for metastatic urothelial cancer in the first-line setting. Results from IMvigor130 support clinical activity of the atezolizumab plus chemotherapy combination as a potential first-line treatment option for metastatic urothelial carcinoma.