Background
Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma.
Methods
In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m 2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m 2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov, NCT02807636.
Findings
Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1–17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5–8·3) in group A and 6·3 months (6·2–7·0) in group C (stratified hazard ratio [HR] 0·82, 95% CI 0·70–0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9–18·9) in group A and 13·4 months (12·0–15·2) in group C (0·83, 0·69–1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1–17·8) for group B and 13·1 months (11·7–15·1) for group C (1·02, 0·83–1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo.
Interpretation
Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma.
Funding
F Hoffmann-La Roche and Genentech.
Cisplatin-based chemotherapy remains the only treatment known to offer the potential for cure in advanced/metastatic urothelial carcinoma, albeit in only a small subset of patients. PD-L1 and PD-1 inhibitors alone have demonstrated significant activity as both first- and second-line immunotherapies in this setting, but in only a modest subset of patients. In the Lancet, Matthew Galsky and colleagues reported the results of IMvigor130, which investigated atezolizumab alone or in combination with chemotherapy in this setting.
IMvigor130 was a three-arm randomized trial, which compared atezolizumab monotherapy versus SOC (platinum-based chemotherapy) versus platinum-based chemotherapy with atezolizumab, which enrolled 1213 patients in first-line metastatic urothelial carcinoma. Patients received 21-day cycles of gemcitabine (1000 mg/m2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. The atezolizumab monotherapy arm received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival.
The chemotherapy plus atezolizumab combination arm achieved a statistically significant increase in progression-free survival, with a median of 8.2 months (95% CI 6.5-8.3) compared with 6.3 months (6.2-7.0) in the chemotherapy alone plus placebo group (HR: 0.82, 95% CI 0.70-0.96; one-sided p=0.007), thus meeting the primary endpoint of the study. After a median follow-up of 11·8 months, overall survival was not significantly different between these two groups at the interim analysis (0.83; 0.69-1.00; one-sided p=0.027). Withdrawal rates due to adverse events were 34% with either atezolizumab plus chemotherapy or with chemotherapy alone (34%) and only 6% with atezolizumab alone.
The IMvigor130 data raise several questions. First, it is becoming apparent that immune checkpoint inhibitors and their companion biomarkers do not perform predictably across different tumor types, or even within the same tumor type (different setting and drug). Therefore, translation of data from one tumor type to another should be avoided. Second, the debate over whether there is a preferable immune checkpoint inhibitor in advanced urothelial carcinoma is ongoing. As things stand, it is hard to formulate a clear position suggesting one drug is clearly more effective than another.
The IMvigor130 results presented here could be the first of several positive trials in this setting with several new drugs on the block, which will have a substantial long-term impact on the treatment of advanced/metastatic urothelial carcinoma.