As reported in The Lancet by Matthew D. Galsky, MD, of Icahn School of Medicine at Mount Sinai, and colleagues, the phase III IMvigor130 trial has shown prolonged progression-free survival with first-line atezolizumab plus platinum-based chemotherapy vs platinum-based chemotherapy alone in patients with locally advanced or metastatic urothelial cancer. No significant difference was observed between the two groups in overall survival, a co-primary endpoint, on interim analysis. No formal statistical analysis of overall survival for atezolizumab monotherapy vs chemotherapy, an additional co-primary endpoint, was performed due to the lack of significant difference between the atezolizumab/chemotherapy group vs chemotherapy group.  

Matthew D. Galsky, MD

Study Details

The trial initially enrolled and randomly assigned patients to an atezolizumab/chemotherapy arm or a placebo/chemotherapy arm; a subsequent protocol amendment added an atezolizumab monotherapy arm. Based on an unplanned independent data monitoring committee review of early survival data showing poorer survival with atezolizumab monotherapy vs chemotherapy, the monotherapy arm was closed to patients with programmed cell death ligand 1 (PD-L1) tumor expression of < 5%.

The placebo-controlled, partly blinded trial enrolled 1,213 patients with locally advanced or metastatic (88% to 92% of patients) disease from sites in 35 countries. Patients were randomly assigned between July 2016 and July 2018 to receive atezolizumab (blinded) plus platinum-based chemotherapy (n = 451, 37%), atezolizumab alone (open-label; n = 362, 30%), or placebo plus chemotherapy (n = 400, 33%). Randomization stratification factors included PD-L1 immune cell expression status of IC0 (< 1%) vs IC1 (≥ 1% and < 5%) vs IC2/3 (≥ 5%). Treatment consisted of 21-day cycles of gemcitabine at 1,000 mg/m² on days 1 and 8 of each cycle plus either (chosen by investigator prior to randomization) carboplatin at area under the curve of 4.5 mg/mL/min or cisplatin at 70 mg/m² on day 1 of each cycle, plus either atezolizumab at 1,200 mg or placebo on day 1 of each 21-day cycle; the monotherapy group received atezolizumab at 1,200 mg on day 1 of each 21-day cycle.

The co-primary endpoints, all in the intention-to-treat population, were investigator-assessed progression-free survival according to RECIST version 1.1 criteria and overall survival for the atezolizumab/chemotherapy group vs the chemotherapy alone group and overall survival for the atezolizumab alone group vs the chemotherapy group; the latter was to be formally tested only if  atezolizumab/chemotherapy showed an overall survival benefit vs chemotherapy.

Progression-Free and Overall Survival

Median follow-up for survival was 11.8 months for all patients.

At the time of final progression-free survival analysis and interim overall survival analysis (May 2019), median progression-free survival was 8.2 months (95% confidence interval [CI] = 6.5–8.3 months) in the atezolizumab/chemotherapy group vs 6.3 months (95% CI = 6.2–7.0 months) in the chemotherapy group (stratified hazard ratio [HR] = 0.82, P = .007). Median overall survival was 16.0 months (95% CI = 13.9–18.9 months) vs 13.4 months (95% CI = 12.0–15.2 months), with a stratified hazard ratio of 0.83 and P value of .027, which did not meet the prespecified interim efficacy boundary for statistical significance of P = .007.

Median progression-free survival for the atezolizumab/chemotherapy group vs the chemotherapy group according to PD-L1 expression level was 6.5 vs 6.2 months (HR = 0.79, 95% CI = 0.61–1.03) among 278 patients with IC0, 8.1 vs 6.7 months (HR = 0.89, 95% CI = 0.70–1.13) among 374 patients with IC1, and 8.6 vs 6.3 months (HR = 0.68, 95% CI = 0.49–0.95) among 199 patients with IC2/3. Median overall survival durations according to the respective PD-L1 expression levels were 14.2 vs 12.8 months (HR = 0.82, 95% CI = 0.60–1.12), 14.9 vs 13.4 months (HR = 0.87, 95% CI = 0.66–1.15), and 23.6 vs 15.9 months (HR = 0.74, 95% CI = 0.49–1.12).   

Efficacy comparisons for the atezolizumab monotherapy group vs the chemotherapy group included only the predefined subset of patients (n = 359) in the chemotherapy group enrolled after the amendment adding the atezolizumab monotherapy group, and before the amendment to limit enrollment in the monotherapy group to patients with PD-L1 expression ≥ 5%. Median overall survival was 15.7 months (95% CI = 13.1–17.8 months) in the atezolizumab monotherapy group vs 13.1 months (95% CI = 11.7–15.1 months) in the chemotherapy group (stratified HR = 1.02, 95% CI = 0.83–1.24). Among 88 vs 85 patients with PD-L1 IC2/3 tumors, median overall survival was not reached vs 17.8 months (HR = 0.68, 95% CI = 0.43–1.08). Among the 272 vs 274 patients with PD-L1 IC0/1 tumors, median overall survival was 13.5 vs 12.9 months (HR = 1.07, 95% CI = 0.86–1.33).

Adverse Events

Grade 3 or 4 adverse events occurred in 85% of patients in the atezolizumab/chemotherapy group, 42% of patients in the atezolizumab monotherapy group, and 86% of patients in the chemotherapy group; serious adverse events occurred in 52%, 43%, and 49% of patients, respectively. Withdrawal of any agent due to adverse events occurred in 34% of patients in the atezolizumab/chemotherapy group (atezolizumab in 11%), 6% of the atezolizumab monotherapy group, and 34% of the chemotherapy group (placebo in 7%). Adverse events led to death in 6%, 8%, and 5% of patients. Potentially immune-related adverse events of any grade occurred in 50%, 37%, and 35% of patients, and were grade 3 or 4 in 8%, 8%, and 4%. Six patients died from potentially immune-related adverse events, including three patients in the atezolizumab/chemotherapy group (due to hepatic failure, hepatitis, and pneumonitis), two in the atezolizumab monotherapy group (due to hepatic failure and interstitial lung disease), and one patient in the chemotherapy group (due to hepatitis).

The investigators concluded, “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.”

Dr. Galsky, of Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, is the corresponding author for The Lancet article.

Disclosure: The study was funded by F. Hoffmann-La Roche and Genentech. For full disclosures of the study authors, visit thelancet.com.