Immune Checkpoint Inhibition and Long-Term Survival in Patients With Metastatic Urothelial Cancer

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In an analysis reported in JAMA Network Open, Zhu et al found that immune checkpoint inhibitor treatment did not appear to be associated with long-term survival in patients with metastatic urothelial cancer.

Study Details

The analysis included data from six trials of pembrolizumab, avelumab, and nivolumab in the first-line, maintenance, and salvage settings for metastatic urothelial cancer; only U.S. Food and Drug Administration–approved treatments were included in the analysis. Of the trials, two were in first-line treatment (n = 1,021); one was in first-line maintenance (n = 344), and three were in salvage treatment (n = 782).

Key Findings

Follow-up in the trials ranged from a median of ≥ 19 months to a minimum of 33.7 months. In analyses of overall survival and progression-free survival, the numbers of patients at risk declined sharply over time in each of the trials.

In the two trials in the first-line setting, median overall survival was 17.0 months (95% confidence interval = 14.5–19.5 months) with pembrolizumab plus chemotherapy and 15.6 months (95% CI = 12.1–17.9 months) with pembrolizumab alone in KEYNOTE-361, and 11.3 months (95% CI = 9.7–13.1 months) with pembrolizumab in KEYNOTE-052. Median progression-free survival was 8.3 months with pembrolizumab plus chemotherapy in KEYNOTE-361 and 2.2 months with pembrolizumab in KEYNOTE-052.

In the one trial in the maintenance setting (JAVELIN Bladder 100), median overall survival and progression-free survival were 21.4 months (95% CI = 18.9–26.1) and 3.7 months with avelumab. In the three trials in the salvage setting, median overall survival and progression-free survival were: 10.1 months (95% CI = 8.0–12.3 months) and 2.1 months with pembrolizumab in KEYNOTE-045; 8.6 months (95% CI = 6.1–11.3 months) and 1.9 months with nivolumab in CheckMate 275; and 7.0 months (95% CI = 5.9–8.5 months) and 1.6 months with avelumab in the JAVELIN Solid Tumor trial.

Among all patients, none with continued follow-up were progression-free or alive at 48 months.

The investigators stated, “The significant decrease of patients at risk within the treatment groups of these trials seems to reflect a lack of durable survival benefit for most patients with metastatic urothelial cancer. Our study is limited by its reliance on published clinical trial data, and the decrease in number at risk likely reflects both a lack of long-term follow-up for later time points and survival. Although a small proportion of patients achieve long-term survival in the real-world setting, it remains difficult to identify such outliers a priori due to lack of robust predictive biomarkers with proven clinical utility. Novel therapeutic combinations (eg, antibody-drug conjugates or targeted therapies with immune checkpoint inhibitors and future biomarkers with clinical utility) may further improve outcomes for this disease. Our findings are hypothesis-generating and need validation.”

Jonathan E. Shoag, MD, of Case Western Reserve University School of Medicine, is the corresponding author for the JAMA Network Open article.

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