In the phase III DANUBE trial, reported in The Lancet Oncology, Thomas Powles, MD, PhD, and colleagues found that durvalumab monotherapy did not prolong overall survival vs standard chemotherapy in previously untreated patients with largely metastatic urothelial carcinoma with high PD-L1 expression. Additionally, treatment with durvalumab plus the CTLA-4 inhibitor tremelimumab did not improve overall survival vs chemotherapy in the intent-to-treat population.

Thomas Powles, MD, PhD

Study Details

In the open-label trial, 1,032 patients from 224 sites in 23 countries with unresectable locally advanced or metastatic urothelial carcinoma were randomly assigned 1:1:1 between November 2015 and March 2017 to receive durvalumab (n = 346), durvalumab plus tremelimumab (n = 342), or chemotherapy (n = 344). Treatment consisted of either:

• Durvalumab at 1,500 mg every 4 weeks
• Durvalumab at 1,500 mg plus tremelimumab at 75 mg every 4 weeks for up to four doses, followed by durvalumab maintenance at 1,500 mg every 4 weeks
• Standard-of-care chemotherapy with gemcitabine plus either cisplatin or carboplatin, depending on cisplatin eligibility, for up to six cycles.

The co-primary endpoints were overall survival with durvalumab monotherapy vs chemotherapy in patients with high PD-L1 expression, and with durvalumab/tremelimumab vs chemotherapy in the intent-to-treat population.

High PD-L1 expression was defined ≥ 25% of tumor cells with membrane staining or ≥ 25% of immune cells staining for PD-L1 at any intensity if > 1% of the tumor area contained immune cells, or 100% of immune cells staining for PD-L1 at any intensity if 1% of the tumor area contained immune cells. Overall, 209 (60%) of 346 patients in the durvalumab group, 205 (60%) of 342 in the durvalumab/tremelimumab group, and 207 (60%) of 344 in the chemotherapy group had high PD-L1 expression. Additionally, 57% of patients in the durvalumab group, 57% in the durvalumab/tremelimumab group, and 56% in the chemotherapy group were eligible for cisplatin. Disease was metastatic in 97%, 96%, and 94% of patients, respectively.

Overall Survival

At data cutoff for final analysis of overall survival (January 2020), median follow-up for survival was 41.2 months. In the PD-L1–high population, median overall survival was 14.4 months (95% confidence interval [CI] = 10.4–17.3 months) in the durvalumab monotherapy group vs 12.1 months (95% CI = 10.4–15.0 months) in the chemotherapy group (hazard ratio [HR] = 0.89, 95% CI = 0.71–1.11, P = .30). In the intent-to-treat population, median overall survival was 15.1 months (95% CI = 13.1–18.0 months) in the durvalumab/tremelimumab group vs 12.1 months (95% CI = 10.9–14.0 months) in the chemotherapy group (HR = 0.85, 95% CI = 0.72–1.02, P = .075). For each treatment group within the intent-to-treat and PD-L1­­–high populations, overall survival was similar between cisplatin-eligible and cisplatin-ineligible patients.

Adverse Events

Grade 3 or 4 treatment-related adverse events occurred in 14% of the durvalumab group, 27% of the durvalumab/tremelimumab group, and 60% of the chemotherapy group, with the most common being increased lipase in the durvalumab group (2%) and the durvalumab/tremelimumab group (5%) and neutropenia in the chemotherapy group (21%). Serious treatment-related adverse events occurred in 9%, 23%, and 16% of patients, respectively. Treatment-related deaths occurred in two patients in the durvalumab group (due to acute hepatic failure and hepatitis), two in durvalumab/tremelimumab group (due to septic shock and pneumonitis), and one in the chemotherapy group (due to acute kidney injury).

The investigators concluded, “This study did not meet either of its co-primary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.”

Dr. Powles, of the Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by AstraZeneca. For full disclosures of the study authors, visit thelancet.com.