Durvalumab/Tremelimumab Combo Misses OS Endpoints in Metastatic Bladder Cancer

Durvalumab alone did not improve overall survival compared with standard-of-care chemotherapy in patients with unresectable urothelial cancer whose tumors had high levels (≥25%) of PD-L1 expression, missing both primary endpoints of the phase III DANUBE trial.

Jose Baselga

Jose Baselga, executive vice president, Oncology R&D, AstraZeneca

José Baselga

Durvalumab (Imfinzi) alone did not improve overall survival (OS) compared with standard-of-care chemotherapy in patients with unresectable urothelial cancer whose tumors had high levels (≥25%) of PD-L1 expression, nor did it improve OS when given in combination with tremelimumab for this patient population regardless of PD-L1 expression, missing both primary endpoints of the phase III DANUBE trial (NCT02516241).1

The safety and tolerability profiles for durvalumab as a single agent and plus tremelimumab were found to be consistent with results of prior studies. Full findings will be presented at an upcoming medical meeting, AstraZeneca, the developer of the PD-L1 and CTLA-4 inhibitors, stated in a press release.

"AstraZeneca remains committed to addressing unmet needs in bladder cancer and the potential for immunotherapy to improve outcomes for these patients. The results from this trial will inform our comprehensive phase III development program in bladder cancer," Jose Baselga, executive vice president, Oncology R&D, AstraZeneca, stated in the press release. "We look forward to the results of the phase III NILE trial also in the first-line metastatic setting, and we continue to advance clinical trials for patients at earlier stages of the disease."

Durvalumab was approved by the FDA in May 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. DANUBE addresses a post-approval commitment in agreement with the FDA from this approval, AstraZeneca stated.

In the open-label, multicenter, international, controlled, phase III DANUBE trial, investigators evaluated durvalumab alone or in combination with tremelimumab compared with cisplatin/gemcitabine or gemcitabine/carboplatin in the frontline setting for 1126 patients with either cisplatin-eligible or -ineligible, unresectable, metastatic urothelial cancer. Patients were randomized 1:1:1 to received durvalumab monotherapy, durvalumab plus tremelimumab, or standard chemotherapy. The intravenous treatments were administered until disease progression, unacceptable toxicity, withdrawal or content, or another discontinuation criterion was met; patients were followed for ≤2 years.

DANUBE was conducted in more than 220 centers across 24 countries, including those in the United States, Canada, Europe, South America, Asia, Australia and the Middle East.

Patients who were eligible for enrollment included those with transitional cell carcinoma of the urothelium, including renal pelvis, ureters, urinary bladder, and urethra. High PD-L1 expression was defined as ≥25% of tumor cells (TC) or tumor-infiltrating immune cells (IC) expressing membrane PD-L1 if ICs involved >1% of the tumor area, or TC ≥25% or IC = 100% if ICs involved ≤1% of the tumor area.

Those who received prior exposure to immunotherapy, had a history of allogenic organ transplantation that required immunosuppressive agents, active or prior autoimmune or inflammatory disorders, brain metastases or spinal cord compression, active infection, current or prior use of immunosuppressive medication within 14 days of first study dose, or receipt of live attenuated vaccine within 30 days prior to the first dose were excluded from enrollment.

The primary endpoints were OS in PD-L1-high patients who received single-agent durvalumab, as well as OS in patients treated with the combination of durvalumab plus tremelimumab, regardless of PD-L1 status. Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) with both regimens, disease-related symptoms and health-related quality of life with both regimens, pharmacokinetics of both regimens, and ORR in both cisplatin-eligible and -ineligible patients. Safety was also assessed.

The March 2017 approval for single-agent durvalumab based on findings from the single-arm phase I/II Study 1108, which included 182 patients with locally advanced or metastatic urothelial carcinoma who experienced disease progression following platinum-containing chemotherapy.

Updated results showed that the ORR was 17.8% (95% CI, 12.7-24.0), which included 7 complete responses.2 Moreover, the median time to response was 1.41 months, and the median duration of response was not reached. In patients with high PD-L1 expression, the ORR was 27.6% (95% CI, 19.0%-37.5%) and was 5.1% (95% CI, 1.4%-12.5%) in those with low or negative PD-L1 expression. The median PFS and OS were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively. The 1-year OS rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method.

Durvalumab continues to be evaluated in ongoing trials of bladder cancer. For example, the phase III NILE trial (NCT03682068) is evaluating the combination of durvalumab and chemotherapy with or without tremelimumab in patients with unresectable, locally advanced or metastatic bladder cancer. The PD-L1 inhibitor is also being evaluated in combination with chemotherapy in the neoadjuvant setting and as monotherapy in the adjuvant setting for patients with muscle-invasive bladder cancer in the phase III NIAGARA trial (NCT03732677).

The phase III POTOMAC trial (NCT03528694) is investigating durvalumab in combination with Bacillus Calmette-Guerin in patients with non-muscle invasive bladder cancer.


  1. Update on Phase III DANUBE trial for Imfinzi and tremelimumab in unresectable, Stage IV bladder cancer [news release]: AstraZeneca. Published March 6, 2020. https://bit.ly/3cFFeAu. Accessed March 6, 2020.
  2. Powles T, O'Donnell PH, Massard C, et al. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol. 2017;3(9):e172411. doi: 10.1001/jamaoncol.2017.2411
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