According to results from the phase III DANUBE bladder cancer trial, neither of the co-primary end points of the trial were met. The combination of durvalumab, and tremelimumab did not show an improvement in overall survival in treatment-naïve patients with unresectable, stage IV bladder cancer. Also, durvalumab alone failed to show an OS benefit over standard-of-care chemotherapy alone in patients with high PD-L1 expression.
Jose Baselga, MD, PhD
Jose Baselga, MD, PhD
According to results from the phase III DANUBE bladder cancer trial, neither of the co-primary end points of the trial were met, AstraZeneca revealed in a press release. The combination of durvalumab (Imfinzi), and tremelimumab did not show an improvement in overall survival (OS) in treatment-naïve patients with unresectable, stage IV bladder cancer. Also, durvalumab alone failed to show an OS benefit over standard-of-care (SOC) chemotherapy alone in patients with high PD-L1 expression.
The PD-L1 and CTLA-4 inhibitors demonstrated safety and tolerability profiles similar to what has been seen in previous trials of the agents. Further findings from the trial will be presented at an upcoming medical meeting, and the agents will continue to be studied in patients with bladder cancer in other ongoing phase III trials.
“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,” José Baselga, MD, PhD, executive vice president of Oncology Research and Development, AstraZeneca, said in a statement. “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.”
The randomized, open-label, controlled, multicenter phase III DANUBE trial explored the efficacy and safety of frontline durvalumab with or without added tremelimumab in comparison with SOC chemotherapy in cisplatin eligible and ineligible patients with unresectable stage IV bladder cancer (NCT02516241). The trial was created in agreement with the FDA following the accelerated approval of durvalumab for patients with locally advanced or metastatic bladder cancer who have been previously treated.
The trial enrolled more than 1000 patients from 220 medical centers across 24 countries. Patients were eligible if they had histologically or cytologically documented transitional cell carcinoma of the urothelium and had not received prior first-line chemotherapy. PD-L1 testing with an immunohistochemical assay was required prior to randomization.
Prior exposure to immune-mediated therapy or recent immunosuppressive therapy, a history of allogeneic organ transplantation, active or prior autoimmune or inflammatory disorders, HIV or other active infections, and brain metastases or spinal cord compressions were all causes for exclusion from the trial.
Participants in the trial were randomized 1:1:1 to either combination therapy, durvalumab monotherapy, or SOC chemotherapy of cisplatin and gemcitabine or carboplatin and gemcitabine, according to the patient’s cisplatin eligibility. All patients were to be followed for up to 2 years.
The co-primary end points were OS for the combination of durvalumab and tremelimumab versus chemotherapy in the total patient population and OS for durvalumab monotherapy versus chemotherapy in patients with PD-L1high bladder cancer. High PD-L1 was defined as ≥25% expression on tumor cells or tumor-infiltrating immune cells.
Secondary end points include progression-free survival (PFS) in the total patient population with the combination therapy, PFS for durvalumab monotherapy in patients with high PD-L1 expression, objective response rate (ORR) for the combination arm versus the control arm, ORR for the durvalumab arm versus the chemotherapy arm, duration of response, safety, health-related quality of life, and pharmacokinetics.
The phase III NILE trial (NCT03682068) is continuing to explore the use of durvalumab with chemotherapy or with both tremelimumab and chemotherapy in comparison with chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer. Additionally, the efficacy of durvalumab is also being explored in the phase III NIAGARA study (NCT03732677) in combination with chemotherapy in patients with muscle-invasive bladder cancer and in the phase III POTOMAC trial (NCT03528694) in combination with the Bacillus Calmette-Guerin immunotherapy vaccine.
Update on Phase III DANUBE trial for Imfinzi and tremelimumab in unresectable, Stage IV bladder cancer [news release]. Wilmington, DE: AstraZeneca; March 6, 2020. https://bit.ly/2THDTAm. Accessed March 6, 2020.