DANUBE does not meet its primary endpoint
DANUBE does not meet its primary endpoint
Most patients with metastatic urothelial cancer respond to first-line chemotherapy but relapse soon. The randomised phase 3 DANUBE trial evaluated the efficacy of first-line treatment of the PD-L1 inhibitor durvalumab, the combination of durvalumab plus the CTLA4 inhibitor tremelimumab, and standard chemotherapy in patients with metastatic, unresectable urothelial cancer.
Platinum-based chemotherapy remains the standard of care for the first-line treatment of metastatic urothelial cancer. Although responses to this treatments are initially high, many patients relapse and long-term durable remissions are rare. For patients who are ineligible for first-line platinum-based chemotherapy, treatment with either pembrolizumab or atezolizumab is approved for patients with high tumour expression of PD-L1, based on two single-arm phase 2 studies [1,2].
DANUBE is a randomised, three-arm phase 3 study evaluating the efficacy of first-line treatment of the PD-L1 inhibitor durvalumab, the combination of durvalumab plus the CTLA4 inhibitor tremelimumab, and standard chemotherapy in patients with metastatic, unresectable urothelial cancer, irrespective of platinum-eligibility. Prof. Thomas Powles (Barts Cancer Institute, UK) presented the results .
A total of 1,032 patients were 1:1:1 randomized to durvalumab 1.5 g Q4W), durvalumab plus tremelimumab (durvalumab 1.5 g IV Q4W plus tremelimumab 75 mg IV Q4W for up to 4 doses, followed by durvalumab 1.5 g IV Q4W), or chemotherapy (gemcitabine plus cisplatin or carboplatin) for up to 6 cycles, until disease progression or unacceptable toxicity. Randomisation was stratified by cisplatin eligibility, PD-L1 status (high [≥25%] vs low [<25%]), and presence/absence of visceral metastases. Dual primary endpoints of the study compared overall survival (OS) for durvalumab versus chemotherapy in patients with high PD-L1 expression, and durvalumab plus tremelimumab versus chemotherapy in the intention-to-treat population. Minimum follow-up time (from the date the last patient was randomised) was 34 months.
Median OS was not significantly different between durvalumab and chemotherapy among patients with high PD-L1 expression: 14.4 months versus 12.1 months (HR 0.80; P=0.31). Survival curves showed the characteristic crossing, with chemotherapy performing best in the first months of the disease process and more durable remissions associated with immune therapy. OS rates at 24 months were 36% and 29% in the durvalumab and chemotherapy arm, respectively. A similar pattern was seen comparing OS in the durvalumab plus tremelimumab with chemotherapy in the ITT population: median OS was 15.1 months in the durvalumab plus tremelimumab arm versus 12.1 months in the chemotherapy arm (HR 0.85; P=0.075). OS rates at 24 months were 39% and 29% in the durvalumab plus tremelimumab arm and chemotherapy arm, respectively. Response rate for durvalumab was lower than for chemotherapy: 26% versus 49%. Response rate for durvalumab plus tremelimumab was also lower compared with chemotherapy, but was higher in the PD-L1-high population compared with the ITT population: 47% versus 36%. In line with this, OS rate at 24 months for durvalumab plus tremelimumab in the PD-L1-high population was higher than in the ITT population at 44%. This is an important observation for future trials, Prof. Powles said. Both experimental arms had lower grade 3 and 4 toxicity than chemotherapy.
- Balar AV, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18: 1483-1492.
- Balar AV, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017; 389: 67-76.
- Powles TB, et al. A phase III, randomized, open-label study of first-line durvalumab (D) with or without tremelimumab (T) vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE). ESMO 2020 Virtual Meeting, abstract 697O.
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