medwireNews: The DANUBE trial has ruled out the first-line use of durvalumab monotherapy or alongside tremelimumab in patients with metastatic urothelial carcinoma (UC) after failing to show an overall survival (OS) advantage for either option relative to standard of care chemotherapy.
As reported simultaneously at the ESMO Virtual Congress 2020 and in The Lancet Oncology, the primary endpoint of OS in the PD-L1-high population was not significantly improved with single-agent durvalumab versus chemotherapy, at a median of 14.4 and 12.1 months, respectively, after a median follow-up of 41.2 months.
There was also no significant improvement in the other primary endpoint of OS in the intention-to-treat (ITT) population with the combination of durvalumab plus tremelimumab relative to chemotherapy, at a median of 15.1 versus 12.1 months.
Thomas Powles outlines the DANUBE trial (4:37).
“These findings could add to our understanding of immune checkpoint inhibitors in urothelial carcinoma and dampen enthusiasm for this approach in light of the recent positive study that sequenced chemotherapy and avelumab,” write Thomas Powles, from Barts Cancer Institute in London, UK, and co-investigators.
In the phase 3 study, 1032 individuals who had not received prior systemic therapy for unresectable, locally advanced, or metastatic disease were randomly assigned to receive durvalumab 1500 mg every 4 weeks, either alone or alongside up to four doses of tremelimumab 75 mg followed by maintenance durvalumab, or to receive gemcitabine plus cisplatin or carboplatin.
Sixty percent of patients in each group had high levels of PD-L1 as indicated by the presence of at least 25% of PD-L1-positive tumor cells with membrane staining or at least 25% of immune cells staining positive for PD-L1 at any intensity on the VENTANA SP263 assay (Ventana Medical Systems, Tucson, Arizona, USA).
Median progression-free survival was shorter in the durvalumab monotherapy and combination groups than in the chemotherapy group, both in the ITT (2.3 and 3.7 months, respectively, vs 6.7 months) and PD-L1-high (2.4 and 4.1 months, respectively, vs 5.8 months) populations.
Objective response rates (ORRs) were also generally lower in the durvalumab treatment arms than the chemotherapy arm.
The only exception was among the PD-L1-high population, for whom durvalumab–tremelimumab was associated with similar ORRs to those achieved with chemotherapy (47 vs 48%). And the combination appeared to significantly improve OS in this PD-L1-high population, at a median of 17.9 versus 12.1 months with chemotherapy, giving a hazard ratio for death of 0.74.
Although these secondary analyses pointed to greater activity of the combination than durvalumab alone, the authors highlight that durvalumab–tremelimumab was “associated with a higher frequency of adverse events than durvalumab monotherapy and a higher proportion of patients had to discontinue therapy due to toxicity (24% vs 12%).”
They add that “[t]his is an important consideration for tumours such as urothelial carcinoma for which comorbidities are common.”
Overall, “in our study, chemotherapy appeared better than durvalumab at achieving initial control of disease, showing higher response rates and longer progression-free survival,” say Powles et al.
“This pattern, in which immunotherapy is inferior to chemotherapy during the initial period of treatment, has previously been described with other immune checkpoint inhibitors (eg, atezolizumab), and it might account for the negative result of the study.”
The team therefore concludes: “Further studies and analyses are needed to identify the potential role of immune checkpoint inhibitors, alone or in combination, as first-line treatments for metastatic urothelial carcinoma.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2020 Springer Healthcare Ltd, part of the Springer Nature Group
This independent news story was supported by an educational grant from Pfizer and Merck Healthcare KGaA, Darmstadt, Germany
ESMO Virtual Congress 2020: 19–21 September
Lancet Oncol 2020; doi:10.1016/S1470-2045(20)30541-6