Atezolizumab (anti-PDL1) and pembrolizumab (anti-PD1) have been approved for the first-line treatment of cisplatin-ineligible patients with metastatic UC and high tumor PD-L1 expression, based on single-arm, phase 2 studies.2,3 Durvalumab (anti-PD-L1) had received FDA approval for the treatment of platinum-refractory metastatic UC.4 Tremelimumab (anti-CTLA-4) and the combination of Durvalumab + Tremelimumab have shown activity in platinum-refractory, metastatic UC regardless of PD-L1 expression.5
The presented DANUBE trial by Thomas B. Powles, MBBS, MRCP, MD, was a randomized, phase 3 trial aimed to evaluate Durvalumab, with or without Tremelimumab, vs. platinum-based chemotherapy as a first-line treatment for metastatic UC (Figure 1). The key inclusion and exclusion criteria of the study are shown in Table 1.
Figure 1 – DANUBE trial design:
Table 1- Key inclusion and exclusion criteria of the DANUBE trial:
The trial planned to randomize 1005 patients in a 1:1:1 ratio to each arm. The coprimary endpoints included:
- Overall survival (OS) among patients whose tumors had high PD-L1 expression
- OS in the intention to treat (ITT) analysis
- To control for type 1 error, the overall alpha of 5% was split for the coprimary statistical comparisons of OS with:
- Durvalumab vs. chemotherapy (PD-L1 high): 3.5%
- Durvalumab + Tremelimumab vs. chemotherapy (ITT): 1.5%
Table 1 – Baseline characteristics:
Figure 2 – Coprimary endpoint of overall survival in the PD-L1 high population:
Figure 3 – Subgroup analyses in the PD-L1 high population:
The OS of Durvalumab + Tremelimumab vs. chemotherapy in the ITT population is shown in Figure 4.
Figure 4 – OS in the ITT population:
Next, Dr. Powles showed the anti-tumor activity shown with the objective response rate (by RECIST v 1.1) in the ITT population in figure 5. More details on the anti-tumor activity are shown in figure 6. Details on subsequent anti-cancer therapies can be seen in Figure 7.
Figure 5 — Anti-tumor activity: Objective response rate:
Figure 6 – Antitumor activity:
Figure 7 – Subsequent anti-cancer therapies:
Next, Dr. Powles moved on to show some of the secondary endpoints, including OS in the ITT population (figure 8), and OS in the PD-L1 high population (Figure 9), showing a benefit to the Durvalumab + Tremelimumab in the high PD-L1 population.
Figure 8 – OS in the ITT population:
Figure 9 – OS in the PD-L1 high population:
The safety data are summarized in Figure 10, showing that the most common treatment-related adverse events of grade 3 or 4 were increased lipase (in both Durvalumab and Durvalumab+trememiumab treatment arms), and neutropenia and anemia in the chemotherapy group.
Figure 10 - Safety summary data:
Concluding his presentation, Dr. Powles stated that the DANUBE trial did not meet either of the coprimary endpoints for OS for both Durvalumab monotherapy vs. chemotherapy in the PD-L1 high population, and for the Durvalumab + Tremelimumab vs. chemotherapy in the overall (ITT) population. The secondary analyses suggested that the combination of Durvalumab and Tremelimumab has activity, which is enhanced in patients with tumors that have high PD-L1 expression. This suggests that the current biomarker strategy enriches for patients that are likely to receive benefit from both Durvalumab and Durvalumab + Tremelimumab. Further investigation in the context of all immune checkpoint inhibitors may be warranted. The safety profile of these medications was quite manageable, with no new safety signals noticed. Durvalumab, with or without Tremelimumab, resulted in durable clinical activity in some of the patients. Lastly, this study has a median follow-up duration of 41.2 months, which is the longest follow-up data for a randomized trial of immunotherapy in previously untreated metastatic UC patients.
Presented by: Thomas B. Powles, MBBS, MRCP, MD, Professor of Genitourinary Oncology, Lead for Solid Tumour Research at Barts Cancer Institute, Director of Barts Cancer Institute, London, United Kingdom
Written by: Hanan Goldberg, MD, MSc., Assistant Professor of Urology, SUNY Upstate Medical University, Syracuse, NY, USA, Twitter: @GoldbergHanan, at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020.
References:
- von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2005; 23(21): 4602-8.
- Balar AV, Castellano D, O'Donnell PH, 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. The Lancet Oncology 2017; 18(11): 1483-92.
- Balar AV, Galsky MD, Rosenberg JE, 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 (London, England) 2017; 389(10064): 67-76.
- Massard C, Gordon MS, Sharma S, et al. Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2016; 34(26): 3119-25.
- Sharma P, Sohn J, Shin SJ, et al. Efficacy and Tolerability of Tremelimumab in Locally Advanced or Metastatic Urothelial Carcinoma Patients Who Have Failed First-Line Platinum-Based Chemotherapy. Clinical Cancer Research 2020; 26(1): 61-70.