Durvalumab Demonstrates Compelling Activity in Urothelial Carcinoma

The PD-L1 inhibitor durvalumab demonstrated compelling clinical activity and a manageable safety profile as second-line therapy for locally advanced or metastatic urothelial cancer.

Thomas Powles, MBBS

Thomas Powles, MBBS

The PD-L1 inhibitor durvalumab demonstrated compelling clinical activity and a manageable safety profile as second-line therapy for locally advanced or metastatic urothelial cancer, according to updated data from a phase I/II study presented at the 2017 Genitourinary Cancers Symposium.

Following treatment with durvalumab, one-fourth of 103 patients (24%) remained alive without progression at 6 months as did 17% at 12 months. The overall survival rate was 60% at 6 months and 51% at 12 months. Durvalumab led to an overall response rate (ORR) of 20.4%, and patients with and without PD-L1 expression had objective responses, said lead investigator Thomas Powles, MD.

“The median overall survival of 14.1 months is quite compelling,” said Powles, a medical oncologist at Barts Cancer Center and Queen Mary University in London, reported. “The median progression-free survival of 2.2 months is very much in line with what we’ve seen previously.”

Durvalumab is a selective, high-affinity human IgG1 monoclonal antibody against PD-L1, binding to both PD-1 and CD80. The antibody does not interfere with interaction between PD-1 and PD-L2. Studies have suggested that urothelial caner may exploit inhibitor checkpoint pathways that suppress T-cell response, such as the PD1/PD-L1 pathway, Powles noted. Inhibition of PD-L1 may overcome the immune checkpoint to prolong T-cell activation and potentially enhance tumor rejection.

Powles reported data from an ongoing trial of durvalumab in patients with previously treated advanced urothelial cancer. Investigators enrolled 191 patients, 103 of whom were evaluable for response and safety. All the patients had progressive disease, and patients with exposure to any number of prior lines of therapy were eligible.

The analysis included patients treated for a minimum of 13 weeks prior to a planned data analysis. All the patients included in the analysis had stage IV disease. In more than 90% of cases, the disease had progressed during or after platinum-based chemotherapy or within 12 months of receiving neoadjuvant or adjuvant chemotherapy.

Powles reported that 21 patients (20.4%) attained objective responses with durvalumab, including 4 complete responses. Responses occurred after a 1.4-month median duration of treatment, and 17 of the responses persisted for at least 6 months. The median duration of response had yet to be reached.

Among 83 patients with target lesions at baseline and at least one follow-up scan, 30 (38.6%) had target lesion reductions ≥30% from baseline. The overall disease control rate (ORR plus stable disease) was 42.7%.

Objective responses occurred in all key subgroups and in patients with and without PD-L1 expression. The 103 evaluable patients had a median PFS of 2.2 months and median overall survival of 14.1 months.

In the full 191 patients, 51.3% had high PD-L1 expression (≥25% expression on tumor and immune cells). Although PD-L1 positivity was not required to enter the trial, there may have been some enrichment of the population in favor of those who expressed the ligand, according to Powles.

“We’ve had some enrichment of the biomarker in the validating cohort, and the biomarker has continued to pan out, which is reassuring,” said Powles. “The one caveat is that with the enrichment that has occurred, this is not an unselected patient population, so although it’s representative, it’s not 100% accurate.”

In those with PD-L1—high disease (n = 51), the ORR was 31.1%, which included 2 complete responses and 17 partial responses. In those with PD-L1–low/negative disease (n = 39), the ORR was 5.1%.

“This is really attractive and representative of what we have seen with other drugs, and I think it is very likely to go on to receive FDA approval,” noted Powles.

The FDA granted a priority review to a biologics license application for durvalumab in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or after one standard platinum‑based regimen in December 2016. This application was based on findings from the phase I/II trial, also known as Study 1108. The FDA will decide on the application within the next few months.


Powles T, O'Donnell PH, Massard C, et al. Updated Efficacy and Tolerability of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma.J Clin Oncol.2017;35 (suppl 6S; abstract 286).

The safety analysis included all 191 patients. The total rate of treatment-related adverse events (TRAEs, all grades) was 60.7%, and the incidence of grade 3/4 TRAEs was 6.8%. Two patients had fatal TRAEs (one case each of autoimmune hepatitis and pneumonitis). Three patients had TRAEs leading to permanent discontinuation, and 21 others had TRAEs that necessitated treatment interruption or dose delay. Immune-mediated adverse events occurred in 11.5% and were grade 1/2 in most cases, said Powles.

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