Durvalumab was granted approval by the FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or whose disease has progressed within 12 months of receiving platinum-containing neoadjuvant or adjuvant chemotherapy.
Durvalumab is approved under the FDA's accelerated approval pathway, based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. It is also under investigation in the phase III DANUBE trial as first-line treatment in urothelial carcinoma as monotherapy and in combination with tremelimumab.
Additionally, VENTANA PD-L1 (SP263) Assay was approved by the FDA as a complementary diagnostic to provide PD-L1 status for patients with mUC who are being considered for treatment with durvalumab. The test evaluates patient PD-L1 status using both tumor and immune cell staining and scoring within the tumor microenvironment, providing clinicians with information that may guide treatment decisions. Understanding the expression of PD-L1 in tumors can help identify patients most likely to benefit from immunotherapy.
"The usual course of treatment for patients with advanced bladder cancer begins with a standard platinum-containing chemotherapy. Patients who have disease progression during or following chemotherapy are left with few other treatment options, said Nicholas J. Vogelzang, MD, FACP, FASCO, Clinical Professor at the University of Nevada School of Medicine; SWOG GU Vice Chair; US Oncology Research GU Chair; Comprehensive Cancer Centers of Nevada, said. "The approval of durvalumab to treat this population of select patients signifies hope for those who are currently suffering, or may find themselves with limited options in the future."
The recommended dose of durvalumab is 10 mg/kg body weight administered as an IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
The accelerated FDA approval of durvalumab, a human monoclonal antibody that blocks PD-L1, is based on data from Study 1108. This phase I/II trial evaluated the safety and efficacy in patients with locally advanced or metastatic urothelial carcinoma of the bladder. Patients had progressed while on or after a platinum-containing chemotherapy, including those who progressed within 12 months of receiving therapy in a neoadjuvant or adjuvant setting.
In the trial, durvalumab demonstrated rapid and durable responses, with an objective response rate (ORR) of 17.0 percent (95% confidence interval [CI]: 11.9; 23.3) in all evaluable patients, regardless of PD-L1 status, and 26.3 percent (95% CI: 17.8; 36.4) in patients with PD-L1 high-expressing tumors (as determined by the VENTANA PD-L1 (SP263) Assay).
PD-L1 high was defined as ≥25 percent of tumor cells (TC) or tumor-infiltrating immune cells (IC) expressing membrane PD-L1 if ICs involved >1 percent of the tumor area, or TC≥25 percent or IC=100 percent if ICs involved ≤1 percent of the tumor area. Additionally, approximately 14.3 percent of all evaluable patients achieved partial response and 2.7 percent achieved complete response. Of patients who had received only neoadjuvant or adjuvant therapy prior to trial entry, 24 percent (n=9) responded. Based on a secondary endpoint in this single-arm trial, median time to response was 6 weeks. Among the total 31 responding patients, 14 patients (45%) had ongoing responses of 6 months or longer and five patients (16%) had ongoing responses of 12 months or longer.
Patients should be monitored for immune-mediated adverse reactions including pneumonitis, hepatitis, colitis, endocrinopathies (including adrenal insufficiency, hypophysitis, or Type 1 diabetes mellitus), nephritis, rash, thrombocytopenic purpura, infection, infusion-related reactions, or embryo-fetal toxicity.
Serious adverse reactions occurred in 46 percent of patients. The most frequent serious adverse reactions (>2%) were acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain, and pyrexia/tumor associated fever (2.7% each). Eight patients (4.4%) who were treated with durvalumab experienced grade 5 adverse events of cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis. Three additional patients were experiencing infection and disease progression at the time of death. Durvalumab was discontinued for adverse reactions in 3.3 percent of patients.
Clinical trials have demonstrated that patients with PD-L1 high-expressing tumors have a higher likelihood of response through blockade of the PD-1/PD-L1 pathway. PD-L1 expression testing may be a useful tool to help guide physicians in their treatment decisions, but it is not required for use of durvalumab.