The FDA has granted accelerated approval to durvalumab (Imfinzi, AstraZeneca/MedImmune) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or after platinum-containing chemotherapy, or whose disease has progressed within 12 months after receiving platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery.
Durvalumab was approved under the FDA’s accelerated approval pathway, based on the tumor response rate and the durability of response. Continued approval for this indication may be contingent on the verification of clinical benefit in confirmatory trials.
The accelerated approval of durvalumab, a human monoclonal antibody that blocks programmed death ligand-1 (PD-L1), was based on positive data from a phase 1/2 trial that evaluated the immunotherapy in patients with locally advanced or metastatic urothelial carcinoma of the bladder. The patients had progressed during or after platinum-containing chemotherapy, including those who progressed within 12 months of receiving therapy in a neoadjuvant or adjuvant setting.
In the study, durvalumab demonstrated rapid and durable responses, with an objective response rate of 17.0% in all evaluable patients regardless of PD-L1 status, and 26.3% in patients with PD-L1 high-expressing tumors, as determined by the Ventana PD-L1 (SP263) assay (Ventana Medical Systems/Roche). In addition, approximately 14.3% of all evaluable patients achieved a partial response and 2.7% achieved a complete response. Of the patients who had received only neoadjuvant or adjuvant therapy before entering the trial, 24% responded to durvalumab.
Based on a secondary endpoint in this single-arm trial, the median time to response was six weeks. Among the total of 31 responding patients, 14 (45%) had ongoing responses of six months or longer, and five patients (16%) had ongoing responses of 12 months or longer.
Patients treated with durvalumab should be monitored for immune-mediated adverse events, including pneumonitis, hepatitis, colitis, endocrinopathies (including adrenal insufficiency, hypophysitis, or type-1 diabetes mellitus), nephritis, rash, thrombocytopenic purpura, infection, infusion-related reactions, and embryo-fetal toxicity.
Serious adverse events occurred in 46% of the patients. The most common frequent serious adverse events included 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 or tumor-associated fever (2.7% each). Eight patients (4.4%) 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 because of adverse events in 3.3% of the patients.
Source: AstraZeneca; May 1, 2017.