The FDA has granted an accelerated approval to the PD-L1 inhibitor durvalumab (Imfinzi) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
A complementary diagnostic for PD-L1, the VENTANA PD-L1 (SP263) Assay, was simultaneously approved.
The approval was based on the single-arm phase I/II Study 1108, which included 182 patients with locally advanced or metastatic urothelial carcinoma who experienced disease progression following platinum-containing chemotherapy.
In the study, the objective response rate (ORR) per blinded independent central review was 17.0% (95% CI, 11.9-23.3). At the data cutoff, the median duration of response was not reached (range, 0.9+ to 19.9+ months).
Among 95 patients with high PD-L1 expression, the ORR was 26.3% (95% CI, 17.8-36.4). In the cohort of 73 patients with low or no PD-L1 expression, the ORR was 4.1% (95% CI, 0.9-11.5).
“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. The approval of Imfinzi 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,” Nicholas J. Vogelzang, MD, 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 in a statement.
The median age of patients in Study 1108 was 67 years (range, 34-88), 64% were white, and 72% were male. Two-thirds of patients had visceral metastasis (bone, liver, or lung), including 34% with liver metastasis. Forty-one percent of patients had a baseline creatinine clearance of less than 60 mL/min and 66% had an ECOG performance score of 1.
Thirty-five percent of patients had received at least 2 prior lines systemic therapy. Prior cisplatin and prior carboplatin were reported in 70% and 35% of patients, respectively. Among the overall population, 20% of patients had progressed after receiving platinum-containing neoadjuvant or adjuvant chemotherapy as their only prior line of therapy.
Patients were not eligible to enroll in the trial if they had a history of immunodeficiency; medical conditions that required systemic immunosuppression (not to exceed 10 mg/day of prednisone or equivalent); history of severe autoimmune disease; untreated CNS metastases; HIV; active tuberculosis, or hepatitis B or C infection.
Expression of PD-L1 on tumor cells (TC) and immune cells (IC) was determined at a central laboratory using the VENTANA PD-L1 (SP263) Assay. Criteria for inclusion in the PD-L1 high cohort were as follows: if ICs involve >1% of the tumor area, TC ≥25% or IC ≥25%; if ICs involve ≤1% of the tumor area, TC ≥25% or IC = 100%.
Durvalumab was administered at 10 mg/kg IV every 2 weeks for up to 1 year or until disease progression or unacceptable toxicity. Tumors were assessed at weeks 6, 12, and 16, then every 8 weeks for the first year and every 12 weeks thereafter.
At a median follow-up of 5.6 months, 31 patients achieved a response, including 5 complete responses (CRs) and 26 partial responses (PRs). Among patients with high PD-L1 expression, responses occurred in 25 patients, with 3 CRs and 22 PRs. Three patients in the PD-L1 low/none cohort had a response, including 1 CR and 2 PRs. Three responses (1 CR and 2 PRs) were also achieved in the group of patients whose PD-L1 status was not evaluable.
All-grade adverse events (AEs) occurring in 15% or more of patients included fatigue (39%), musculoskeletal pain (24%), constipation (21%), decreased appetite (19%), nausea (16%), peripheral edema (15%), and urinary tract infection (15%).
Grade 3/4 AEs occurred in 43% of patients, the most common (≥3%) of which were fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration.
Infection and immune-related AEs observed with durvalumab included pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes.
Forty-six percent of patients experienced serious AEs, including 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).
AEs led to treatment discontinuation in 3.3% of patients. There were 8 patients deaths, due to cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis.
In February 2016, the FDA granted a breakthrough therapy designation to durvalumab as a treatment for patients with PD-L1–positive inoperable or metastatic urothelial bladder cancer following progression on prior treatment with a platinum-based regimen.
Durvalumab is being evaluated as a single agent and in combination with tremelimumab in the phase III DANUBE trial in the frontline setting for patients with metastatic urothelial carcinoma, regardless of their eligibility for cisplatin-based chemotherapy.
More than 30 other ongoing trials are evaluating various combinations of durvalumab with other immunotherapies and targeted agents.
The accelerated approval of durvalumab in bladder cancer is contingent upon results from a confirmatory trial.
“We are excited to offer Imfinzi as a breakthrough therapy for patients with locally-advanced or metastatic bladder cancer. Imfinzi is the cornerstone of our extensive Immuno-Oncology program, in development across many tumor types, as monotherapy and in combination. This first approval for Imfinzi is an important milestone in our return to growth and brings us another step closer to our goal of redefining the way cancer is treated,” Pascal Soriot, CEO of AstraZeneca, the manufacturer of durvalumab, said in a statement.