The FDA ( US Food and Drug Administration ) has granted accelerated approval to Imfinzi ( Durvalumab ). Imfinzi is indicated 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 chemotherapy before ( neoadjuvant ) or after ( adjuvant ) surgery.
Imfinzi is approved under the FDA’s accelerated approval pathway, based on tumour response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Imfinzi is also under investigation in the phase III DANUBE trial as 1st- line treatment in urothelial carcinoma as monotherapy and in combination with Tremelimumab.
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 recommended dose of Imfinzi is 10 mg/kg body weight administered as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity.
The accelerated FDA approval of Imfinzi, 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 of Imfinzi 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, Imfinzi has demonstrated rapid and durable responses, with an objective response rate ( ORR ) of 17.0% ( 95% confidence interval [ CI ]: 11.9; 23.3 ) in all evaluable patients, regardless of PD-L1 status, and 26.3% ( 95% CI: 17.8; 36.4 ) in patients with PD-L1 high-expressing tumours ( as determined by the VENTANA PD-L1 [ SP263 ] Assay, Ventana Medical Systems ).
PD-L1 high was defined as greater than or equal to 25% of tumour cells ( TC ) or tumour-infiltrating immune cells ( IC ) expressing membrane PD-L1 if ICs involved more than 1% of the tumour area, or TC greater than or equal to 25% or IC=100% if ICs involved less than or equal to 1% of the tumour area.
Additionally, approximately 14.3% of all evaluable patients achieved partial response and 2.7% achieved complete response.
Of patients who had received only neoadjuvant or adjuvant therapy prior to trial entry, 24% ( n=9 ) responded. Based on a secondary endpoint in this single-arm trial, median time to response was six weeks.
Among the total 31 responding patients, 14 patients ( 45% ) had ongoing responses of six 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% of patients. The most frequent serious adverse reactions ( more than 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/tumour associated fever ( 2.7% each ). Eight patients ( 4.4% ) who were treated with Imfinzi 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.
Imfinzi was discontinued for adverse reactions in 3.3% of patients.
Clinical trials have demonstrated that patients with PD-L1 high-expressing tumours 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 Imfinzi.
Urothelial bladder cancers arise from the epithelium of the bladder and are the ninth most common form of cancer worldwide. It is estimated that in 2016, about 430,000 people were diagnosed with bladder cancer around the world and 165,000 did not survive.
Metastatic bladder cancer remains an area of unmet medical need in particular; among patients treated with standard-of-care chemotherapy, the five-year survival rate is below 15%.
The tumour microenvironment of urothelial carcinoma significantly impairs lymphocyte function, helping the cancer to evade immune detection by exploiting inhibitory checkpoint pathways, such as PD-L1/PD-1. PD-L1 is widely expressed in tumour and immune cells in urothelial cancer patients and helps tumours to evade detection from the immune system through binding to the PD-1 receptor on cytotoxic T lymphocytes. ( Xagena )
Source: FDA, 2017