Project overview
Background Bladder and urinary tract cancers account for ~10,000 new diagnoses and ~5,000 deaths annually in the UK. 90% are transitional cell carcinomas (TCC) for which advanced disease is treated with platinum based chemotherapy and PD1/PD-L1 directed immunotherapy. Urinary tract squamous cell carcinoma (UTSCC) accounts for about 5% of urinary tract cancers overall making this a rare disease setting. We have yet to establish definitive systemic treatment options for advanced UTSCC, which responds poorly to chemotherapy or radiotherapy. UTSCC patients are frequently disenfranchised by exclusion from TCC clinical trials, including registration studies for immunotherapy. Our preliminary data, from a retrospective cohort with UTSCC, indicate high PDL1 expression and tumour infiltrating lymphocytes (TIL) in a proportion of cases. Both of these features are associated with differential gene expression consistent with a tumour/immune microenvironment predicted to be susceptible to immune checkpoint directed immunotherapy. Aims The AURORA trial will test the hypothesis that PD-L1 inhibition with atezolizumab is active, tolerable and safe, in UTSCC. We will incorporated comprehensive translational research components, to allow prospective investigation of the immune-biology of the disease and potential biomarkers of treatment response. Methods Patients with UTSCC, suitable for treatment with palliative intent, will receive atezolizumab PD-L1 directed immunotherapy for one year if tolerated. The primary endpoint is best overall response rate (ORR, by RECIST v1.1). AURORA has a single arm, Simon 2 stage, statistical design, to allow an independently assessed interim review of efficacy. We will recruit up to 33 patients with SCC histology UTC. If 4 or more, of the first 19 patients (Stage 1), achieve an objective radiological response (RECIST v1.1) then the trial will continue to stage 2 where 8 or more responses in 33 patients will meet the criteria to indicate further investigation is warranted (p1=15%, p2=35%, 1-sided alpha=0.1, power=90%). Secondary endpoints will include overall survival, progression free survival, duration of response, response using irRECIST, quality of life, safety and tolerability (CTCAEv5) and evaluation of potential biomarkers of treatment response. How the results will be used AURORA would represent the first prospective trial of immunotherapy in UTSCC and only the second dedicated study of any systemic therapy. If successful, we hope to define a standard of care approach to intervention for this patient group. The trial is supported by the NCRI Bladder and Renal Group, the International Rare Cancers Initiative and UK patient groups.
