Pembrolizumab with ChemoRadiotherapy for Muscle Invasive Bladder Cancer: the ANZUP PCR-MIB trial

Background: Pembrolizumab leads to responses in 20-30% of metastatic bladder cancer patients. Irradiation of bladder cancer cells in-vitro and in-vivo leads to upregulation of PD-L1, and in immunocompetent mouse models blockade of PD-L1 leads to longer tumour growth delay following irradiation. A trial of chemoradiotherapy with pembrolizumab in muscle invasive localised bladder cancer will assess safety and synergy of the combination. Trial design: This pilot study will enrol patients with maximally resected non-metastatic muscle invasive bladder cancer, who either wish for bladder preservation or are ineligible for cystectomy. This study will assess the safety and feasibility of combining pembrolizumab with chemoradiotherapy in ECOG 0-1 patients without contraindications to pembrolizumab. The study will enrol 30 patients. All patients will be treated with 64Gy of radiation therapy in 32 fractions over 6 weeks and 2 days. Patients will receive cisplatin 35mg/m2 IV concurrently weekly with radiation therapy for 6 doses total. Pembrolizumab will commence concurrently with radiation and be given 200mg IV q21 days, continuing until the 12 week cystoscopy and assessment. Surveillance cystoscopy will be performed 12 and 24 weeks after the commencement of chemoradiotherapy, and assess the rate of complete response to therapy. Patients will enter follow up with clinical assessment, cystoscopy and CT staging performed at intervals until close of study. The primary endpoint assessed will be safety, as defined by a satisfactorily low rate of unacceptable toxicity (G3-4 adverse events or failure of completion of planned chemotherapy and radiotherapy according to defined parameters). The secondary endpoint will be efficacy, as assessed by the proportion of patients achieving a best response of complete responsebased on the first two 12 and 24 week post chemoradiotherapy cystoscopic assessments. Exploratory analysis will include assessment of tumour histopathological, molecular, genetic and immunological parameters. It is expected that it will take two years to accrue the required 30 patients across 5 Australian centres.