Although muscle-invasive urothelial cancer (UC) can be cured by surgery, recurrence rates are high. Despite impressive response rates to neo-adjuvant cisplatin-based chemotherapy, the absolute overall survival benefit is only 5%. Immunotherapy targeting the PD-1/PD-L1-axis has shown promising activity in UC, particularly when combined with anti-CTLA-4, and patients with lymph node only disease treated with frontline immunotherapy appear to benefit most. Since responses to immunotherapy often appear to be durable, neo-adjuvant immunotherapy may improve prognosis, particularly for high risk N+ disease. Preliminary data on neo-adjuvant pembrolizumab showed remarkable pCR rates (38.9%) and a manageable toxicity profile after 3 cycles of pembrolizumab in resectable T2-3N0 UC, underpinning the potential of neo-adjuvant combination trials for high risk UC.
This is a single-arm phase 1B trial to establish whether sequenced pre-operative ipilimumab and nivolumab is safe and effective in high risk UC, defined as upper/lower tract cT3-4aN0 OR ≥T1, cN+ OR ≥T1, any N, resectable retroperitoneal lymph node metastasis. Patients are eligible if they are ≥ 18 years with WHO performance 0-1. Patients must be cisplatin ineligible or refuse cisplatin-based chemo with no previous treatment with PD-(L)1 and CTLA-4 immunotherapy. To mitigate the risk of immune-related toxicity, patients are treated with a mitigated schedule (based on Meerveld-Eggink et al., Ann Oncol 2017): ipi 3 mg/kg (day 1), ipi 3 mg/kg + nivo 1 mg/kg (day 22) and nivo 3 mg/kg (day 43) followed by radical cystectomy or nefro/ureterectomy (day 57-71) with appropriate LN dissection. Six patients will undergo a re-TUR for in-depth analysis of T cell infiltrates. The primary endpoint of this trial is the percentage of patients having surgery <12 weeks after study enrollment. Secondary endpoints are efficacy (pCR) and translational. In total 24 patients will be included. At the time of abstract submission, 5 patients were included.
Clinical trial identification
Legal entity responsible for the study
The Netherlands Cancer Institute.
All authors have declared no conflicts of interest.