[Adjuvant instillation therapy for non-muscle invasive bladder cancer - beyond BCG and mitomycin C]

Due to limited local efficacy of BCG and mitomycin C and the worldwide shortage of BCG, there is a clinical need to develop novel intravesical agents and application forms in order to improve the oncological outcomes in non-muscle invasive bladder cancer (NMIBC). Gemcitabine has been investigated in various clinical trials. It has proven to be superior to BCG rechallenge and MMC in BCG-unresponsive high-risk NMIBC. GemRIS is an implantable novel form of intravesical drug delivery of gemcitabine and is currently being investigated with cetrelimab, a checkpoint inhibitor, in patients with high-risk NMIBC and MIBC. Hyperthermic intravesical chemotherapy (HIVEC) leads to increased concentrations of MMC in the bladder wall and is also being investigated in various NMIBC settings. Nadofaragene firadenovec (rAd-IFN-α/Syn3) is a recombinant adenovirus that induces release of interferon-alpha in the urothelium. In a randomised study on patients with BCG-unresponsive NMIBC, it has shown relatively superior efficacy and tolerability compared with studies evaluating the role of checkpoint inhibitor monotherapies. Opportuzumab monatox is a recombinant fusion protein which binds to EpCAM and induces release of exotoxins, resulting in cytotoxic cell death. N-803 is an interleukin (IL)-15 analogue, which has been investigated in a phase 1b study in combination with BCG and has shown durable complete response in all nine patients for 72 months. It was granted breakthrough designation status by the FDA in 2019.