Behind the FDA Approval of Intravesical Gemcitabine Delivery in NMIBC

In an interview with Targeted Oncology, Joseph Jacob, MD, MCR, associate professor of urology at SUNY Upstate University Hospital, discusses the data that support the FDA approval of gemcitabine intravesical delivery.

The SunRISe-1 study (NCT04640623) was a groundbreaking, randomized, phase 2b trial that explored a new treatment for high-risk, non–muscle-invasive bladder cancer that is unresponsive to Bacillus Calmette-Guérin (BCG) therapy. This challenging patient population, many of whom had carcinoma in situ (CIS) with or without papillary disease, was the focus of the investigation. The trial was initially structured into three cohorts: a combination therapy of gemcitabine intravesical delivery (Inlexzo, formerly TAR-200) and cetrelimab, a checkpoint inhibitor; TAR-200 monotherapy; and cetrelimab monotherapy. An additional fourth cohort, focusing on patients with papillary-only disease, was later added as an exploratory arm.

The trial's findings quickly highlighted the effectiveness of gemcitabine intravesical delivery as a single-agent therapy. Not only did gemcitabine intravesical delivery monotherapy prove to be the most efficacious option, but it also outperformed the combination therapy, a surprising result believed to be due to fewer adverse events (AEs) and greater ease of administration. This led researchers to focus primarily on the TAR-200 monotherapy arm.

Gemcitabine intravesical delivery, is a deployable device designed for sustained release of the chemotherapy drug gemcitabine directly into the bladder. The device, which is placed using a urinary catheter, remains in the bladder for 3 weeks, continuously releasing gemcitabine for up to 7 days. It is then removed via cystoscopy and a new one is replaced, a process akin to removing a stent. This novel approach represents a significant paradigm shift in bladder cancer treatment, moving away from traditional intravesical liquid instillations to a device-based therapy.

Patients in the SunRISe-1 study received gemcitabine intravesical delivery every 3 weeks for the first 24 weeks, followed by maintenance therapy every 12 weeks through Week 96. The primary endpoint was the overall complete response rate, which was rigorously assessed through quarterly cystoscopy, cytology, and mandated bladder biopsies at weeks 24 and 48. Patients who experienced disease recurrence or persistence were immediately removed from the trial, ensuring a true test of the drug's efficacy from the outset.

The results of the trial were highly encouraging. The complete response rate for gemcitabine intravesical delivery was an impressive 82%, the highest ever seen in this difficult-to-treat patient population. Furthermore, the responses were not only rapid but also durable, with over 50% of responding patients maintaining their response for 12 months or longer. In terms of tolerability, gemcitabine intravesical delivery was generally well-tolerated. Patients experienced typical urinary AEs such as dysuria, frequency, and urgency. Only 3 patients discontinued treatment due to drug-related AEs, and a mere 5 patients experienced serious treatment-related AEs, underscoring the drug's safety profile.

Gemcitabine intravesical delivery monotherapy arm's success led to its approval, providing a new and highly effective treatment option for patients with high-risk, BCG-unresponsive non–muscle-invasive bladder cancer.