NEWS & PERSPECTIVE

Shifting the treatment paradigm for low-grade upper tract urothelial cancer with the FDA approved mitomycin gel

Mitomycin gel is approved by the United States Food and Drug Administration (FDA) as the first non-surgical treatment for patients with low-grade upper tract urothelial cancer (UTUC).1 Results from the OLYMPUS, an open-label, single-arm and phase 3 clinical trial, facilitated the FDA approval. The study aimed to establish the chemotherapeutic properties of mitomycin gel in low-grade UTUC patients. The findings evaluated the complete response, durability response and safety profile of the drug. For the primary endpoint, 58% of UTUC patients achieved a complete response after 6 months of six mitomycin gel treatments, administered weekly. Besides, 46% of previously mitomycin gel treated low-grade UTUC patients continued to have a complete response after 12-month post treatment.2 Findings from the OLYMPUS confirmed mitomycin gel’s capability as a non-surgical chemoablation therapy option for low-grade UTUC patients.2

For the past decade, the treatment of UTUC has been challenging for many urologists. Although low-grade UTUC is a rare disease, there has been no notable improvement in survival rates with the majority of patients at risk of losing their kidneys. The current standard of care for treating low-grade UTUC requires surgery involving endoscopic surgery. Radical nephroureterectomy remains the gold standard for advanced staged UTUC patients. Radical nephroureterectomy may include removal of kidney, ureter, renal pelvis, and bladder cuff.3 Moreover, the regimen is not suitable for patients with a compromised kidney function, reflecting a significant unmet medical need for low-grade UTUC.3

A breakthrough and non-surgical method is causing a paradigm shift in the treatment of UTUC. The procedure involves incorporating a mitomycin-containing reverse thermal gel into chemotherapy. Mitomycin gel, recently approved by the FDA, is an alkylating drug which can prevent cancer by inhibiting the transcription of DNA into RNA. In addition, mitomycin gel comprises of a temperature-sensitive water-soluble gel formulation and, when cooled, becomes a liquid, enabling drug instillation via an antegrade or retrograde approach. Consequently, following the contact with urothelium, the liquid is warmed up by the patient's body temperature and becomes a hydrogel that conforms to the anatomy of each patient’s upper urinary tract. Normal urine flow dissolves the gel depot, resulting in sustained exposure of mitomycin to the tissue for 4 to 6 hours.2

"This is the first approval specifically for patients with low-grade UTUC and provides an option for some patients who may otherwise require a nephroureterectomy," said Richard Pazdur, director of the FDA's Oncology Center of Excellence.

Findings from the open-label, single-arm and phase 3 OLYMPUS study supported the FDA approval of mitomycin gel. The clinical trial selected UTUC patients with either treatment- naïve or recurrent low-grade noninvasive UTUC. Classification of recurrent disease defined as at least one measurable papillary tumor located above the ureteropelvic junction.1,2

In the OLYMPUS trial, 71 of the patients received weekly 4mg/mL mitomycin gel instillations via a ureteral catheter or nephrostomy tube for 6 weeks. Subsequently, for patients with a complete response at 3 months, monthly administration of mitomycin gel was given for a maximum of 11 additional months.1, 2

A complete response determined the primary endpoint of the study after 3 months of therapy. Following the initial six weekly treatments, 58% of patients achieved a complete response after completing 6 months of therapy. Furthermore, 46% of these patients continued to demonstrate complete responses after the 12-month treatment. The median response duration had not been reached (range = 0-18.8+ months).1, 2

The most frequent adverse events reported were ureteric stenosis (44%), urinary tract infection (32%), hematuria (31%), flank pain (30%), and nausea (24%). Also, 27% of the patients had drug-related or procedure-related serious adverse events. Nevertheless, no deaths were associated with the treatment.1,2

Dr. Seth P. Lerner, Department of Urology, Baylor College of Medicine, the lead investigator for the OLYMPUS study highlighted the benefits of the treatment stating, The clear benefit is that patients get to keep their kidney. For people who have one kidney, this option also removes the need for dialysis. Other potential beneficiaries would be patients for whom it would be too risky to operate to remove the kidney because of other conditions. Now they have an option for treatment."

Given the challenges related to low-grade UTUC, chemotherapy using a mitomycin-containing reverse thermal gel provides low-grade UTUC patients with an option to avoid nephroureterectomy. Importantly, mitomycin gel is the first non-surgical therapy approval by the FDA indicated for patients with low-grade UTUC.


References
  1. FDA Approves First Therapy for Treatment of Low-Grade Upper Tract Urothelial Cancer. https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-treatment-low-grade-upper-tract-urothelial-cancer. Accessed 15 April 2020.
  2. Kleinmann N et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. The Lancet Oncology.2020.
  3. Leow J et al. Optimal Management of Upper Tract Urothelial Carcinoma: Current Perspectives. Onco Targets Ther.2020;13:1‐15.
FDA
LOW-GRADE UPPER TRACT UROTHELIAL CANCER (UTUC)
MITOMYCIN GEL
OLYMPUS