The FDA has now approved mitomycin C formulated with a reverse thermal hydrogel (JelmytoTM, UroGen Pharma) for the treatment of adults with low-grade upper tract urothelial cancer (UTUC).
Accounting for 5% to 10% of all urothelial cancers, UTUC is a rare disease; low-grade UTUC occurs at an incidence of 6,000 to 8,000 cases per year in the United States. Mitomycin C hydrogel, the first drug to be approved specifically for low-grade UTUC, is an alkylating agent, a drug that halts protein synthesis by inhibiting the transcription of DNA into RNA, thereby preventing cancer cells from multiplying.
"Due to substantial treatment challenges associated with the complex anatomy of the upper urinary tract, many patients need to be treated with radical surgery, usually complete removal of the affected kidney, ureter and bladder cuff," commented Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases in the FDA's Center for Drug Evaluation and Research. Dr. Pazdur noted that mitomycin gel "gives patients, for the first time, an alternative treatment option for low-grade UTUC."
The approval was based on efficacy data from OLYMPUS (NCT02793128), an ongoing, single-arm, multicenter phase 3 trial that enrolled patients with previously untreated or recurrent noninvasive low-grade UTUC. Patients needed to have at least one measurable papillary tumor located above the ureteropelvic junction, and those with larger tumors could have had prior tumor debulking. Patients were given mitomycin gel in 4 mg/mL instillations, administered via ureteral catheter or nephrostomy tube, once a week for 6 weeks. Patients who experienced a complete response at 3 months were given monthly instillations for up to 11 more months. The trial's primary efficacy end points were complete response and durability of complete response, which was assessed at 3, 6, 9, and 12 months after the initial determination of complete response.
Of 71 enrolled patients, 41 patients (58%) achieved a complete response at 3 months following initiation of mitomycin therapy and were involved in the follow-up portion of the trial; 29 patients received at least one maintenance dose. At 12 months after the initial determination of complete response, 19 patients remained in complete response, while 7 had documented recurrences. The median duration of response has not been reached.
Adverse reactions occurring in at least 20% of patients included ureteric obstruction, flank pain, urinary tract infection, hematuria, renal dysfunction, fatigue, nausea, abdominal pain, dysuria, and vomiting. Ureteric obstruction, experienced by 58% of patients, required ureteral stent placement in 88% of cases; in 51% of cases, it did not resolve or only resolved partially. Because mitomycin gel can cause renal dysfunction, it is contraindicated in patients with a glomerular filtration rate under 30 mL/min. Female patients of reproductive potential should use contraception during treatment and for 6 months following the last dose, and male patients who have female partners of reproductive potential should use contraception during treatment and for 3 months afterward.
The recommended dose of mitomycin C hydrogel is 4 mg/mL, administered via ureteral catheter or nephrostomy tube, with total instillation volume based on volumetric measurements using pyelography and not to exceed 15 mL (60 mg of mitomycin).
For More Information
JelmytoTM (mitomycin gel) prescribing information (2020). UroGen Pharma, Inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211728s000lbl.pdf
US Food and Drug Administration (2020). FDA approves first therapy for treatment of low-grade upper tract urothelial cancer. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-treatment-low-grade-upper-tract-urothelial-cancer
Image credit: Nephron. Licensed under CC BY-SA 3.0