A novel formulation of the chemotherapy drug mitomycin demonstrated a 59% complete response rate among patients with unresectable low-grade upper tract urothelial cancer, signaling the potential for a minimally invasive alternative to kidney removal for some individuals with this malignancy,
Seth P. Lerner, MD, FACS
A novel formulation of the chemotherapy drug mitomycin demonstrated a 59% complete response (CR) rate among patients with unresectable low-grade upper tract urothelial cancer (UTUC), signaling the potential for a minimally invasive alternative to kidney removal for some individuals with this malignancy, according to findings from the phase III OLYMPUS trial.1
Results presented during the 2019 American Urological Association (AUA) Annual Meeting indicate that 42 of 71 patients treated with UGN-101 (mitomycin gel) achieved a CR. Among these responders, 24 of 27 patients who have undergone evaluations maintained a CR at ≥6 months.
In a subset of the overall study population with endoscopically unresectable tumors, 59% (20 of 34 patients) experienced a CR, including a CR lasting ≥6 months for 85% (17 of 20 patients).1 The most common adverse events (AEs) were urinary tract infection, ureteral narrowing, and stricture formation. No treatment- related fatalities were reported.2
The results suggest that minimally invasive chemoablation with UGN-101 may provide an alternative for the initial management of patients with low-grade UTUC, including those with endoscopically unresectable disease, study chair Seth P. Lerner, MD, FACS, and colleagues said in their AUA abstract.2
“For this typically elderly patient population, kidney preservation is paramount, and these findings provide evidence-based support for the concept of chemoablation with UGN-101 as an initial kidney-sparing treatment option for low-grade UTUC,” Mark P. Schoenberg, MD, chief medical officer at UroGen Pharma, which is developing the drug, said in a statement. “The analysis also advances our understanding of durability of response, which we are pleased to see has remained consistent as the number of patients who reach the 6-month follow-up timepoint increases,” he added.
The company plans to release full phase III OLYMPUS data later this year.
Landscape for UTUC Care
UTUC, which affects the ureters, the renal pelvis, and the kidneys, is a relatively uncommon malignancy, diagnosed in about 3100 patients in the United States annually.3 Patients with high-risk UTUC are typically treated with radical nephroureterectomy whereas those with low-grade UTUC may be candidates for endoscopic or percutaneous treatment.4
However, because of high-grade histology, tumor burden, or unfavorable tumor location, only 30% of patients with UTUC receive endoscopic, nephron-sparing treatments. Even patients with low-grade UTUC may have endoscopically unresectable disease and will undergo nephroureterectomy, which carries the risk of renal insufficiency and hemodialysis.2
UGN-101, formerly known as MitoGel, is a gel formulation of mitomycin C (MMC) designed to permit longer exposure (4-6 hours) of the drug to urinary tract tissue, which allows for the nonsurgical treatment of these tumors.4 The therapy is administered to patients using standard ureteral catheters.
The prospective single-arm OLYMPUS trial (NCT02793128), conducted in the United States and Israel, was designed to evaluate the efficacy, safety, and tolerability of UGN-101 in patients with low-grade UTUC. To be eligible for enrollment, adult patients had to have treatment-naïve or recurrent disease, ≥1 measurable papillary low-grade tumors ≤15 mm, and a wash urine cytology sampled from the pyelocaliceal system showing the absence of high-grade disease.
“These are patients whom, ideally, you’re trying to spare from extirpative surgery,” Lerner said in a presentation last year.5 Lerner is the Beth and Dave Swalm Chair in Urologic Oncology and the director of urologic oncology at Baylor College of Medicine in Houston, Texas.
The setting includes patients with recurrent, low-grade disease that is difficult to control, Lerner said. “In many cases these are tumors that are difficult to access, particularly the lower pole with angulation. It’s hard to get— you might be able to get your scope there to see it, but you can’t get a fiber through it to actually do any work.”
Lerner said the FDA wanted to ensure that patients with high-grade disease, for whom the standard of care is nephrectomy, were not enrolled in the OLYMPUS trial. The study excluded those who had received bacille Calmette-Guérin within the prior 6 months and had untreated concurrent urothelial cancer in sites other than the target area, prior carcinoma in situ in the urinary tract, prior 5-year history of invasive urothelial carcinoma in the urinary tract, or a prior 2-year history of high-grade papillary urothelial carcinoma in the urinary tract. Participants also could not be receiving chemotherapy or have plans for treatment.
Seventy-one patients were assigned to 4 mg MMC concentration per 1 mL of TC-3 gel, with a maximum dose of 15 mL, for 6 once-weekly intravesical instillations. Patients who demonstrate a CR are eligible to receive UGN-101 once monthly as maintenance treatment for 11 instillations or the first recurrence, whichever comes first.
The coprimary endpoints were CR, which was defined as a negative ureteroscopic evaluation, a negative wash cytology, and AEs. Secondary endpoints were long-term durability of CR; CR rate at 3, 6, and 9 months after evaluation; partial response; and MMC level in the plasma for select patients.
The FDA granted a breakthrough therapy designation to UGN-101 in October 2018 as a treatment for patients with low-grade UTUC. In December 2018, UroGen initiated a rolling submission of a new drug application with the FDA for UGN-101 in this setting. UGN-101 would be the first drug approved for the nonsurgical treatment of low-grade UTUC.
Efforts to develop UGN-101 in the OLYMPUS trial were met with “an extraordinary amount of enthusiasm and support,” Lerner remarked in his 2018 presentation. “For any of us here today who see even a reasonable volume of these patients, it’s troubling to not really have good tools to deal with the large volume, low-grade disease, the intracavitary treatment.”