In this interview, senior author and scientific principal investigator Seth P. Lerner, MD, discusses the results of the OLYMPUS trial and what they mean for the management of this disease
The final report of the OLYMPUS trial, which investigated the durability of response of UGN-101 (Jelmyto) in patients with low-grade upper tract urothelial carcinoma (UTUC), was recently published in the Journal of Urology.1 In this interview, senior author and scientific principal investigator Seth P. Lerner, MD, discusses the results and what they mean for the management of this disease. Lerner is a professor in the Scott Department of Urology and Beth and Dave Swalm Chair in urologic oncology at the Baylor College of Medicine Medical Center in Houston, Texas.
This was a single-arm, phase 3 registration trial of UGN-101, which is now commercially available and called Jelmyto. [This] is a reverse thermal gel, which is admixed with a chemotherapy drug, mitomycin. At cold temperatures, it's a viscous liquid that is injectable through a ureteral catheter, which is how we've treated our patients, but it's also approved for administration through a percutaneous nephrostomy tube. At body temperature, it forms a semi solid gel that is retained in the renal pelvis and the infundibulocalyceal system and provides a longer-term exposure to the chemotherapy drug. So, the gel, it turns out, is retained for about 4 to 6 hours. And with urine production, it essentially dissolve and then passes into the bladder, and the patient then voids. It really overcomes the limitation of the lack of ability to retain a drug for a long enough time for it to get into the submucosa and kill the incipient or present cancer cells. The target population of the clinical trial were patients with biopsy-proven Ta low-grade tumors that were proximal to the ureteropelvic junction and had a target lesion of between 5 and 15 mm in diameter. There could be other tumors. There could be a larger tumor that the surgeon was able to ablate down to this target diameter.
The primary end point was complete response—4 to 6 weeks following 6 weekly instillations. We published the primary end point results in Lancet Oncology in April of 2020, reporting a 59% complete response rate [in] both the resectable [and unresectable] tumor population.2 The urologic surgeon categorized as to resectable and unresectable, and it was 59% in both groups. The unresectable [population was] largely made up of patients with lower pole tumors where it can be very difficult to get the ureteroscope. You can see the tumor, but it may be difficult to get an adequate biopsy or do any meaningful ablation. Patients who achieved a complete response were then eligible to be treated with 11 monthly instillations. Patients were followed with ureteroscopy at 3-month intervals after ureteroscopic assessment of the response to induction therapy. Of the 42 patients who achieved a complete response, 41 of those were evaluable for duration of response, which was the focus of the manuscript that were recently published in the Journal of Urology.
Twenty-nine of these patients who achieved a complete response received at least 1 maintenance treatment, but only 3 received all 11 treatments. The median number of instillations was 6, and the Kaplan Meier estimated durability of complete response was 82% at 12 months. When we compared the duration of response and with or without the monthly instillations, there was no difference, so we can't really say that the monthly instillations helped patients maintain a complete response. But you can certainly do that and that's how we've adapted therapy from how we treat similar tumors in the lower urinary tract. So, when we're doing intravesical chemotherapy, once we get past induction, [if a] patient has a complete response, we'll do monthly treatments out to a year. Remember, we reported a ureteral stenosis rate 44 percent in the original paper, and there does appear to be a slightly higher risk of that with repeated instillations. Keep in mind that patients are also getting repeated instrumentation with ureteroscopy at 3 months, but the majority of these adverse events were manageable with conservative measures. There was nothing terribly surprising other than the lack of benefit with the monthly instillations.
The FDA approved this treatment in April, 2020 for patients with Ta low-grade disease in the upper urinary tract. And so, I think that these data firmly establish UGN-101, or Jelmyto, as a bona fide treatment option for kidney preservation for patients with low-grade, noninvasive urothelial cancer in the upper urinary tract. It clearly has the potential to help patients certainly put off or completely avoid the need for nephrectomy, which is the most common treatment for these patients.
The other thing that we have found is that we are just much more facile and comfortable with intracavitary therapy of the upper urinary tract. I do have to be very clear though that Jelmyto is not a treatment for patients with high-grade disease, but the analogy would be if you have a patient, say with [carcinoma in situ] of the renal pelvis, you can treat this with BCG administered via a retrograde ureteral catheter or percutaneous nephrostomy. I think [that with] all the lessons that we learned through the course of this trial we have incorporated this treatment strategy into the workflow of our practice, and we use this approach to treating upper tract non-invasive cancers much more routinely. In the past, it was [more of] a big effort to try to do this. So, I think that's good for our patients across the spectrum of upper urinary tract non-invasive disease.
Absolutely. I think the community has moved a lot more towards kidney preservation. We see that a lot with tumors in the distal ureter, for instance, where even with high-grade disease, I'm being much more aggressive about resection, reconstruction, and kidney preservation. We are in a new era of conservative treatment for low-grade disease of the upper urinary tract where the current generation of ureteroscopes, instrumentation for access and biopsy, and lasers are so much better [and] the techniques are better. Hopefully, the community's moving away from just de facto, a priori, "Your kidney needs to come out." We now have the first approved chemotherapy drug with an indication for Ta low-grade disease of the upper urinary tract.
We've learned a lot of lessons through the conduct of this trial, and there are a lot of people who now have amassed experience with this. Urologists who have potential patients, but lack personal experience with Jelmyto, can reach out to any of the investigators. The company UroGen can assist with connecting urologists with those of us that have experience. I've received calls to assist urologists in the surrounding community that have eligible patients, and so the message really is [to] please consider kidney preservation for these patients with Ta low-grade disease.
1. Matin SF, Pierorazio PM, Kleinmann N, et al. Durability of response to primary chemoablation of low-grade upper tract urothelial carcinoma using UGH-101, a mitomycin-containing reverse thermal gel: OLYMPUS trial final report. J Urol. Published online December 17, 2021. doi:10.1097/JU.0000000000002350
2. Kleinmann N, Matin SF, Pierorazio PM, 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. Lancet Oncol. 2020;21(6):776-785. doi:10.1016/S1470-2045(20)30147-9