Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel: OLYMPUS Trial Final Report
2021; Lippincott Williams & Wilkins; Volume: 207; Issue: 4 Linguagem: Inglês
10.1097/ju.0000000000002350
ISSN1527-3792
AutoresSurena F. Matin, Phillip M. Pierorazio, Nir Kleinmann, John L. Gore, Ahmad Shabsigh, Brian Hu, Karim Chamie, Guilherme Godoy, Scott G. Hubosky, Marcelino Rivera, Michael A. O’Donnell, Marcus Quek, Jay D. Raman, John J. Knoedler, Douglas S. Scherr, Christopher Weight, Alon Z. Weizer, Michael P. Woods, Hristos Z. Kaimakliotis, Angela Smith, Jennifer Linehan, Jonathan Coleman, Mitchell R. Humphreys, Raymond Pak, David Lifshitz, Michael Verni, Ifat Klein, Marina Konorty, Dalit Strauss‐Ayali, Gil Hakim, Elyse Seltzer, Mark Schoenberg, Seth P. Lerner,
Tópico(s)Urinary and Genital Oncology Studies
ResumoYou have accessJournal of UrologyAdult Urology1 Apr 2022Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel: OLYMPUS Trial Final ReportThis article is commented on by the following:Editorial Comment Surena F. Matin, Phillip M. Pierorazio, Nir Kleinmann, John L. Gore, Ahmad Shabsigh, Brian Hu, Karim Chamie, Guilherme Godoy, Scott G. Hubosky, Marcelino Rivera, Michael O'Donnell, Marcus Quek, Jay D. Raman, John J. Knoedler, Douglas Scherr, Christopher Weight, Alon Weizer, Michael Woods, Hristos Kaimakliotis, Angela B. Smith, Jennifer Linehan, Jonathan Coleman, Mitchell R. Humphreys, Raymond Pak, David Lifshitz, Michael Verni, Ifat Klein, Marina Konorty, Dalit Strauss-Ayali, Gil Hakim, Elyse Seltzer, Mark Schoenberg, and Seth P. Lerner Surena F. MatinSurena F. Matin Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas , Phillip M. PierorazioPhillip M. Pierorazio Brady Urological Institute, The Johns Hopkins University, Baltimore, Maryland , Nir KleinmannNir Kleinmann Department of Urology, Sheba Medical Center, Ramat Gan, Israel , John L. GoreJohn L. Gore Department of Urology, University of Washington Medical Center, Seattle, Washington , Ahmad ShabsighAhmad Shabsigh Department of Urology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio , Brian HuBrian Hu Department of Urology, Loma Linda University, Loma Linda, California , Karim ChamieKarim Chamie Department of Urology, UCLA, Los Angeles, California , Guilherme GodoyGuilherme Godoy Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas , Scott G. HuboskyScott G. Hubosky Department of Urology, Sidney Kimmel Medical College at Thomas Jefferson University Hospitals, Philadelphia, Pennsylvania , Marcelino RiveraMarcelino Rivera Department of Urology, Mayo Clinic Health System, Rochester, Minnesota , Michael O'DonnellMichael O'Donnell Department of Urology, University of Iowa, Iowa City, Iowa , Marcus QuekMarcus Quek Department of Urology, Loyola University Medical Center, Maywood, Illinois , Jay D. RamanJay D. Raman Division of Urology, Pennsylvania State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania , John J. KnoedlerJohn J. Knoedler Division of Urology, Pennsylvania State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania , Douglas ScherrDouglas Scherr Department of Urology, Weill Medical College of Cornell University, New York, New York , Christopher WeightChristopher Weight Cleveland Clinic, Glickman Urological and Kidney Institute, Cleveland, Ohio , Alon WeizerAlon Weizer Department of Urology, University of Michigan, Ann Arbor, Michigan , Michael WoodsMichael Woods Department of Urology, Loyola University Medical Center, Maywood, Illinois , Hristos KaimakliotisHristos Kaimakliotis Department of Urology, Indiana University School of Medicine, Indianapolis, Indiana , Angela B. SmithAngela B. Smith Department of Urology, University of North Carolina School of Medicine, Chapel Hill, North Carolina , Jennifer LinehanJennifer Linehan Department of Urology, John Wayne Cancer Institute, Santa Monica, California , Jonathan ColemanJonathan Coleman Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York , Mitchell R. HumphreysMitchell R. Humphreys Department of Urology, Mayo Clinic-Phoenix, Scottsdale, Arizona , Raymond PakRaymond Pak Department of Urology, Mayo Clinic-Jacksonville, Jacksonville, Florida , David LifshitzDavid Lifshitz Department of Urology, Rabin Medical Center, Tel Aviv, Israel , Michael VerniMichael Verni Urology Center of Las Vegas, Las Vegas, Nevada , Ifat KleinIfat Klein UroGen Pharma, Ra'anana, Israel , Marina KonortyMarina Konorty UroGen Pharma, Ra'anana, Israel , Dalit Strauss-AyaliDalit Strauss-Ayali UroGen Pharma, Ra'anana, Israel , Gil HakimGil Hakim UroGen Pharma, Ra'anana, Israel , Elyse SeltzerElyse Seltzer UroGen Pharma, Princeton, New Jersey , Mark SchoenbergMark Schoenberg UroGen Pharma, Princeton, New Jersey Department of Urology, Albert Einstein College of Medicine, Bronx, New York , and Seth P. LernerSeth P. Lerner ‡‡Correspondence: Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, 7200 Cambridge, Suite 10B, Houston, Texas , 77030 telephone: 713-798-6841; FAX: 713-798-5553; E-mail Address: [email protected]) Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas View All Author Informationhttps://doi.org/10.1097/JU.0000000000002350AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: Our goal was to evaluate long-term safety and durability of response to UGN-101, a mitomycin-containing reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma. Materials and Methods: In this open-label, single-arm, multicenter, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology and negative for-cause biopsy) 4–6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method. Treatment-emergent adverse events (TEAEs) were monitored. Results: Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term followup; 23/41 patients (56%) remained in complete response after 12 months (95% CI 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs. Conclusions: Durability of response to UGN-101 with or without maintenance treatment is clinically meaningful, offering a kidney-sparing therapeutic alternative for patients with low-grade disease. Abbreviations and Acronyms AE adverse event eGFR estimated glomerular filtration rate PDE primary disease evaluation RNU radical nephroureterectomy TEAE treatment-emergent adverse event UTUC upper tract urothelial carcinoma Upper tract urothelial carcinoma (UTUC) is an uncommon malignancy with few standardized treatment options supported by prospective data.1 Patients with high-grade cancer are most commonly treated with radical nephroureterectomy (RNU), while kidney-sparing options such as endoscopic ablation are recommended for patients with low-grade disease and small, favorably located tumors or patients with functionally or anatomically solitary kidneys.1,2 Drug concentration and dwell time are both negatively affected by urine flow, limiting the benefit of aqueous topical therapies in UTUC.3 UGN-101 (JELMYTO® [mitomycin] for pyelocalyceal solution) is a mitomycin-containing reverse thermal gel (4 mg mitomycin per ml gel) indicated for primary chemoablative treatment of low-grade UTUC.4 Liquid when chilled, UGN-101 is instilled via ureteral catheter or nephrostomy tube and becomes a semisolid gel at body temperature that dissolves during urine production over 4–6 hours, resulting in increased dwell time at the tumor site.5 We previously reported interim results from OLYMPUS, a phase 3 clinical trial that evaluated UGN-101 for treatment of low-grade UTUC.6 The trial's primary endpoint was complete eradication of disease in the ipsilateral pyelocalyceal system (defined as negative ureteroscopic evaluation, negative cytology and negative for-cause biopsy) 4–6 weeks following 6 weekly induction instillations of UGN-101. Complete response was observed in 59% of treated patients irrespective of baseline demographic and clinical characteristics, suggesting UGN-101 may offer a kidney-sparing alternative to patients with low-grade, low-volume UTUC. At the time of database lock for the previously reported results (May 22, 2019), fewer than half of patients with complete response at the primary disease evaluation (PDE) visit had been followed for an additional 12 months to evaluate durability of response, the key secondary outcome. As of final database lock on April 30, 2020, all patients with complete response at the PDE visit had either been followed for ≥12 additional months for continued response or had discontinued participation in the study. These longer-term results are presented here. Methods The design of OLYMPUS, an open-label, single-arm, phase 3 trial of UGN-101 conducted at 24 academic centers in the U.S. and Israel (NCT02793128), has been described in detail elsewhere.6 Briefly, eligible patients ≥18 years of age with primary or recurrent biopsy-proven low-grade UTUC were treated with 6 once-weekly instillations of UGN-101. Tumor response was evaluated at the PDE visit, 4–6 weeks after the last instillation. Patients who demonstrated complete response were offered maintenance treatment of up to 11 once-monthly instillations of UGN-101, with followup visits for evaluation of response durability at 3, 6, 9 and 12 months. The key secondary efficacy outcome was durability of response at 12 months. Safety was assessed throughout by laboratory evaluations, physical examination and adverse event (AE) monitoring. All patients provided written informed consent (IRB No. TC-UT-03-P). Methods for sample size determination and analysis of the primary outcome have been described in detail previously.6 The key secondary endpoint of long-term durability of response was determined for those patients who achieved complete response at the PDE visit. Durability of response was measured as ureteroscopically observed complete response at 12 months and duration of response estimated by the Kaplan-Meier method. Duration of response was defined as the time from PDE visit until disease recurrence. Patients who did not have documented disease recurrence or who died prior to recurrence were censored at their last assessment or date of death. All statistical analyses were performed using SAS®, version 9.4 or higher (SAS, Cary, North Carolina). Safety data were summarized descriptively. Results The study was initiated April 6, 2017 and the final data cutoff was April 30, 2020. Of 74 patients enrolled 71 received ≥1 dose of UGN-101 (comprising both the intent-to-treat and safety populations) and 61 (86%) completed the 6 planned weekly instillations. At the PDE visit, 42/71 patients (59%) achieved complete response; however, 1 patient withdrew consent prior to followup (fig. 1). Thus, the population followed for evaluation of response durability comprised 41/71 patients (58%). The median duration of followup for patients with complete response was 11.8 months (IQR 11.0, 12.7). Figure 1. Patient flow diagram, modified from Kleinmann et al6 to show final disposition of patients at the April 30, 2020 final data cutoff. a, more than 1 reason could be given. b, patient traveled out of the country. Baseline demographic and clinical characteristics of patients entering the maintenance phase are shown in table 1. Most patients were White, male, older than 70 years (median age 72, range 49–87) and had 2 kidneys. Maintenance regimens varied; 12/41 patients (29%) received no maintenance therapy, while 29/41 (71%) received at least 1 dose of maintenance treatment (table 2). Among the 29 patients who received any maintenance treatment, the median number of maintenance instillations was 6 (range 1–11). Table 1. Summary of baseline demographic and clinical characteristics of 41 patients with complete response at PDE Characteristic Received ≥1 Maintenance Treatment Received No Maintenance Treatment No. pts 29 12 Mean yrs age (SD) 69.4 (9.4) 74.7 (10.8) No. age <75 yrs (%) 20 (69) 6 (50) No. age ≥75 yrs (%) 9 (31) 6 (50) No. male (%) 21 (72) 6 (50) Mean kg/m2 body mass index (SD) 29.3 (7.0) 26.3 (5.2) No. race or ethnicity (%) Caucasian 24 (83) 11 (92) African American 2 (6.9) 1 (8.3) Hispanic 2 (6.9) 0 (0) Asian 1 (3.4) 0 (0) No. 2 kidneys at enrollment (%) 27 (93) 10 (83) No. history of UTUC (%) 17 (59) 3 (25) No. previous transurethral resection of bladder tumors (%) 10 (34) 2 (17) No. previous endoscopic ablative surgery (%) 14 (48) 7 (58) No. any previous surgery related to urothelial carcinoma (%) 26 (90) 10 (83) Mean No. of papillary tumors (SD) 2.4 (1.78) 1.9 (1.08) Mean mm diameter of largest tumor (SD)* 12.7 (9.63) 16.9 (9.16) Mean mm total tumor burden (SD) 17.2 (12.50) 21.2 (16.39) No. tumor unreachable by laser (%) 15 (52) 5 (42) Pre-debulking. Data are summarized descriptively; no statistical analyses were performed. Table 2. Number of UGN-101 maintenance instillations and number of urinary obstruction AEs during maintenance period in 41 patients with complete response at PDE Number of UGN-101 Maintenance Instillations No. Pts (%) No. Urinary Obstruction AEs 0 12 (29) 10 1 4 (10) 2 2 2 (4.9) 2 3 3 (7.3) 2 4 1 (2.4) 1 5 2 (4.9) 3 6 4 (10) 11 7 2 (4.9) 1 8 4 (10) 7 9 2 (4.9) 3 10 2 (4.9) 5 11 3 (7.3) 3 Urinary obstruction includes any TEAEs of ureteric stenosis, hydronephrosis, urinary tract obstruction, pelvi-ureteric obstruction, ureteric obstruction and obstructive uropathy. Of 41 patients who achieved complete response at PDE 23 (56%) remained in complete response after 12 months (95% CI 40, 72), 8 experienced disease recurrence and 10 were unable to be evaluated. In the Kaplan-Meier analysis durability of response was estimated as 82% (95% CI 66, 91) 12 months after the PDE visit (fig. 2). The Kaplan-Meier median time to recurrence was not estimable. Figure 2. Kaplan-Meier analysis for durability in 41 patients with complete response at PDE during maintenance/followup. Among the 23/41 patients without disease recurrence at 12 months 17/29 (59%) received ≥1 maintenance treatment and 6/12 (50%) did not receive any maintenance treatment. Exploratory subgroup analyses to evaluate treatment effect showed no individual parameter appeared to affect durability of response (table 3). Among the 4 patients with a single kidney 2 had durable response at 12 months, 1 had durable response at 9 months but did not have a 12-month evaluation and 1 had disease recurrence. Table 3. Subgroup analysis of durable complete response 12 months post-PDE visit (complete responder at PDE analysis set) Covariate Complete Responder at PDE Analysis Set (41 pts) Subgroup Total No. No. Durable Complete Response (%)* 95% CI Age (yrs) <65 10 7 (70) (35, 93) 65 to 30 14 9 (64) (35, 87) Country USA 31 16 (52) (33, 70) Israel 10 7 (70) (35, 93) Pre-debulking No. of papillary lesions 1 18 12 (67) (41, 87) >1 23 11 (48) (27, 69) Post-debulking No. of papillary lesions 1 29 18 (62) (42, 79) >1 12 5 (42) (15, 72) Pre-debulking largest lesion diameter (mm) ≤10 20 14 (70) (46, 88) >10 20 9 (45) (23, 68) Post-debulking largest lesion diameter (mm) ≤10 35 19 (54) (37, 71) >10 6 4 (67) (22, 96) Pre-debulking total tumor burden (mm) ≤15 21 12 (57) (34, 78) >15 16 9 (56) (30, 80) Post-debulking total tumor burden (mm) ≤10 25 15 (60) (39, 79) >10 16 8 (50) (25, 75) No. treatments received 6 35 21 (60) (42, 76) <6 6 2 (33) (4, 77) Tumor is unresectable No 21 11 (52) (30, 74) Yes 20 12 (60) (36, 81) Past urothelial carcinoma episodes 0 15 10 (67) (38, 88) ≥1 26 13 (50) (30, 70) Past UTUC episodes 0 21 12 (57) (34, 78) ≥1 20 11 (55) (32, 77) No. maintenance dose 0 12 6 (50) (21, 79) ≥1 29 17 (59) (39, 76) At 12 months post-PDE. Among the 8 patients with disease recurrence 3 recurrences were documented approximately 3 months after the PDE visit; the other 5 recurrences were documented at later assessments (fig. 3). Maintenance regimens varied among patients with disease recurrence. Although 2 patients with recurrences had received no maintenance, the others had received 1, 2, 3, 6, 9 and 11 maintenance instillations. Figure 3. Swimmer plot for 41 individual patients with complete response at PDE during maintenance/followup. Among 41 patients with complete response at PDE 12 did not receive maintenance treatment, while 29 received ≥1 maintenance instillation of UGN-101. There were 8 patients with documented disease recurrence and 23 patients without disease recurrence at 12 months. Patients who did not have documented disease recurrence or who died prior to recurrence were censored at their last assessment or date of death. Asterisk indicates none of the deaths was considered related to study drug or study procedure. There were 8 patients who were considered to have partial response to UGN-101 at the PDE visit. Although not eligible for maintenance treatment, there was evidence of clinical benefit for some of these patients through modification of their treatment plans. One patient who planned to receive endoscopic ablation plus adjuvant topical agents was changed to receive only endoscopic ablation, while 2 patients who planned to undergo RNU were changed to endoscopic ablation or observation and followup every 3 months with ureteroscopy. None of the partial responders underwent RNU. Of the 71 patients enrolled in the trial who received ≥1 instillation of UGN-101 a total of 8 (11%) eventually underwent RNU (table 4). Of these, 2 were considered complete responders; 1 received 6 maintenance instillations of UGN-101 while the other did not receive any maintenance treatment. In both cases, an AE of ureteric stenosis that did not resolve resulted in the patients' election to undergo RNU, with no cancer found at time of nephroureterectomy. The remaining 6 patients received 5 (1 patient) or 6 (5) instillations of UGN-101, but were considered nonresponders and recommended for RNU by their treating urologists. Table 4. Demographic and clinical characteristics of patients who underwent RNU during the study or long-term followup* Pt No. Age Sex Race No. UGN-101 Instillations Outcome at PDE Reason/Timing for RNU Induction Maintenance 1 50 F Caucasian 6 6 Complete response AE of ureteric stenosis with hydronephrosis reported 33 days after last maintenance treatment; AE did not resolve + pt elected to undergo lt RNU 166 days after last maintenance treatment. Post-RNU pathology identified no residual carcinoma. 2 68 F Caucasian 6 0 Complete response AE of ureteric stenosis reported 145 days after last treatment; AE did not resolve + pt elected to undergo lt RNU 290 days after last treatment. Post-RNU pathology identified no residual carcinoma. 3 63 F Hispanic 6 0 Emergence of high-grade disease not detected at baseline Ureteroscopy with biopsy identified large (approximately 2 cm) papillary tumor filling the renal pelvis + upper pole calyx; pt underwent rt RNU 183 days after last treatment. 4 67 M Caucasian 6 0 Emergence of high-grade disease not detected at baseline Ureteroscopy with biopsy identified high-grade T1 urothelial carcinoma; pt underwent rt RNU 90 days after last treatment. 5 71 M Caucasian 6 0 Emergence of high-grade disease not detected at baseline Ureteroscopy with biopsy identified foci of high-grade carcinoma in the background of low-grade carcinoma; pt underwent lt RNU 149 days after last treatment. Post-RNU pathology identified yp Ta papillary urothelial carcinoma. 6 78 M Asian 6 0 No complete response AE of ureteric stenosis reported 28 days after last treatment; cytology and biopsy identified low-grade Ta papillary urothelial carcinoma; pt underwent lt RNU 85 days after last treatment. 7 77 M Caucasian 5 0 Emergence of high-grade disease not detected at baseline Discontinued treatment due to urinary tract obstruction; ureteroscopy with biopsy identified superficial fragment of papillary urothelial carcinoma, predominantly low-grade with focal high-grade areas; pt underwent lt RNU 107 days after last treatment. 8 62 F Caucasian 6 0 No complete response Ureteroscopy evaluation indeterminate due to blood clot in upper calyx; pt underwent lt RNU 157 days after last treatment. As reported through December 18, 2019 among 71 patients enrolled in the study who received ≥1 instillation of UGN-101. Post-RNU pathology reported if available. Safety There were few differences in treatment emergent AEs (TEAEs), either qualitatively or quantitatively, in this final analysis compared with the interim analysis presented previously.6 The most common TEAEs were ureteric stenosis, urinary tract infection, hematuria and flank pain, and most were considered to be related to study drug or procedure (table 5). There were differences in the incidences of individual AEs between the 29 patients who received ≥1 maintenance treatment and the 42 patients who did not receive any maintenance treatment (comprising 12 patients who were complete responders at the PDE visit but did not receive maintenance and 30 patients who were not complete responders at the PDE visit and were therefore ineligible for maintenance treatment). There appeared to be an association between the total number of UGN-101 instillations and the most commonly reported TEAEs from the renal and urinary disorders organ class. Ureteric stenosis was the most frequently reported TEAE in the safety population, occurring in 31/71 patients (44%); however, it was reported in 19/29 patients (66%) who received ≥7 instillations of UGN-101 (ie ≥1 maintenance instillation) compared with 12/42 patients (29%) who received ≤6 instillations of UGN-101. Patients with a TEAE of ureteric stenosis had completed a mean 8.0±3.2 instillations before their first reported event. TEAEs of urinary tract infection, flank pain, nausea, dysuria, abdominal pain and vomiting occurred in a higher percentage of patients who received ≥1 maintenance instillation of UGN-101, although no statistical analyses were performed. Table 5. TEAEs occurring in ≥10 patients, safety population (71) No. Pts with ≤6 Instillations of UGN-101 (%) No. Pts with ≥7 Instillations of UGN-101 (%) Pts 42 29 Any TEAE 38 (90) 29 (100) Serious AE 18 (43) 10 (34) TEAE leading to death 3 (7.1) 2 (6.9) TEAE related to study drug 26 (62) 26 (90) TEAE related to study procedure 27 (64) 28 (97) Ureteric stenosis 12 (29) 19 (66) Urinary tract infection 11 (26) 12 (41) Hematuria 13 (31) 10 (34) Flank pain 9 (21) 13 (45) Nausea 7 (17) 11 (38) Dysuria 7 (17) 9 (31) Abdominal pain 4 (9.5) 10 (34) Vomiting 6 (14) 8 (31) Renal impairment 7 (17) 7 (24) Hydronephrosis 7 (17) 6 (21) Fatigue 6 (14) 5 (17) Anemia 5 (12) 5 (17) Back pain 5 (12) 5 (17) Pollakiuria 3 (7.1) 7 (24) Data are summarized descriptively according to the Medical Dictionary for Regulatory Activities, version 19.1. No statistical analyses were performed. A total of 90 urinary obstruction TEAEs (defined as ureteric stenosis, hydronephrosis, urinary tract obstruction, pelvi-ureteric obstruction, obstructive uropathy and ureteric obstruction) occurred in 41/71 patients (58%) in the safety population; however, the majority resolved without sequelae (supplementary table, https://www.jurology.com). Of 23 urinary obstruction TEAEs that occurred in 19 patients and did not resolve or resolved with sequelae 21 events occurred after ≥6 instillations of UGN-101. Among patients with renal and urinary TEAEs (49/71, 69%), mean changes from baseline for creatinine values were generally small and transient both during the treatment and maintenance periods, and were not considered clinically relevant. Similarly, mean changes for estimated glomerular filtration rate (eGFR) were not considered clinically relevant during the treatment period; however, mean changes were considered moderate (decreases of ≥10 ml/minute/1.73 m2) for some visits during the maintenance period, but interpretation of clinical relevance is limited by the small number of patients. Among 3/4 patients with a single kidney there were generally small and clinically insignificant changes in creatinine levels and eGFR; 1 patient experienced significant, nonreversible decline in eGFR. With further followup, 2 more patients died (from hypotension/septic shock/pneumonia in a 79-year-old male and metastatic urothelial carcinoma in an 83-year-old male) in addition to the 3 deaths previously reported.6 There was no evidence of recurrent primary UTUC in the patient whose cause of death was cancer; the patient had achieved 6 months of durable complete response and was diagnosed with metastatic disease approximately 4.5 months after the last dose of study medication. None of the deaths was considered related to study drug or study procedure. Discussion The previous interim report of the efficacy and safety of UGN-101 in primary chemoablation of low-grade UTUC demonstrated that a substantial proportion of patients (59%) achieved complete response following 6 weekly instillations, and suggested the response may be durable.6 The current study, in which the cohort of patients who achieved complete response and entered maintenance treatment and followup, confirms that durability of response to UGN-101 is clinically meaningful. In the Kaplan-Meier analysis, durability was estimated to be 82% at 12 months followup. Because there were few documented recurrences of UTUC in this analysis, the median time to recurrence could not be estimated. From trial initiation (April 6, 2017) through final database lock (April 30, 2020) 23/71 patients (32%) have had no recurrence in the treated kidney and remain alive. The durable response to UGN-101 observed in this study is encouraging, especially considering that some patients' lesions were deemed unresectable at baseline. Even among patients who achieved partial but not complete response there was evidence of clinical benefit in the modification of treatment plans to less invasive options; however, this observation must be interpreted cautiously given the small number of patients involved. Direct comparison of the recurrence rate in this study and local recurrence rates in UTUC patients treated endoscopically is not possible given the retrospective nature of published series with heterogeneous patient populations and lengths of followup. However, a meta-analysis of predominantly low- and intermediate-grade UTUC patients treated endoscopically found a local recurrence rate of 53% in 20 series among 736 patients whose followup ranged from 14–73 months.7 In a prospective series of 66 low-grade UTUC patients a 77% rate of local recurrence at a mean of 12 months was observed,8 but mean tumor size was 23 mm, greater than the maximum allowable tumor size of 15 mm in the current study. Although patients who achieved complete response after induction therapy were eligible for up to 11 monthly maintenance treatments with UGN-101, use of maintenance was inconsistent. Twelve patients received no maintenance while just 3/41 (7%) received the maximum number of instillations allowed. There was no clear association between durability of response and any number of maintenance treatments with UGN-101. At 12 months followup durable complete response was observed in 59% of patients who had received any amount of maintenance treatment compared with 50% of patients who did not receive any maintenance treatment. Given the variability in maintenance treatment across the cohort of patients and the high estimate of durable response, it is not possible to draw conclusions about the value of maintenance therapy in sustaining complete response. Conversely, this analysis provides some evidence that maintenance therapy and an increasing number of UGN-101 instillations are associated with increased incidence and severity of ureteric stenosis and incidence of urinary obstruction events that do not resolve or resolve with sequelae. Indeed, the incidence of ureteric stenosis may help explain the variability in the number of maintenance instillations patients received. Given the nature of UGN-101 delivery directly to the target organ, it can be difficult to differentiate between relationship of AEs to study drug and relationship to study procedure, particularly in the case of renal and urinary TEAEs. A detailed discussion of treatment-related morbidity that may occur as a result of multiple instillations of UGN-101 for the management of low-grade UTUC has been presented previously, including AEs of special interest (ie renal and urinary disorders, immune system disorders, and blood and lymphatic system disorders).6 TEAEs in this final analysis did not differ qualitatively from the interim analysis previously presented,6 although there were some differences in the incidences of TEAEs between patients who received ≤6 instillations of UGN-101 (induction only) and patients who received ≥7 instillations (≥1 maintenance instillation), reflecting the increased risk of AEs associated with increased exposure to mitomycin and an increased number of procedures. Two additional deaths occurred during the extended followup, but neither was considered related to study drug or treatment. There are limitations to the current study. The small size of the study population reflects the rarity of low-grade UTUC and may limit the generalizability of the findings regarding durability of complete response. Additionally, the lack of a control group may introduce bias, in that benefits and harms may be over or under assessed; however, there are no other nonsurgical ablative therapies with which UGN-101 could be compared. Conclusions Instillation of UGN-101 once weekly for 6 weeks has been shown to be effective and clinically meaningful for primary chemoablation of low-grade UTUC. Results from this final analysis suggest durability of response in a majority of patients for up to 12 months following induction therapy, with or without maintenance treatment. No new safety signals were identified and the overall safety profile in this analysis was consistent with the known safety profile of endoscopic administration of intravesical mitomycin. Based on results to date, the benefit-risk profile of UGN-101 for induction treatment of low-grade UTUC appears favorable, and suggests that kidney-sparing endoscopic treatment can be augmented in patients with multifocal disease and those whose tumors are difficult to treat endoscopically. The use of maintenance treatment for patients achieving complete response requires full consideration of the potential benefits and risks associated with maintenance therapy. Acknowledgments The study team thanks the patients and their families and caregivers for volunteering to participate in this trial. We also thank Mary Susan Prescott of Prescott Medical Communications Group (Chicago, Illinois) for editorial assistance with financial support from UroGen Pharma. References 1. : An analysis of staging and treatment trends for upper tract urothelial carcinoma in the national cancer database. Clin Genitourin Cancer 2018; 16: e743. Google Scholar 2. : European Association of Urology guidelines on upper urinary tract urothelial carcinoma: 2020 update. Eur Urol 2021; 79: 62. Google Scholar 3. : Endocavitary treatment for upper tract urothelial carcinoma: a meta-analysis of the current literature. Urol Oncol 2019; 37: 430. Google Scholar 4. U.S. Food and Drug Administration: FDA approves mitomycin for low-grade upper tract urothelial cancer [news release], April 15, 2020. Silver Spring, Maryland. Available at https://bit.ly/2xxaVMu. Google Scholar 5. : Thermo reversible hydrogel based delivery of mitomycin C (UGN-101) for treatment of upper tract urothelial carcinoma (UTUC). Bladder Cancer 2019; 5: 21. Google Scholar 6. : 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: 776. Google Scholar 7. : Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review. BJU Int 2012; 110: 614. Google Scholar 8. : Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: a 15-year comprehensive review of 160 consecutive patients. BJU Int 2012; 110: 1618. Google Scholar Funding: UroGen Pharma. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.© 2022 The Author(s). Published on behalf of the American Urological Association, Education and Research, Inc.FiguresReferencesRelatedDetailsCited BySiemens D (2022) This Month in Adult UrologyJournal of Urology, VOL. 207, NO. 4, (749-750), Online publication date: 1-Apr-2022.Ghoreifi A and Djaladat H (2022) Editorial CommentJournal of Urology, VOL. 207, NO. 6, (1309-1309), Online publication date: 1-Jun-2022.Related articlesJournal of UrologyJan 4, 2022, 12:00:00 AMEditorial Comment Volume 207Issue 4April 2022Page: 779-788Supplementary Materials Advertisement Copyright & Permissions© 2022 The Author(s). Published on behalf of the American Urological Association, Education and Research, Inc.Keywordsclinical trialurinary bladder neoplasmsmitomycinAcknowledgmentsThe study team thanks the patients and their families and caregivers for volunteering to participate in this trial. We also thank Mary Susan Prescott of Prescott Medical Communications Group (Chicago, Illinois) for editorial assistance with financial support from UroGen Pharma.MetricsAuthor Information Surena F. Matin Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas Equal study contribution. Financial interest and/or other relationship with Johnson&Johnson, Merck and QED. More articles by this author Phillip M. Pierorazio Brady Urological Institute, The Johns Hopkins University, Baltimore, Maryland Equal study contribution. More articles by this author Nir Kleinmann Department of Urology, Sheba Medical Center, Ramat Gan, Israel More articles by this author John L. Gore Department of Urology, University of Washington Medical Center, Seattle, Washington Financial interest and/or other relationship with FerGene Pharmaceuticals, Inc. More articles by this author Ahmad Shabsigh Department of Urology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio Financial interest and/or other relationship with UroGen Pharma. More articles by this author Brian Hu Department of Urology, Loma Linda University, Loma Linda, California Financial interest and/or other relationship with UroGen Pharma. More articles by this author Karim Chamie Department of Urology, UCLA, Los Angeles, California Financial interest and/or other relationship with UroGen Pharma. More articles by this author Guilherme Godoy Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas More articles by this author Scott G. Hubosky Department of Urology, Sidney Kimmel Medical College at Thomas Jefferson University Hospitals, Philadelphia, Pennsylvania More articles by this author Marcelino Rivera Department of Urology, Mayo Clinic Health System, Rochester, Minnesota More articles by this author Michael O'Donnell Department of Urology, University of Iowa, Iowa City, Iowa More articles by this author Marcus Quek Department of Urology, Loyola University Medical Center, Maywood, Illinois More articles by this author Jay D. Raman Division of Urology, Pennsylvania State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania Financial interest and/or other relationship with UroGen Pharma. More articles by this author John J. Knoedler Division of Urology, Pennsylvania State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania More articles by this author Douglas Scherr Department of Urology, Weill Medical College of Cornell University, New York, New York More articles by this author Christopher Weight Cleveland Clinic, Glickman Urological and Kidney Institute, Cleveland, Ohio Financial interest and/or other relationship with Abbot Molecular. More articles by this author Alon Weizer Department of Urology, University of Michigan, Ann Arbor, Michigan More articles by this author Michael Woods Department of Urology, Loyola University Medical Center, Maywood, Illinois More articles by this author Hristos Kaimakliotis Department of Urology, Indiana University School of Medicine, Indianapolis, Indiana More articles by this author Angela B. Smith Department of Urology, University of North Carolina School of Medicine, Chapel Hill, North Carolina Financial interest and/or other relationship with UroGen Pharma. More articles by this author Jennifer Linehan Department of Urology, John Wayne Cancer Institute, Santa Monica, California Financial interest and/or other relationship with UroGen Pharma and Intuitive Surgical. More articles by this author Jonathan Coleman Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York More articles by this author Mitchell R. Humphreys Department of Urology, Mayo Clinic-Phoenix, Scottsdale, Arizona More articles by this author Raymond Pak Department of Urology, Mayo Clinic-Jacksonville, Jacksonville, Florida Financial interest and/or other relationship with Ethicon Surgery. More articles by this author David Lifshitz Department of Urology, Rabin Medical Center, Tel Aviv, Israel More articles by this author Michael Verni Urology Center of Las Vegas, Las Vegas, Nevada Financial interest and/or other relationship with UroGen Pharma. More articles by this author Ifat Klein UroGen Pharma, Ra'anana, Israel Financial interest and/or other relationship with UroGen Pharma. More articles by this author Marina Konorty UroGen Pharma, Ra'anana, Israel Financial interest and/or other relationship with UroGen Pharma. More articles by this author Dalit Strauss-Ayali UroGen Pharma, Ra'anana, Israel Financial interest and/or other relationship with UroGen Pharma. More articles by this author Gil Hakim UroGen Pharma, Ra'anana, Israel Financial interest and/or other relationship with UroGen Pharma. More articles by this author Elyse Seltzer UroGen Pharma, Princeton, New Jersey Financial interest and/or other relationship with UroGen Pharma. More articles by this author Mark Schoenberg UroGen Pharma, Princeton, New Jersey Department of Urology, Albert Einstein College of Medicine, Bronx, New York Financial interest and/or other relationship with UroGen Pharma. More articles by this author Seth P. Lerner Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas ‡‡Correspondence: Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, 7200 Cambridge, Suite 10B, Houston, Texas , 77030 telephone: 713-798-6841; FAX: 713-798-5553; E-mail Address: [email protected]) Financial interest and/or other relationship with UroGen Pharma, QED, Endo and FKD; Clinical trials: Endo, FKD, JBL (SWOG), Genentech (SWOG), QED, UroGen, Vaxiion, Viventia; Consultant/Advisory Board: Aura Bioscience, C2i Genomics, FerGene, Genentech, Merck, Pfizer/EMD Serono, Stimit, UroGen, Vaxiion, Verity; Patent: TCGA classifier; Honoraria: Annenberg, Clinical Care Options, Grand Rounds Urology, Ology, UroToday. More articles by this author Expand All Funding: UroGen Pharma. Advertisement Advertisement PDF DownloadLoading ...
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