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Recent Findings from Clinical Trials, Observational Studies, and Molecular and Genomic Research in Upper Tract Urothelial Carcinoma

Thank you for visiting UroToday’s Center of Excellence on upper tract urothelial carcinoma (UTUC). We examine expert content in a variety of formats to help practicing clinicians stay up to date. This letter highlights some of the most exciting recent findings from clinical trials, observational studies, and molecular and genomic research.


A quick review: UTUCs are malignancies of the urothelium of the renal pelvis, renal calices, and/or ureters that comprise about 5%-10% of urothelial cell carcinomas.1 Known risk factors include older age, male sex, smoking, germline alterations in mismatch repair genes (Lynch syndrome), prior bladder and upper tract cancer, alcohol consumption, and exposure to certain carcinogens.2,3 Early-stage UTUCs often are asymptomatic, while later-stage, locally advanced disease can present with gross or microscopic hematuria, flank pain, hydronephrosis, urinary obstruction, urinary tract infections, and/or renal insufficiency.3

About 30% of UTUCs are low-grade; these usually papillary tumors are typically indolent, but they can lead to hematuria and ureteral obstruction that require treatment. Radical nephroureterectomy (RNU) negatively affects renal function and does not improve overall survival in low-grade UTUC when compared with kidney-sparing therapies.1,4 Because conventional endoscopic management is technically challenging and associated with a high rate of local recurrence, developing other kidney-sparing treatment options is a priority. For patients with high-grade UTUC, the aim is to identify adjuvant and particularly neoadjuvant regimens that improve outcomes over RNU alone. In both low-grade and high-grade UTUC, investigators are exploring molecular and genomic assays to identify prognostic and predictive biomarkers.

Updates from clinical trials

An area of particular interest is photodynamic therapy, a treatment for localized upper tract urothelial tumors. This therapy involves intravenously administering a photosensitizing agent that reacts with light (usually applied via laser) to generate cytotoxic oxygen radicals that cause tumor cell death.5 Vascular-targeted photodynamic therapy (VTPD) is a more refined method in which the photosensitizing agent is confined to and targets the tumor vasculature, causing its occlusion and subsequent tumor cell death while limiting damage to healthy tissue.

At AUA 2022, we saw relevant intriguing data on padeliporfin (WST-11; TookadÒ), a novel, short-acting, water-soluble bacteriochlorophyll derivative6 being investigated as a photosensitizing agent for use in VTPD of genitourinary tumors. Padeliporfin has shown promise for treating low-grade prostate cancer7,8 and has been approved by the European Medicines Agency for this indication.9 Although the US FDA has declined to approve padeliporfin for low-risk prostate cancer due to a preference for active monitoring, the FDA in 2021 granted padeliporfin a Fast Track designation for therapeutic development in low-grade UTUC and unifocal high-grade UTUC.10

The Fast Track designation was based on data from a phase 1 study in which 18 surgery-refusing or surgery-ineligible patients with residual or recurrent UTUC after endoscopic treatment received WST-11 via endoluminal application. The complete response (CR) rate was 50%, meaning that half of patients had no visual tumor and negative urine cytology 30 days post-treatment. Furthermore, the CR rate rose to 68% after eight partial responders received an additional dose of WST-11 (the single non-responder in this small study had high-grade UTUC). Adverse events were nearly always grade 1 or 2, and no ureteral strictures, obstructions, or perforations were observed during follow-up; the most common adverse events were transient flank pain and hematuria. These phase 1 findings are compelling and clearly justify a larger study. The phase 3, single-arm, multicenter ENLIGHTENED trial (NCT04620239) of padeliporfin in low-grade UTUC has opened and aims to enroll about 100 patients, with initial results expected in 2023.

Adjuvant chemotherapy is effective in high-grade UTUC,11 but many patients are not eligible for intensive chemotherapy after RNU.4 Therefore, researchers are exploring the feasibility, safety, and clinical impact of neoadjuvant (pre-RNU) treatment. At ASCO GU 2022, we saw the results of a first-in-kind, multicenter, phase 2 trial (NCT01261728) of neoadjuvant gemcitabine and cisplatin in patients with unilateral, locally advanced, high-grade UTUC.12 Researchers reported that the regimen was well tolerated and induced responses in a promising percentage of patients without significantly delaying time to surgery or increasing the likelihood of clinically significant perioperative complications.

Among 57 patients evaluated, 70% completed all four cycles of neoadjuvant gemcitabine and cisplatin, and 89% completed at least three cycles. The primary endpoint of pathologic response (<pT2N0) was 63%, and 19% of patients had a CR (pT0N0). The 90-day rate of grade 3 or higher perioperative complications was 7%. After a median follow-up of 3.1 years, progression-free survival (PFS) was 78% at 2 years and 6% at 5 years, and the corresponding OS was 93% and 79%. Importantly, pathologic response correlated strongly with improved PFS and OS, with log-rank p-values of less than .001 for each comparison. These are thought-provoking results that may influence treatment choices for cisplatin-eligible patients with high-grade UTUC for whom we are considering RNU.

The findings of this study also establish a new benchmark for other neoadjuvant studies in high-grade UTUC. A study of neoadjuvant checkpoint inhibitor monotherapy with the PD-1 inhibitor pembrolizumab previously posted negative results,13 but researchers are now examining multi-agent combinations that include novel agents and chemotherapy. For example, in a phase 3 trial (EA8192; NCT04628767), patients with high-grade UTUC are randomly assigned to receive neoadjuvant therapy with either durvalumab (a PD-L1 checkpoint inhibitor) plus conventional chemotherapy or chemotherapy alone.14 For patients who are eligible to receive cisplatin, conventional chemotherapy consists of accelerated methotrexate, vinblastine, adriamycin, and cisplatin (aMVAC). A separate (third) arm of cisplatin-ineligible patients receives neoadjuvant durvalumab plus gemcitabine. The co-primary endpoints are pathologic CR and event-free survival. This study is enrolling patients at more than 170 centers in the United States, with primary findings anticipated in 2027.

Most clinicians would agree that neoadjuvant chemotherapy is potentially more “administrable” than adjuvant chemotherapy because patients have not yet undergone nephron loss after RNU. At the same time, most clinicians are aware of the Level 1 POUT data that demonstrated a significant benefit with adjuvant chemotherapy after RNU.11 A randomized head-to-head study in Europe, which is currently recruiting patients, will compare neoadjuvant versus adjuvant gemcitabine plus cisplatin, as well as neoadjuvant versus adjuvant MVAC. (This study also includes a separate arm of patients who will receive only RNU because they are ineligible for cisplatin based on a low glomerular filtration rate (GFR <55 mL/min) or for another reason.) Primary results from this approximately 200-patient study are expected in 2023 and should provide some evidence-based direction with respect to the clinical dilemma that clinicians face during the perioperative period of RNU.

Antegrade treatment with mitomycin gel

In 2020, a novel reverse thermal mitomycin gel became the first agent to receive FDA approval for treating adults with low-grade UTUC. In the pivotal, single-arm, phase 3 OLYMPUS trial, patients with confirmed low-grade UTUC received six volume-based instillations of mitomycin gel once weekly via retrograde catheter to the renal pelvis and calyces.15,16 Induction treatment led to a CR rate of CR 59%, and 56% of all treated patients maintained CRs at 12 months. In the final report of the OLYMPUS trial published this year, the Kaplan-Meier estimate of durability was 82% at 12 months, a compelling finding. However, 44% of OLYMPUS patients developed ureteral strictures during follow-up. It was unclear whether these strictures primarily resulted from chemoablation itself, or from repeated instrumentation during successive instillations. If the latter was the case, then another method of instillation might be safer while maintaining efficacy.

At AUA 2022, researchers presented real-world data suggesting that this hypothesis may indeed be true. In their observational study, 32 patients with low-grade UTUC received six instillations of mitomycin gel via antegrade insertion of a percutaneous nephrostomy tube.17,18 Only three (9%) patients developed ureteral strictures requiring balloon dilation or (transient) stent placement, while 50% demonstrated a CR (note that all patients were treated at high-volume centers). Although this was a small retrospective study, its safety findings are compelling, and the efficacy signal was comparable to that in the OLYMPUS trial.

Although the FDA approval of mitomycin gel covers both retrograde and antegrade instillation, this was the first published report of the antegrade experience. In a similar report published this year, eight patients with low-grade UTUC received six instillations of mitomycin gel via the antegrade route.19 After a median follow-up time of 7 months, 4 patients had CRs, and only one ureteral stricture was identified. Although was a very small single-center study, the findings mirror those from the 32-patient study. Together, the studies provide early evidence that that instilling mitomycin gel via the percutaneous antegrade method reduces the risk for ureteral strictures without significantly compromising efficacy. Note, too, that antegrade instillation of mitomycin gel does not require fluoroscopy-guided insertion of a ureteral catheter and can be performed in an outpatient office setting. At our own institution, the treatment route has been via the antegrade approach, albeit with a limited number of patients.

Molecular and genomic characterization of UTUC

UTUC and bladder cancer share some overlapping features seem to be distinct biologic entities—for example, UTUC is more likely than bladder cancer to be high-grade at diagnosis, is uniquely associated with exposure to aristolochic acid and with Lynch syndrome, and arises from mesoderm-derived, rather than endoderm-derived, epithelium.20,21

Recent studies also confirm that UTUC and bladder cancer are genetically similar but differ significantly in their frequencies of alterations in clinically relevant genes, such as FGFR3, TP53, RB1, ERBB2, and HRAS.21-23 In UTUC, some of the most common alterations are of FGFR3, chromatin remodeling genes, TP53/MDM2, and other tumor suppressor genes. Indeed, experts have described FGFR3 as a biologic driver and major target in UTUC;24 furthermore, at least one FGFR3 alteration (R248C) is more prevalent in UTUC associated with Lynch syndrome than in sporadic UTUC.25

At ASCO GU 2022, we saw intriguing new data on targetable mutations that exhibit distinct biologic pathways in urothelial carcinoma, including UTUC. Researchers at Memorial Sloan Kettering Cancer Center and the University of California San Francisco analyzed gene alterations, frequencies, and co-mutations from 381 unique, prospectively collected specimens of ERBB2 or FGFR3 mutated urothelial carcinomas (both upper and lower tract urothelial carcinoma were included).26 As has been demonstrated in high-grade non-muscle invasive bladder cancer,27 alterations in ERBB2 and FGFR3 were nearly always mutually exclusive, indicating that they are tied to distinct molecular pathways. In addition, FGFR3 mutated tumors were significantly associated with younger age and the presence of CDKN2A/B and STAG2 mutations, while ERBB2 mutated tumors were significantly associated with male sex, more advanced/aggressive (>pT2) disease at diagnosis, and co-mutations with RB1, P53, and ARID1A.

Note that alterations in ERBB2 are known to be associated with more advanced and higher-grade bladder cancer and may be prognostic for poorer outcomes.28,29 EBRR2 encodes human epidermal growth factor receptor 2 (HER2), a receptor tyrosine kinase in the epidermal growth factor receptor family that is targeted by commercially available antibody-drug conjugates. These include trastuzumab emtansine and trastuzumab deruxtecan, which the FDA has approved for use in HER2-positive breast cancers and (in the case of trastuzamab deruxtecan) gastric cancers, and which have shown promise for the targeted treatment of urothelial carcinoma.30

Studies like these exemplify the recent explosion of interest in using biomarkers to help us better classify, prognosticate, and select treatments for urothelial carcinoma. A crucial goal is to identify the most clinically useful biomarkers for risk-stratifying patients and predicting therapeutic response. Because UTUC is a relatively rare disease, most biomarker studies have been of small, single-institution cohorts. To reduce bias and improve the reliability of results, it is important to collect and bank high quality UTUC specimens and to focus on studies of patients who have no concomitant or metachronous cancers of the lower urinary tract.24 Also, keep in mind that different institutions might use distinct assays, with unique cutoffs to identify enrichment in proteins such as HER2.31 Biomarker studies in UTUC are an exciting area of progress, and we look forward to seeing more results in the future.

Written by: Sam S. Chang, M.D., M.B.A. Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center

References:

  1. Rouprêt M, Babjuk M, Burger M, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2020 Update. Eur Urol. 2021;79(1):62-79.
  2. Zaitsu M, Kawachi I, Takeuchi T, Kobayashi Y. Alcohol consumption and risk of upper-tract urothelial cancer. Cancer Epidemiol. 2017;48:36-40.
  3. European Association of Urology. EAU guidelines on upper urinary tract urothelial carcinoma.EAU Guidelines Office, Arnhem, The Netherlands.  https://uroweb.org/guidelines/upper-urinary-tract-urothelial-cell-carcinoma. Updated 2022. Accessed June 23, 2022.
  4. Raman JD, Lin Y-K, Kaag M, et al. High rates of advanced disease, complications, and decline of renal function after radical nephroureterectomy. Urologic Oncology: Seminars and Original Investigations. 2014;32(1):47.e49-47.e14.
  5. Juarranz A, Jaén P, Sanz-Rodríguez F, Cuevas J, González S. Photodynamic therapy of cancer. Basic principles and applications. Clin Transl Oncol. 2008;10(3):148-154.
  6. Mazor O, Brandis A, Plaks V, et al. WST11, a novel water-soluble bacteriochlorophyll derivative; cellular uptake, pharmacokinetics, biodistribution and vascular-targeted photodynamic activity using melanoma tumors as a model. Photochem Photobiol. 2005;81(2):342-351.
  7. Noweski A, Roosen A, Lebdai S, et al. Medium-term follow-up of vascular-targeted photodynamic therapy of localized prostate cancer using TOOKAD Soluble WST-11 (Phase II Trials). Eur Urol Focus. 2019;5(6):1022-1028.
  8. Taneja SS, Bennett J, Coleman J, et al. Final results of a phase i/ii multicenter trial of WST11 vascular targeted photodynamic therapy for hemi-ablation of the prostate in men with unilateral low risk prostate cancer performed in the United States. J Urol. 2016;196(4):1096-1104.
  9. European Medicines Agency. Tookad.  https://www.ema.europa.eu/en/medicines/human/EPAR/tookad. Updated February 18, 2022. Accessed June 24, 2022.
  10. Cision Newswire/Steba Biotech. FDA Grants Fast Track Designation to Padeliporfin ImPACT for Steba Biotech.  https://www.prnewswire.com/il/news-releases/fda-grants-fast-track-designation-to-padeliporfin-impact-for-steba-biotech-824291565.html. Published 2021. Accessed June 24, 2022.
  11. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020;395(10232):1268-1277.
  12. Yip W, Coleman J, Wong NC, et al. Final results of a multicenter prospective phase II clinical trial of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade upper tract urothelial carcinoma. J Clin Oncol. 2022;40(6_suppl):440-440.
  13. Necchi A, Martini A, Raggi D, et al. A feasibility study of preoperative pembrolizumab before radical nephroureterectomy in patients with high-risk, upper tract urothelial carcinoma: PURE-02. Urol Oncol. 2022;40(1):10.e11-10.e16.
  14. ECOG-ACRIN Cancer Research Group. Testing the addition of MEDI4736 (durvalumab) to chemotherapy before surgery for patients with high-grade upper urinary tract cancer.  https://ecog-acrin.org/clinical-trials/ea8192-upper-urinary-tract-cancer/. Accessed June 22, 2022.
  15. Matin SF, Pierorazio PM, Kleinmann N, et al. 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. J Urol. 2022;207(4):779-788.
  16. 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.
  17. Rose K, Narang G, Rosen G, et al. Antegrade administration of reverse thermal mitomycin gel for primary chemoablation of upper tract urothelial carcinoma via percutaneous nephrostomy tube: A multi-institutional real-world experience. J Urol. 2022;207(supp_5):e1013.
  18. AUA 2022: Antegrade Administration of Reverse Thermal Mitomycin Gel for Primary Chemoablation of Upper Tract Urothelial Carcinoma via Percutaneous Nephrostomy Tube: a Multi-Institutional Real-World Experience.  https://www.urotoday.com/conference-highlights/2022-annual-meeting/aua-2022-bladder-caner/137305-aua-2022-pd58-06-antegrade-administration-of-reverse-thermal-mitomycin-gel-for-primary-chemoablation-of-upper-tract-urothelial-carcinoma-via-percutaneous-nephrostomy-tube-a-multi-institutional-real-world-experience.html. Updated 2022. Accessed June 24, 2022.
  19. Rosen GH, Nallani A, Muzzey C, et al. Antegrade instillation of UGN-101 (mitomycin for pyelocalyceal solution) for low-grade upper tract urothelial carcinoma: Initial clinical experience. J Urol. 2022;207(6):1302-1311.
  20. Singla N, Margulis V. Differences between upper tract urothelial carcinoma and bladder cancer. AUA News. 2021;26(7):15-16.
  21. De Lorenzis E, Albo G, Longo F, et al. Current knowledge on genomic profiling of upper tract urothelial carcinoma. Genes (Basel). 2021;12(3).
  22. Audenet F, Isharwal S, Cha EK, et al. Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma. Clin Cancer Res. 2019;25(3):967-976.
  23. Sfakianos JP, Cha EK, Iyer G, et al. Genomic characterization of upper tract urothelial carcinoma. Eur Urol. 2015;68(6):970-977.
  24. UroToday. SUO 2021: State of the Art: Molecular Classification of Upper Tract Urothelial Carcinoma (presented by Dr. Jonathan Coleman of Memorial Sloan Kettering Cancer Center, New York, NY).  https://www.urotoday.com/conference-highlights/suo-2021/suo-2021-upper-tract-urothelial-carcinoma/134224-suo-2021-state-of-the-art-molecular-classification-of-upper-tract-urothelial-carcinoma.html. Published 2021. Accessed June 28, 2022.
  25. Donahu TF, Bagrodia A, Audenet F, et al. Genomic characterization of upper-tract urothelial carcinoma in patients with lynch syndrome. JCO Precis Oncol. 2018;2018:PO.17.00143.
  26. Chu CE, Escano MDJ, Yip W, et al. Human epidermal growth factor receptor 2 (HER2) and fibroblast growth factor receptor 3 (FGFR3) mutations to reveal biological pathways in urothelial carcinoma. J Clin Oncol. 2022;40(6_suppl):567-567.
  27. Pietzak EJ, Bagrodia A, Cha EK, et al. Next-generation sequencing of nonmuscle invasive bladder cancer reveals potential biomarkers and rational therapeutic targets. Eur Urol. 2017;72(6):952-959.
  28. Sikic D, Eckstein M, Weyerer V, et al. High expression of ERBB2 is an independent risk factor for reduced recurrence-free survival in patients with stage T1 non-muscle-invasive bladder cancer. Urol Oncol. 2022;40(2):63.e69-63.e18.
  29. Breyer J, Wirtz RM, Laible M, et al. ESR1, ERBB2, and Ki67 mRNA expression predicts stage and grade of non-muscle-invasive bladder carcinoma (NMIBC). Virchows Archiv. 2016;469(5):547-552.
  30. Galsky MD, Conte GD, Foti S, et al. Primary analysis from DS8201-A-U105: A phase 1b, two-part, open-label study of trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing urothelial carcinoma (UC). J Clin Oncol. 2022;40(6_suppl):438-438.
  31. UroToday. Biological Pathways in Urothelial Carcinoma - Carissa Chu, MD, of the University of California San Francisco.  https://www.urotoday.com/video-lectures/bladder-cancer/video/2552-biological-pathways-in-urothelial-carcinoma-carissa-chu.html. Published April 12, 2022. Accessed June 28, 2022.
Published Date: July 2022