To date, only three UTUC-specific perioperative trials have been published, and they focus on assessing the efficacy and toxicity of platinum-based chemotherapy in the localized setting. A phase 2 study of neoadjuvant split dose cisplatin and gemcitabine, and the phase 2 ECOG-ACRIN 8141 study of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (aMVAC) demonstrated that both regimens were safe and effective for patients with localized high-risk UTUC.1,2 The phase 3 POUT study, the only phase 3 study for UTUC, demonstrated improved disease-free (DFS) and a trend for overall (OS) survival with adjuvant platinum-based chemotherapy compared to surveillance (HR: 0.45;95% CI: 0.30–0.68; P= 0.0001).3 Despite these encouraging data supporting the use of perioperative chemotherapy for high-risk localized UTUC, deterioration of renal function following nephroureterectomy can often limit patients’ ability to receive adjuvant cisplatin.
Additional phase 3 randomized studies have demonstrated the benefit of adjuvant nivolumab and adjuvant pembrolizumab for high-risk UC, and these studies included patients with UTUC.4,5 A phase 3 randomized trial evaluated adjuvant nivolumab vs. placebo in patients with UC who had undergone surgery for locally advanced disease at high risk of recurrence.5 DFS was the primary endpoint and was significantly higher in the nivolumab group (HR 0.70; 98.22% 95% CI: 0.55– 0.90; P < 0.001).5 A subgroup analysis showed that the DFS benefit was not as strong in patients with UTUC, compared to bladder UC.5 This subgroup analysis is hypothesis-generating, and important factors such as prior chemotherapy and the extent of lymphadenectomy were not controlled for in this study. The use of adjuvant nivolumab in high-risk UC, including UTUC, remains guideline endorsed.
No UTUC-specific trial exists to date for assessing patient outcomes in the advanced disease setting, and platinum-based chemotherapy has been the standard of care for decades. However, in recent years, emerging therapeutic classes including immunotherapy, antibody drug conjugates (ADCs) and targeted therapies have shown promise as alternative treatment options. Most of these agents are less nephrotoxic compared to platinum-based chemotherapy and therefore have particular relevance in patients with UTUC who often have decreased renal function due to baseline comorbidities, obstruction, or prior nephroureterectomy.
The phase 3 EV-302 study demonstrated improved OS in patients with advanced UC treated with first-line enfortumab vedotin and pembrolizumab (EV+P) compared to platinum-based chemotherapy, leading to the approval of EV+P as first line treatment for bladder UC and UTUC.6 Next-line options include other ADCs, such as sacituzumab govitecan, and targeted therapies, including erdafitinib and trastuzumab deruxtecan.7–9 However, the identification of specific biomarkers to inform treatment decisions and trials powered to evaluate the efficacy of these agents specifically in UTUC remain unmet needs.
Written by: Evangelia Vlachou,1 Jeannie Hoffman-Censits,1 Nirmish Singla1,2
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Philadelphia, PA
- Department of Urology, The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD
- Coleman JA, Yip W, Wong NC, Sjoberg DD, Bochner BH, Dalbagni G, et al. Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma. Journal of Clinical Oncology [Internet]. 2023 Mar 10 [cited 2024 Aug 26];41(8):1618–25.
- Margulis V, Puligandla M, Trabulsi EJ, Plimack ER, Kessler ER, Matin SF, et al. Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery in Patients with High Grade Upper Tract Urothelial Carcinoma. J Urol [Internet]. 2020 Apr 1 [cited 2022 Jul 8];203(4):690–8.
- Birtle A, Johnson M, Chester J, Jones R, Dolling D, Bryan RT, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. The Lancet [Internet]. 2020 Apr 18 [cited 2022 Jun 23];395(10232):1268–77.
- Ballman K V., Sonpavde GP, Berg SA, Kim WY, Parikh RA, Teo MY, et al. AMBASSADOR Alliance A031501: Phase III randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma (MIUC) vs observation. [Internet]. 2024 Jan 29 [cited 2024 Aug 28];42(4_suppl):LBA531–LBA531.
- Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. New England Journal of Medicine [Internet]. 2021 Jun 3 [cited 2022 Aug 7];384(22):2102–14.
- Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. [Internet]. 2024 Mar 6 [cited 2024 Mar 11];390(10):875–88.
- Tagawa ST, Balar A V., Petrylak DP, Kalebasty AR, Loriot Y, Fléchon A, et al. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. Journal of Clinical Oncology [Internet]. 2021 Aug 1 [cited 2024 Aug 28];39(22):2474–85.
- Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. New England Journal of Medicine [Internet]. 2019 Jul 25 [cited 2023 Dec 9];381(4):338–48.
- Meric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee S, González-Martín A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. Journal of Clinical Oncology [Internet]. 2024 Jan 1 [cited 2024 Jul 22];42(1):47.