Adjuvant immunotherapy for muscle-invasive urothelial carcinoma of the bladder

References

• Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014. p. 315–322. DOI:https://doi.org/10.1038/nature12965
   Google Scholar
• McGrail DJ, Pilié PG, Rashid NU, et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol Off J Eur Soc Med Oncol. 2021;32:661–672.
   PubMed Web of Science ®Google Scholar
• Tanaka MF, Sonpavde G Diagnosis and management of urothelial carcinoma of the bladder. Postgrad Med. 2011;123:43–55.
   PubMed Web of Science ®Google Scholar
• Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol Off J Am Soc Clin Oncol. 2001;19:666–675.
   PubMed Web of Science ®Google Scholar
• Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349:859–866.
   PubMed Web of Science ®Google Scholar
• Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet. 2003;361:1927–1934.
   PubMed Web of Science ®Google Scholar
• Dash A, Galsky MD, Vickers AJ, et al. Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer. 2006;107:506–513.
   PubMed Web of Science ®Google Scholar
• Pal SK, Agarwal N, Grivas P, et al. Adjuvant chemotherapy for bladder cancer: using population-based data to fill a void of prospective evidence. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. United States; 2016. p. 777–779. DOI:https://doi.org/10.1200/JCO.2015.65.4368
   Google Scholar
• Donat SM, Shabsigh A, Savage C, et al. Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. Eur Urol. 2009;55:177–185.
   PubMed Web of Science ®Google Scholar
• Mollica V, Rizzo A, and Montironi R, et al. Current strategies and novel therapeutic approaches for metastatic urothelial carcinoma. Cancers (Basel). 2020;12(6):1449.
   Web of Science ®Google Scholar
• Rizzo A, Mollica V, Massari F Expression of programmed cell death ligand 1 as a predictive biomarker in metastatic urothelial carcinoma patients treated with first-line immune checkpoint inhibitors versus chemotherapy: a systematic review and meta-analysis. Eur Urol Focus. 2021; DOI:https://doi.org/10.1016/j.euf.2021.01.003
   Google Scholar
• Rouanne M, Bajorin DF, Hannan R, et al. Rationale and outcomes for neoadjuvant immunotherapy in urothelial carcinoma of the bladder. Eur Urol Oncol. 2020;3:728–738.
   PubMed Web of Science ®Google Scholar
• Food and Drug Administration. FDA approves nivolumab for adjuvant treatment of urothelial carcinoma [Internet]. 2021 cited 2021 Aug 25. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-adjuvant-treatment-urothelial-carcinoma.
   Google Scholar
• Vuky J, Balar AV, Castellano D, et al. Long-Term outcomes in KEYNOTE-052: phase II study investigating first-line pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2020;38:2658–2666.
   PubMed Web of Science ®Google Scholar
• Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet (London England). 2017;389:67–76.
   PubMed Web of Science ®Google Scholar
• Powles T, Csőszi T, Özgüroğlu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22:931–945.
   PubMed Web of Science ®Google Scholar
• Galsky MD, Arija JÁA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395:1547–1557.
   PubMed Web of Science ®Google Scholar
• Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383:1218–1230.
   PubMed Web of Science ®Google Scholar
• Fradet Y, Bellmunt J, Vaughn DJ, et al. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up. Ann Oncol Off J Eur Soc Med Oncol. 2019;30:970–976.
   PubMed Web of Science ®Google Scholar
• Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18:312–322.
   PubMed Web of Science ®Google Scholar
• Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19:51–64.
   PubMed Web of Science ®Google Scholar
• Bellmunt J, Théodore C, Demkov T, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27:4454–4461.
   PubMed Web of Science ®Google Scholar
• Powles T, van der Heijden MS, Castellano D, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (Danube): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol [Internet]. 2020;21:1574–1588. Available from:
   PubMed Web of Science ®Google Scholar
• Necchi A, Raggi D, Gallina A, et al. Updated results of PURE-01 with preliminary activity of neoadjuvant pembrolizumab in patients with muscle-invasive bladder carcinoma with variant histologies. Eur Urol. 2020;77:439–446.
   PubMed Web of Science ®Google Scholar
• Powles T, Rodriguez-Vida A, Duran I, et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). J Clin Oncol [Internet]. 2018;36:4506. Available from:
   Web of Science ®Google Scholar
• van Dijk N, Gil-Jimenez A, Silina K, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 2020;26:1839–1844.
   PubMed Web of Science ®Google Scholar
• Grande E, Guerrero F, Puente J, et al. DUTRENEO trial: a randomized phase II trial of DUrvalumab and TREmelimumab versus chemotherapy as a NEOadjuvant approach to muscle-invasive urothelial bladder cancer (MIBC) patients (pts) prospectively selected by an interferon (INF)-gamma immune signatur. J Clin Oncol [Internet]. 2020;38:5012. Available from:
   Google Scholar
• Gao J, Navai N, Alhalabi O, et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat Med. 2020;26:1845–1851.
   PubMed Web of Science ®Google Scholar
• Rodriguez-Moreno JF, de Velasco G, Bravo Fernandez I, et al. Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer: NEODURVARIB trial. J Clin Oncol [Internet]. 2020;38:542. Available from:
   Web of Science ®Google Scholar
• Hoimes CJ, Adra N, Fleming MT, et al. Phase Ib/II neoadjuvant (N-) pembrolizumab (P) and chemotherapy for locally advanced urothelial cancer (laUC): final results from the cisplatin (C)- eligible cohort of HCRN GU14-188. J Clin Oncol [Internet]. 2020;38:5047. Available from:
   Google Scholar
• Gupta S, Sonpavde G, Weight CJ, et al. Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy. J Clin Oncol [Internet]. 2020;38:439. Available from:
   Web of Science ®Google Scholar
• Cathomas R, Petrausch U, Hayoz S, et al. Perioperative chemoimmunotherapy with durvalumab (Durva) in combination with cisplatin/gemcitabine (Cis/Gem) for operable muscle-invasive urothelial carcinoma (MIUC): preplanned interim analysis of a single-arm phase II trial (SAKK 06/17). J Clin Oncol [Internet]. 2020;38:499. Available from:
   Web of Science ®Google Scholar
• NCCN Guidelines. Bladder Cancer [Internet]. NCCN Clin. Pract. Guidel. Oncol. 2021. Cited 2021 September 21. Available from: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
   Google Scholar
• Advanced Bladder Cancer (ABC) Meta-analysis Collaborators Group. Adjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and meta-analysis of individual participant data from randomised controlled trials. Eur Urol. 2022;81:50–61.
   PubMed Web of Science ®Google Scholar
• Zhegalik AG, Polyakov SL, Rolevich AI, et al. Long-term results of a single-center prospective randomized trial assessing efficacy of a shortened course of adjuvant chemotherapy after radical cystectomy in patients with locally advanced bladder cancer. Cent Eur J Urol. 2020;73:26–32.
   PubMed Web of Science ®Google Scholar
• Cognetti F, Ruggeri EM, Felici A, et al. Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol Off J Eur Soc Med Oncol. 2012;23:695–700.
   PubMed Web of Science ®Google Scholar
• Paz-Ares LG, Solsona E, Esteban E, et al. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. J Clin Oncol [Internet]. 2010;28:LBA4518–LBA4518. Available from:
   Web of Science ®Google Scholar
• Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015;16:76–86.
   PubMed Web of Science ®Google Scholar
• Birtle AJ, Chester JD, Jones RJ, et al. Updated outcomes of POUT: a phase III randomized trial of peri-operative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). J Clin Oncol [Internet]. 2021;39:455. Available from:
   Web of Science ®Google Scholar
• Lane G, Risk M, Fan Y, et al. Persistent muscle-invasive bladder cancer after neoadjuvant chemotherapy: an analysis of surveillance, epidemiology and end results-medicare data. BJU Int. 2019;123:818–825.
   PubMed Web of Science ®Google Scholar
• Galsky MD, Hahn NM, Rosenberg J, et al. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet Oncol. 2011;12:211–214.
   PubMed Web of Science ®Google Scholar
• Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384:2102–2114.
   PubMed Web of Science ®Google Scholar
• Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22:525–537.
   PubMed Web of Science ®Google Scholar
• Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021;595:432–437.
   PubMed Web of Science ®Google Scholar
• Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2019;37:1547–1557.
   PubMed Web of Science ®Google Scholar
• A study of atezolizumab versus placebo as adjuvant therapy in patients with high-risk muscle-invasive bladder cancer who are ctDNA positive following cystectomy (IMvigor011) [Internet]. Cited 2021 September 21. Available from: https://clinicaltrials.gov/ct2/show/NCT04660344.
   Google Scholar
• Treatment of metastatic bladder cancer at the time of biochemical reLApse following radical cystectomy [Internet]. cited 2021 Sep 21. Available from: https://clinicaltrials.gov/ct2/show/NCT04138628.
   Google Scholar
• Testing MK-3475 (Pembrolizumab) After Surgery for Localized Muscle-Invasive Bladder Cancer and Locally Advanced Urothelial Cancer (AMBASSADOR) [Internet]. cited 2021 Aug 25. Available from: https://clinicaltrials.gov/ct2/show/NCT03244384.
   Google Scholar
• Laubach JP, Faber EAJ, Voorhees P, et al. The challenge of cross-trial comparisons using limited data. Haematologica. 2014. 145–146. DOI:https://doi.org/10.3324/haematol.2013.103135
   Google Scholar
• 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;395:1268–1277.
   PubMed Web of Science ®Google Scholar
• Administration F and D. Nivolumab full prescribing information. [Internet]. 2021 [cited 2021 Aug 25]. p. 1–58. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/12555.
   Google Scholar
• Kim HS, Jeong CW, Kwak C, et al. Disease-Free survival at 2 and 3 years is a significant early surrogate marker predicting the 5-year overall survival in patients treated with radical cystectomy for urothelial carcinoma of the bladder: external evaluation and validation in a cohort of K. Front Oncol. 2015;5:246.
   PubMed Web of Science ®Google Scholar
• Shah SC, Kayamba V, and Peek RM, et al. Cancer control in low- and middle-income countries: is it time to consider screening?. J Glob Oncol [Internet]. 2019;5:1–8. Cited 2021 September 21. Available from: https://pubmed.ncbi.nlm.nih.gov/30908147
   Web of Science ®Google Scholar
• Gyawali B, Bouche G, Crisp N, et al. Challenges and opportunities for cancer clinical trials in low- and middle-income countries. Nat Cancer [Internet]. 2020;1:142–145. Available from:
   PubMedGoogle Scholar
• Tata memorial centre. Bladder Cancer Adjuvant Radiotherapy Trial (BART) [Internet]. cited 2021 Aug 25. Available from: https://clinicaltrials.gov/ct2/show/NCT02951325.
   Google Scholar
• QED Therapeutics I. Study of oral infigratinib for the adjuvant treatment of subjects with invasive urothelial carcinoma with susceptible FGFR3 genetic alterations [Internet]. cited 2021 Aug 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT04197986.
   Google Scholar
• Daneshmand S, Grivas P, Sridhar SS, et al. PROOF 302: a randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring susceptible FGFR3 alterations. J Clin Oncol [Internet]. 2020;38:TPS5095. Available from:
   PubMed Web of Science ®Google Scholar
• Laukhtina E, Sari Motlagh R, Mori K, et al. Chemotherapy is superior to checkpoint inhibitors after radical surgery for urothelial carcinoma: a systematic review and network meta-analysis of oncologic and toxicity outcomes. Crit Rev Oncol Hematol. 2022;169:103570.
   PubMed Web of Science ®Google Scholar
• Powles T, Meeks JJ, Galsky MD, et al. A phase III, randomized, open-label, multicenter, global study of efficacy and safety of durvalumab in combination with gemcitabine plus cisplatin for neoadjuvant treatment followed by durvalumab alone for adjuvant treatment in muscle-invasive bladder can. J Clin Oncol [Internet]. 2021;39:TPS505. Available from:
   PubMedGoogle Scholar
• Siefker-Radtke AO, Steinberg GD, Bedke J, et al. Phase III study of perioperative pembrolizumab (pembro) plus neoadjuvant chemotherapy (chemo) versus placebo plus neoadjuvant chemo in cisplatin-eligible patients (pts) with muscle-invasive bladder cancer (MIBC): KEYNOTE-866. J Clin Oncol [Internet]. 2020;38:TPS599. Available from:
   Google Scholar
• Hoimes CJ, Bedke J, Loriot Y, et al. KEYNOTE-B15/EV-304: randomized phase 3 study of perioperative enfortumab vedotin plus pembrolizumab versus chemotherapy in cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC). J Clin Oncol [Internet]. 2021;39:TPS4587. Available from:
   PubMedGoogle Scholar
• Galsky MD, Necchi A, Shore ND, et al. KEYNOTE-905/EV-303: perioperative pembrolizumab or pembrolizumab plus enfortumab vedotin (EV) and cystectomy compared to cystectomy alone in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC). J Clin Oncol [Internet]. 2021;39:TPS507. Available from:
   Web of Science ®Google Scholar
• A study of nivolumab plus bempegaldesleukin (Bempeg/NKTR-214) vs nivolumab alone vs standard of care in participants with bladder cancer that has invaded the muscle wall of the bladder and who cannot get cisplatin, a type of medicine given to treat bladde [Internet]. cited 2021 Sep 21. Available from: https://clinicaltrials.gov/ct2/show/NCT04209114?term=adjuvant+chemotherapy+immunotherapy&cond=Bladder+Cancer&draw=2&rank=11.
   Google Scholar
• Sharma M, Khong H, Fa’ak F, et al. Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy. Nat Commun. 2020;11:661.
   PubMed Web of Science ®Google Scholar
• A study of chemo only versus chemo plus nivo with or without BMS-986205, followed by post- surgery therapy with nivo or nivo and BMS-986205 in patients with MIBC [Internet]. cited 2021 Sep 21. Available from: https://clinicaltrials.gov/ct2/show/NCT03661320.
   Google Scholar
• Tang K, Wu Y-H, Song Y, et al. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy. J Hematol Oncol [Internet]. 2021;14:68. Available from
   PubMed Web of Science ®Google Scholar
• Atezolizumab after chemo-radiotherapy for MIBC patients not eligible for radical cystectomy (BladderSpar) [Internet]. cited 2021 Sep 21]. Available from: https://clinicaltrials.gov/ct2/show/NCT03697850?term=adjuvant+chemotherapy+immunotherapy&cond=Bladder+Cancer&draw=2&rank=10.
   Google Scholar
• Intravesical recombinant BCG followed by perioperative chemo-immunotherapy for patients with MIBC [Internet]. cited 2021 Sep 21]. Available from: https://clinicaltrials.gov/ct2/show/NCT04630730?term=adjuvant+chemotherapy+immunotherapy&cond=Bladder+Cancer&draw=2&rank=3.
   Google Scholar