Society for Immunotherapy of Cancer (SITC) Clinical Practice Guideline on Immunotherapy for the Treatment of Urothelial Cancer - Beyond the Abstract

Immunotherapy in the form of intravesical Bacillus Calmette-Guérin (BCG) has been a staple treatment for non-muscle-invasive bladder cancer (NMIBC) for several decades. More recently, immune checkpoint inhibitors (ICIs) have been incorporated into the standard of care for urothelial cancer (a term that encompasses cancers of the bladder, urethra, and upper urinary tract) across all stages of the disease. To provide guidance to urologists amidst a rapidly evolving treatment landscape, the Society for Immunotherapy of Cancer (SITC)—the world’s leading member-driven organization devoted to advancing the science and application of cancer immunotherapy—convened a panel of experts to update the society’s 2017 clinical practice guideline.1 The new manuscript, “Society for Immunotherapy of Cancer clinical practice guideline on immunotherapy for the treatment of urothelial cancer,” provides recommendations on approved indications for use of BCG and ICIs, emerging immunotherapy strategies including neo/adjuvant approaches and novel combinations, biomarker testing, patient education and quality of life, and more.2

The expert panel drew upon published literature as well as their own experience to develop evidence- and consensus-based recommendations on the clinical aspects of urothelial cancer immunotherapy treatment. Recommendations from the expert panel for the treatment of NMIBC and metastatic urothelial carcinoma (mUC) are summarized in table 1 and table 2. During the writing process, the expert panel also identified an unmet need for guidance on identifying optimal endpoints, study design, and biomarkers for urothelial cancer clinical trials. Highlighting this need for guidance in the field was the 2021 United States (US) Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) industry-wide review of accelerated approvals for ICIs, which included a review of pembrolizumab and atezolizumab for the treatment of cisplatin-ineligible patients with PD-L1-positive metastatic urothelial cancer. Ultimately ODAC voted in support of maintaining indications for both ICIs,3 although subsequent analyses of pembrolizumab in the confirmatory KEYNOTE-361 trial did not show benefit in the biomarker-enriched population.4 On the other hand, IMvigor011 demonstrated that circulating tumor DNA (ctDNA) has the potential to inform adjuvant immunotherapy treatment decisions for patients with muscle-invasive bladder cancer.5 A forthcoming collaborative publication from SITC and the International Bladder Cancer Group (IBCG) will offer guidance on bladder cancer clinical trial design across disease stages as a follow-up to the 2016 guidance focused on NMIBC6 and a complement to the new clinical practice guideline.

Table 1: NMIBC immunotherapy treatment algorithm (Adapted from Galsky et al. JITC, 20212)

NMIBC risk category 



BCG not recommended 

Intermediate-risk (BCG available) 

BCG† induction and 1 year maintenance 

Intermediate-risk (BCG unavailable) 

Intravesical chemotherapy 

If recurrence occurs 



BCG† induction and 3 years maintenance 

If BCG-unresponsive high-risk CIS NMIBC with or without papillary tumors

Individual rows represent treatment decision options that can be followed from left to right horizontally cell-to-cell in adjacent columns.
* Including NMIBC high-risk cases with CIS or papillary tumors. 
† BCG should not be administered to patients with active infection or gross hematuria, but BCG may be administered to patients experiencing asymptomatic bacteriuria. Best supportive measures should be employed to ensure that patients receive a full, adequate course of BCG.
Abbreviations: BCG, Bacillus Calmette-Guérin; CIS, carcinoma in situ; NMIBC, non-muscle invasive bladder cancer

Table 2: mUC treatment algorithm (Adapted from Galsky et al. JITC, 20212)
Patient population  Management
First-line Maintenance or second-line


Platinum-based chemotherapy 

If no disease progression 

Avelumab maintenance  

If disease progression  



PD-L1-positive tumors* 

Carboplatin-based chemotherapy#


Dependent on initial therapy and response

PD-L1-negative tumors*

Carboplatin-based chemotherapy

If no disease progression

Avelumab maintenance 

If disease progression 




Cisplatin- and carboplatin-ineligible


Individual rows represent treatment decision options that can be followed from left to right horizontally cell-to-cell in adjacent columns. 
* As determined by the appropriate FDA-approved companion diagnostic (ie, PD-L1 staining immune cells (IC) ≥ 5% of the tumor area by the VENTANA PD-L1 (SP142) assay for atezolizumab and combined positive score (CPS) ≥ 10 by the PD-L1 IHC 22C3 pharmDx assay for pembrolizumab). 
† Recommendation based on US-only indication. 
‡ Accelerated approvals contingent on confirmatory trials at the time of guideline publication.
# Table has been updated from the published version to include carboplatin-based chemotherapy for cisplatin-ineligible patients
Abbreviations: mUC, advanced/metastatic urothelial cancer; PD-L1, programmed death-ligand 1 

The number of available treatments for urothelial cancer has increased considerably since Morales et al published the first use of intravesical BCG for superficial bladder cancer in 1976.7 Immunotherapy including ICIs and BCG will likely continue to be a cornerstone of urothelial cancer treatment for some patients, and further prospective trials to validate biomarkers for patient selection are needed to guide the optimal use of these agents. Ongoing clinical trials hold promise for the development of novel immunotherapies for the treatment of urothelial cancer, including gene therapy, antibody-drug conjugates, engineered cytokines, and new strains of BCG. Furthermore, the COVID-19 pandemic availed opportunities to innovate patient-provider communication and apply technology for follow-up and quality of life support for patients with urothelial cancer. As the field continues to evolve, SITC and the expert panel will work to update the guideline as needed.

Written by:

  • Matthew D. Galsky, MD, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY
  • Ashish M. Kamat, MD, MBBS, Department of Urology under Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX


  1. Kamat AM, Bellmunt J, Galsky MD, et al. Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma. Journal for ImmunoTherapy of Cancer 2017;5:68. doi: 10.1186/s40425-017-0271-0
  2. Galsky MD, Balar AV, Black PC, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer. Journal for ImmunoTherapy of Cancer 2021;9:e002552. doi: 10.1136/jitc-2021-002552
  4. Powles T, Csőszi T, Özgüroğlu M, Matsubara N, 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 Jul;22(7):931-945. doi: 10.1016/S1470-2045(21)00152-2.
  5. Powles T, Assaf ZJ, Davarpanah N, et al. Clinical outcomes in post-operative ctDNA-positive muscle-invasive urothelial carcinoma (MIUC) patients after atezolizumab adjuvant therapy. Ann Oncol. 2020;31(suppl_7):S1417-S1424
  6. Kamat AM, Sylvester RJ, Böhle A, et al. Definitions, End Points, and Clinical Trial Designs for Non-Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group. J Clin Oncol. 2016 Jun 1;34(16):1935-44. doi: 10.1200/JCO.2015.64.4070.
  7. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976 Aug;116(2):180-3. doi: 10.1016/s0022-5347(17)58737-6. PMID: 820877.

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