NCCN Guidelines® Insights: Bladder Cancer, Version 2.2022

Featured Updates to the NCCN Guidelines

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  • 1 University of Colorado Cancer Center;
  • | 2 Moffitt Cancer Center;
  • | 3 Duke Cancer Institute;
  • | 4 Huntsman Cancer Institute at the University of Utah;
  • | 5 Patient advocate;
  • | 6 Mayo Clinic Cancer Center;
  • | 7 Stanford Cancer Institute;
  • | 8 City of Hope National Medical Center;
  • | 9 Vanderbilt-Ingram Cancer Center;
  • | 10 UCSF Helen Diller Family Comprehensive Cancer Center;
  • | 11 Fox Chase Cancer Center;
  • | 12 Roswell Park Comprehensive Cancer Center;
  • | 13 Memorial Sloan Kettering Cancer Center;
  • | 14 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 15 UCLA Jonsson Comprehensive Cancer Center;
  • | 16 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 17 Fred & Pamela Buffett Cancer Center;
  • | 18 Abramson Cancer Center at the University of Pennsylvania;
  • | 19 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 20 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 21 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 22 University of Michigan Rogel Cancer Center;
  • | 23 O’Neal Comprehensive Cancer Center at UAB;
  • | 24 UC Davis Comprehensive Cancer Center;
  • | 25 St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center;
  • | 26 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 27 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 28 University of Wisconsin Carbone Cancer Center;
  • | 29 The University of Texas MD Anderson Cancer Center;
  • | 30 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; and
  • | 31 National Comprehensive Cancer Network.

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non–muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non–muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody–drug conjugates for metastatic bladder cancer.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-22-008-H01-P

Physician Assistants: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until August 10, 2023. PAs should only claim credit commensurate with the extent of their participation.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/91104; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.

Release date: August 10, 2022; Expiration date: August 10, 2023

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • • Integrate into professional practice the updates to the NCCN Guidelines for Bladder Cancer

  • • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Bladder Cancer

Disclosure of Relevant Financial Relationships

None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

Individuals Who Provided Content Development and/or Authorship Assistance:

The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.

Philippe E. Spiess, MD, MS, Panel Vice Chair

Rick C. Bangs, MBA, PMP, Patient Advocate

Lisa Gurski, PhD, Manager, Licensed Clinical Content, NCCN

Mary Dwyer, MS, Sr. Director, Guidelines Operations, NCCN

Carly J. Cassara, MSc, Guidelines Layout Specialist, NCCN

The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.

Thomas W. Flaig, MD, Panel Chair, has disclosed receiving grant/research support from Agensys, Inc., Astellas Pharma US, Inc., AstraZeneca Pharmaceuticals, LP, Bristol-Myers Squibb Company, Genentech, Inc., Janssen Pharmaceutica Products, LP, Merck & Co., Inc., sanofi-aventis U.S., and Seattle Genetics, Inc.; serving as scientific advisor for Janssen Pharmaceutica Products, LP, and Seattle Genetics, Inc.; having equity interest/stock options in Aurora Oncology; and licensing intellectual property rights to Aurora Oncology.

Ronac Mamtani, MD, MSCE, Panel Member, has disclosed receiving grant/research support from Astellas Pharma US, Inc., and Merck & Co., Inc.; and receiving consulting fees from Bristol-Myers Squibb Company, and Seagen Inc.

Mamta Parikh, MD, MS, Panel Member, has disclosed receiving consulting fees from AstraZeneca Pharmaceuticals LP, Exelixis Inc., and OncoCyte Corporation; and receiving grant/research support from Karyopharm Therapeutics.

Elizabeth R. Plimack, MD, MS, Panel Member, has disclosed receiving consulting fees from Astellas Pharma US, Inc., AstraZeneca Pharmaceuticals LP, AVEO Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Calithera Biosciences, Inc., EMD Serono, Exelixis Inc., IMV Inc., Janssen Pharmaceutica Products, LP, MEI Pharma Inc., Merck & Co., Inc., Natera, Inc., Pfizer Inc., Regeneron Pharmaceuticals, and Seattle Genetics, Inc.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels

This activity is supported by educational grants from AstraZeneca; BeiGene; Exact Sciences; Gilead Sciences, Inc.; GlaxoSmithKline; Lantheus Medical Imaging Inc.; Novartis; Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Astellas. This activity is supported by an education grant from Astellas and Seagen Inc. This activity is supported by a medical education grant from Karyopharm® Therapeutics. This activity is supported through an Independent Medical Education grant from Merck & Co., Inc.

Overview

An estimated 81,180 new cases of urinary bladder cancer (61,700 men and 19,480 women) will be diagnosed in the United States in 2022, with approximately 17,100 deaths (12,120 men and 4,980 women) occurring during this same period.1 Bladder cancer, the sixth most common cancer in the United States, is rarely diagnosed in individuals aged <40 years. Given that the median age at diagnosis is 73 years,2 medical comorbidities are a frequent consideration in patient management.

The clinical spectrum of bladder cancer can be divided into 3 categories that differ in prognosis, management, and therapeutic aims. The first category consists of non–muscle-invasive bladder cancer (NMIBC), for which treatment is directed at reducing recurrences and preventing progression to a more advanced stage. The second group encompasses muscle-invasive disease. The risk for progression to metastatic disease is increased with muscle-invasive disease, and therefore definitive local therapy is necessary. Definitive therapy may include surgery to remove the bladder, and sometimes the surrounding organs, or radiation with the goal of organ preservation, as appropriate based on the clinical context and patient-specific characteristics. Chemotherapy is combined with these modalities to increase the chance of cure. The critical concern for the third group, consisting of metastatic disease, is how to prolong quantity and maintain quality of life. Numerous agents with different mechanisms of action have antitumor effects on this disease. The goal is how to use these agents to achieve the best possible outcome.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, such as the treatment of NMIBC, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors (ICIs) in non–muscle-invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody–drug conjugates for metastatic bladder cancer.

Treatment of NMIBC

In 2021, the NCCN Bladder Cancer Panel revised management recommendations for NMIBC to reflect American Urological Association (AUA)/Society of Urologic Oncology (SUO) risk stratification,3 with the caveat that an individual patient within each of the risk strata may have more or less concerning features that can influence care decisions (see “AUA Risk Stratification for Non–Muscle-Invasive Bladder Cancer” in the full version of the guidelines, available online at NCCN.org [page BL-2]). This change was made based on consensus that management and surveillance of NMIBC should be adapted based on the AUA/SUO risk groups. Retrospective reviews have shown that the AUA/SUO risk classification accurately stratifies patients with NMIBC by the likelihood of recurrence and progression.4 Clinical trials for NMIBC also frequently stratify patients based on these risk groups.

After the initial transurethral resection of the bladder tumor (TURBT) shows NMIBC, a repeat TURBT is recommended for visually incomplete or high-volume tumors and for high-grade NMIBC, which is found to be T1 on the initial TURBT.5 This is supported by a trial that prospectively randomized 142 patients with pT1 tumors to a second TURBT within 2 to 6 weeks of the initial TURBT or no repeat TURBT.6 All patients received adjuvant intravesical therapy. Although overall survival (OS) was similar, the 3-year recurrence-free survival was significantly higher in the repeat TURBT arm versus the control arm (69% vs 37%, respectively), especially among patients with high-grade tumors. Similarly, a randomized 10-year extension trial of 210 patients with pT1 NMIBC found that those who underwent repeat TURBT had significantly higher 5-, 7-, and 10-year relapse-free survival (RFS) and progression-free survival (PFS) and, in addition, the 10-year OS rate was significantly higher in patients with repeat TURBT (59.1% vs 40.8%; P=.004).7 Repeat TURBT was found to be an independent determinant of prolonged OS on multivariate analysis.

Repeat TURBT may also be considered for select patients with Ta disease on initial TURBT, particularly if the tumor is large and/or there was no muscle present in the initial TURBT specimen. Restaging TURBT detected residual disease in 27% of patients with Ta disease when muscle was present in the original TURBT.8 In the absence of muscularis propria in the initial TURBT specimen, 49% of patients with non–muscle-invasive disease will be understaged versus 14% if muscle is present.9

If muscle-invasive disease is found during repeat TURBT, then additional staging for muscle-invasive disease and appropriate treatment depending on stage should be followed.

Treatment of Low-Risk NMIBC

By the AUA/SUO risk stratification, low-risk NMIBC includes papillary urothelial neoplasm of low malignant potential and low-grade urothelial carcinoma that is a solitary Ta and ≤3 cm.3 For these tumors, risk of recurrence or progression is low following TURBT and no further treatment is necessary,10 although a single instillation of intravesical chemotherapy immediately post-TURBT can be helpful in reducing the risk of recurrence.11 An appropriate surveillance schedule is recommended for early detection of disease recurrence (see BL-3, page 868).

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Treatment of Intermediate-Risk NMIBC

Intermediate-risk NMIBC includes low-grade urothelial carcinoma that has any of the following characteristics: T1, size >3 cm, multifocal, or recurrence within 1 year. In addition, high-grade urothelial carcinoma that is solitary, Ta, and ≤3 cm is also considered intermediate risk.3 Although a complete TURBT alone can eradicate intermediate-risk NMIBC, there is a relatively high risk for recurrence. Therefore, after TURBT and immediate intravesical chemotherapy, the panel recommends a 6-week induction course of intravesical therapy. Options for intravesical therapy for intermediate-risk NMIBC include BCG or chemotherapy (see BL-3, page 868). The availability of BCG should be considered in decision-making, because it may be prioritized for treatment of higher-risk disease. A systematic review and meta-analysis has reported that intravesical treatment with BCG does not appear superior to chemotherapy for reduction of disease recurrence in patients with intermediate-risk NMIBC.12 If maintenance is planned following the induction course, data support limiting maintenance BCG to 1 year for intermediate-risk disease because no additional benefit is derived from the full 3 years.13 Although an induction course of intravesical therapy is preferred, surveillance is also an option for intermediate-risk disease.

The value of an induction course of intravesical therapy depends on the patient’s prognosis and likelihood of disease recurrence. Factors to consider include the size, number, T category, and grade of the tumor(s), as well as concomitant carcinoma in situ (CIS) and prior recurrence.14 Meta-analyses have confirmed the efficacy of adjuvant (induction) intravesical chemotherapy in reducing the risk of recurrence.15,16 In the literature, 4 meta-analyses have confirmed that BCG after TURBT is superior to TURBT alone or TURBT + chemotherapy in preventing recurrences of Ta and T1 tumors.1720 Close follow-up of all patients is needed, although the risk for progression to a more advanced stage is low (see “Surveillance” in the discussion and algorithm in the full version of the guidelines, available online at NCCN.org).

Treatment of High-Risk NMIBC

High-risk NMIBC has a relatively high risk for recurrence and progression toward more invasiveness. According to the AUA/SUO risk stratification, high-risk NMIBC includes high-grade urothelial carcinoma that has any of the following characteristics: CIS, T1, size >3 cm, or multifocal. In addition, a subgroup of very-high-risk features includes BCG unresponsiveness, variant histologies, lymphovascular invasion, and prostatic urethral invasion.3 Based on the histologic differentiation, most cT1 lesions are high-grade and considered to be potentially dangerous with a higher risk for recurrence and progression. These tumors may occur as solitary lesions or as multifocal tumors with or without an associated Tis component. The presence of CIS is associated with an increased risk of invasive disease, including increased cancer progression rates and worse cancer-specific outcomes.21 If untreated, 50% of CIS progresses to muscle-invasive disease within 5 years and, even with treatment, 30% to 40% progresses within 10 years.22

Pembrolizumab is a PD-1 inhibitor that has been evaluated as treatment for BCG-unresponsive NMIBC with CIS in the single-arm, phase II KEYNOTE-057 study (pembrolizumab is also indicated for treatment of metastatic urothelial carcinoma, as described later). In the KEYNOTE-057 study, 101 patients who received previous BCG therapy and were either unable or unwilling to undergo cystectomy were treated with pembrolizumab23; 96 patients were eligible for inclusion in the efficacy analysis. The 3-month complete response rate was 41% (95% CI, 30.7%–51.1%), and the median duration of response (DoR) from time of onset was 16.2 months (95% CI, 6.7–36.2 months). Forty-six percent of complete responses were maintained for at least 1 year. Grade ≥3 treatment-related adverse events (trAEs) were reported in 13% of patients, with arthralgia and hyponatremia being the most common. Serious trAEs occurred in 8% of patients. The NCCN panel consensus supported adding pembrolizumab as an option for NMIBC, mirroring the FDA indication for treatment of patients with BCG-unresponsive, high-risk NMIBC with Tis (± papillary) tumors who are ineligible for or have elected not to undergo cystectomy.

Treatment options for high-risk NMIBC depend on whether the tumor has previously been shown to be unresponsive or intolerant to BCG (see BL-3, page 868). For BCG-naïve NMIBC, the options are cystectomy or BCG. When very high-risk features are present, cystectomy is preferred due to the high risk for progression to a more advanced stage,24,25 whereas BCG is preferred when these are not present. BCG is also a category 1 recommendation for BCG-naïve, high-risk NMIBC without very-high-risk features. For some patients, BCG is not an option due to adverse effects or a tumor that is BCG-unresponsive or BCG-intolerant. For these patients, cystectomy is preferred, although other intravesical chemotherapy or pembrolizumab are also options. A prospective study randomized 51 patients with high-risk BCG-naïve NMIBC to either radical cystectomy or maintenance BCG.26 During follow-up, 2 (10%) patients in the BCG arm developed metastatic bladder cancer, whereas all participants in the cystectomy arm remained disease-free. When high-risk NMIBC has been shown to be BCG-unresponsive or BCG-intolerant, cystectomy is the preferred option, with intravesical chemotherapy or pembrolizumab as other options for select patients.

BCG Shortage

In 2019, several organizations, including the AUA, American Association of Clinical Urologists (AACU), Bladder Cancer Advocacy Network (BCAN), SUO, the Large Urology Group Practice Association (LUGPA), and the Urology Care Foundation (UCF), issued a notice outlining strategies to maximize care for patients with NMIBC in the context of an ongoing shortage of BCG that exists in the United States.27 In response to this notice, the NCCN Bladder Cancer Panel held an interim meeting to discuss implications of the shortage and develop strategies included within the NCCN Guidelines to help alleviate problems associated with this shortage.

Panel members agreed that the BCG shortage presented significant challenges in their practices, with some institutions having to cancel or reschedule BCG maintenance appointments and triage which patients receive available BCG. Similar to the recommendations outlined in the notice, there was panel consensus that in the event of a shortage, priority for treatment should be to provide induction BCG to patients with high-risk NMIBC (cT1 high-grade and/or CIS). For patients who do not receive BCG, intravesical chemotherapy may be used as an alternative. The intravesical chemotherapies most commonly used for this purpose are gemcitabine28,29 and mitomycin.30 Two separate meta-analyses of randomized trials reported that there were no differences in risk of recurrence between BCG and mitomycin,31,32 although BCG may show more favorable outcomes from maintenance regimens.32 Other options include sequential gemcitabine/docetaxel,33 epirubicin,34,35 valrubicin,36 docetaxel,37 or sequential gemcitabine/mitomycin.38 Some panel members commented that, of these alternative options, they prefer sequential gemcitabine/docetaxel based on a multicenter study supporting its use as an option post–BCG failure.39 Rates of 1- and 2-year recurrence-free survival were 65% and 52%, respectively, for the regimen in this setting. Another post hoc database analysis reported similar outcomes between sequential gemcitabine/docetaxel and BCG/interferon for recurrent NMIBC.40 Another alternative to intravesical BCG for patients with NMIBC at high risk of recurrence and, particularly, at high risk of progression, is initial radical cystectomy.41

Another option during a shortage is splitting the dose of BCG so that multiple patients may be treated using a single vial. Although several randomized trials have reported that one-third-dose BCG showed similar outcomes when compared with full-dose BCG,4244 a phase III trial of 1,355 patients with intermediate- or high-risk NMIBC reported that those receiving the full dose of BCG show a longer disease-free interval compared with those receiving the one-third dose.13 In this study, the 5-year disease-free rate was 58.5% for the one-third dose compared with 61.7% for the full dose; therefore, the null hypothesis of inferiority for duration of the disease-free interval of one-third dose BCG could not be rejected (hazard ratio [HR], 1.15; 95% CI, 0.98–1.35; P=.045), although there were no differences in progression or survival rates.13 Panel members confirmed that the split-dose BCG approach is being adopted during times of shortage in many of their institutions. They shared that the logistics of splitting vials among multiple patients can be challenging, leading some centers to facilitate the process by coordinating BCG clinics so that all patients scheduled to receive BCG arrive around the same time. Some panel members reported that their institutions add interferon to reduced-dose BCG, and there are some data to support this approach.40,4547 However, there was a lack of consensus on the benefit of adding interferon to reduced-dose BCG and, therefore, addition of this approach as a recommendation within the NCCN Guidelines was not supported by the panel.

As a result of this meeting, changes were made to the “Principles of Intravesical Treatment” (BL-F 1 of 3, page 870) to recommend alternative intravesical therapy agents that may be given in the event of a BCG shortage. In addition, the NCCN Guidelines recommend that the dose of BCG may be split in half or thirds so that multiple patients may be treated by a single vial during a shortage, if feasible. The panel stressed that BCG induction therapy should be prioritized over maintenance BCG in the event of a shortage. If supply allows for maintenance doses, maintenance BCG should be prioritized for patients with high-risk NMIBC (cT1 high-grade and/or CIS) in the early maintenance period (eg, 3 and 6 months postinduction). Although strategies to effectively treat NMIBC in the event of a BCG shortage have been in place for several years now, panel members stressed that the shortage continues to be widespread and to present challenges for clinicians. Therefore, active participation in clinical trials for alternatives to BCG and reduced-dose BCG is strongly encouraged.

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Updates in Systemic Therapy

Nivolumab as Adjuvant Therapy for Muscle-Invasive Urothelial Cancer

ICIs have been investigated in the adjuvant setting for urothelial carcinoma, with the phase III CheckMate 274 trial of adjuvant nivolumab reporting positive results for its primary endpoints across the entire study population, including 79% of patients with urinary bladder cancer and 21% of patients with upper tract urothelial carcinoma (UTUC; 14% renal pelvis and 7% ureter).48 In the intention-to-treat population of 709 patients with muscle-invasive urothelial carcinoma treated with radical surgery on CheckMate 274, disease-free survival was 20.8 months with nivolumab compared with 10.8 months with placebo (HR, 0.70; 98.22% CI, 0.55–0.90; P<.001). Importantly, adjuvant nivolumab was tested both in patients who had received neoadjuvant therapy and in those who did not; 43.4% of the trial participants had received previous cisplatin-based neoadjuvant therapy. trAEs of grade ≥3 occurred in 17.9% of those treated with nivolumab and 7.2% of those treated with placebo. Further follow-up is ongoing to assess OS outcomes. Although the authors note that the analysis shows the possibility of a larger effect size for bladder urothelial carcinoma compared with UTUC, they caution that the trial was designed to measure the treatment effect in the entire trial population rather than within each subgroup.

The NCCN Guidelines suggest that adjuvant systemic therapy should be discussed with patients with high-risk pathology after cystectomy. If cisplatin-based neoadjuvant therapy was not given and the tumor is found to be pT3, pT4, or pN+ following resection, adjuvant cisplatin-based chemotherapy is the preferred approach, although adjuvant nivolumab may also be considered (see BL-6, page 869). If cisplatin-based neoadjuvant therapy was given and the tumor is ypT2–ypT4a or ypN+, nivolumab may be considered, although consideration of this approach should balance efficacy in delaying disease progression with the risk of AEs. For UTUC, the recommendation for adjuvant nivolumab when cisplatin-based neoadjuvant therapy was given is a category 2B recommendation, reflecting some panel members’ hesitation to recommend nivolumab in this setting considering the possibility of a lesser benefit in UTUC compared with urothelial bladder cancer (see UTT-3 in the full version of the guidelines, available online at NCCN.org). It should be noted that patients with tumors that are ≤pT2 and have no nodal involvement or lymphovascular invasion after cystectomy are considered to have lower risk and are not recommended to receive adjuvant therapy.

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ICIs for Metastatic Disease

The role of ICIs for treatment of metastatic urothelial carcinoma has grown rapidly in the past 5 years. This article details a few of the more recent, notable changes related to ICI therapy in the NCCN Guidelines for Bladder Cancer. Refer to the guidelines for a full discussion of the use of ICIs for metastatic urothelial carcinoma.

Avelumab Maintenance Therapy

For patients with advanced or metastatic disease who show either response or stable disease through their full course of platinum-based first-line chemotherapy, maintenance therapy with the PD-L1 inhibitor avelumab is now a preferred treatment approach. The randomized phase III JAVELIN Bladder 100 trial showed that avelumab significantly prolonged OS in all 700 randomized patients compared with best supportive care alone (median OS of 21.4 vs 14.3 months; HR, 0.69; 95% CI, 0.56–0.86; P=.001).49 The OS benefit was observed in all prespecified subgroups, including patients with PD-L1–positive tumors. Grade ≥3 AEs were reported in 47.4% of patients treated with avelumab versus 25.2% with best supportive care alone. Based on these positive OS data in a phase III trial, the NCCN panel has assigned avelumab maintenance therapy a category 1 recommendation (see BL-G 2 of 7, page 871).

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ICIs as Second-Line Therapy

Pembrolizumab is a PD-1 inhibitor that has been evaluated as second-line therapy for patients with bladder cancer who previously received chemotherapy and subsequently experienced disease progression or metastasis.50 An open-label, randomized, phase III trial compared pembrolizumab versus chemotherapy (paclitaxel, docetaxel, or vinflunine) in 542 patients with advanced urothelial carcinoma that recurred or progressed after platinum-based chemotherapy. Data from this trial showed a longer median OS for patients treated with pembrolizumab compared with chemotherapy (10.3 vs 7.4 months; P=.002). In addition, fewer grade 3, 4, or 5 trAEs occurred in the pembrolizumab-treated patients compared with those treated with chemotherapy (15.0% vs 49.4%).51 Long-term results (>2 years’ follow-up) from this same phase III trial were consistent with earlier reports, with longer 1- and 2-year OS and PFS results for pembrolizumab compared with chemotherapy.52 The median DoR was not reached for pembrolizumab compared with 4.4 months for chemotherapy. Pembrolizumab also showed lower rates of any-grade (62% vs 90.6%) and grade ≥3 AEs (16.5% vs 50.2%) compared with chemotherapy. Results from this phase III trial led the NCCN panel to assign pembrolizumab a category 1 recommendation as a second-line therapy post-platinum (see BL-G 3 of 7, page 872). Pembrolizumab is preferred over the other ICI therapies currently recommended in the second-line setting (nivolumab and avelumab) based on the higher-quality data and demonstrated OS benefit in this setting. In addition to its second-line use, pembrolizumab is also an option for first-line treatment of patients with advanced or metastatic urothelial carcinoma who are not eligible for any platinum-containing chemotherapy.

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Two ICIs, durvalumab and atezolizumab, were previously FDA-indicated and recommended in the NCCN Guidelines for treatment of patients with previously treated advanced or metastatic urothelial carcinoma. The initial approval for durvalumab was based on early results from a phase I/II multicenter study of 61 patients with PD-L1–positive inoperable or metastatic urothelial bladder cancer that progressed following a platinum-based regimen.53 This trial showed that 46.4% of patients who were PD-L1–positive had disease that responded to treatment; no response was seen in those who were PD-L1–negative. An update on this study (n=191) showed an objective response rate (ORR) of 17.8% and a median OS of 18.2 months, with 55% of patients surviving at 1 year.54 However, the makers of durvalumab subsequently withdrew this indication based on negative results from the phase III DANUBE trial.55 The trial did not meet its primary endpoints, with both durvalumab alone and in combination with tremelimumab failing to improve OS compared with chemotherapy.56

Likewise, the initial approval for atezolizumab was based on the IMvigor210 trial, which showed a significantly improved ORR compared with historical controls with metastatic urothelial carcinoma post-platinum treatment (15% vs 10%; P=.0058).57 Subsequently, the multicenter, randomized phase III IMvigor211 study compared atezolizumab to chemotherapy (vinflunine, paclitaxel, or docetaxel) in 931 patients with locally advanced or metastatic urothelial carcinoma following progression with platinum-based chemotherapy.58 The primary endpoint of this study, median OS in patients with IC2/3 PD-L1 expression levels (n=234), showed no significant difference between atezolizumab and chemotherapy (11.1 vs 10.6 months; P=.41). Likewise, confirmed ORR was similar between the 2 treatments (23% vs 22%). Therefore, the makers of atezolizumab voluntarily withdrew their post-platinum indication based on these results.59

In response to these voluntary withdrawals, the NCCN panel voted to remove atezolizumab and durvalumab as treatment options for patients with metastatic urothelial carcinoma in the second-line post-platinum setting (see BL-G 3 of 7, page 872). Atezolizumab is still recommended in the guidelines as a first-line therapy option for patients who are ineligible for cisplatin and whose tumors express PD-L1, or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression.

Antibody–Drug Conjugates for Metastatic Disease

Antibody–drug conjugates have played an increasingly prominent role in the treatment of urothelial cancers. Two such agents, enfortumab vedotin-ejfv and sacituzumab govitecan-hziy, are currently indicated for metastatic urothelial carcinoma.

Enfortumab Vedotin-ejfv

Enfortumab vedotin is a Nectin-4–directed antibody–drug conjugate that was evaluated in the global, phase II, single-arm EV-201 study of 125 patients with metastatic urothelial carcinoma who had previously received both a platinum-containing chemotherapy regimen and a PD-1/PD-L1 checkpoint inhibitor.60 The confirmed ORR was 44% (95% CI, 35.1%–53.2%), including 12% complete responses. Similar response rates were seen in subgroups of patients with liver metastases and in those with no response to prior ICI therapy. The median DoR was 7.6 months. Grade ≥3 trAEs were reported in 54% of patients and trAEs led to dose reductions or discontinuation of therapy in 32% and 12% of patients, respectively. Subsequently, an open-label, phase III trial of enfortumab vedotin (EV-301) evaluated the therapy in 608 patients with advanced urothelial carcinoma who had previously received both a platinum-containing regimen as well as an ICI.61 Patients were randomized 1:1 to either enfortumab vedotin or the investigator’s choice of chemotherapy (docetaxel, paclitaxel, or vinflunine). After a median follow-up of 11.1 months, OS was longer with enfortumab vedotin than with chemotherapy (12.88 vs 8.97 months; HR, 0.70; 95% CI, 0.56–0.89; P=.001). Median PFS was also longer for enfortumab vedotin (5.55 vs 3.71 months; HR, 0.62; 95% CI, 0.51–0.75; P<.001). The incidence of grade ≥3 AEs was similar in both groups: 51.4% with enfortumab vedotin versus 49.8% with chemotherapy. Based on the OS advantage demonstrated in the phase III EV-301 trial, enfortumab vedotin was given category 1 and preferred designations in the subsequent-line setting (see BL-G 4 of 7, page 873).

F6

Enfortumab vedotin has also been evaluated as a second-line treatment option. Cohort 2 of the phase II EV-201 study enrolled 91 patients who had previously been treated with a PD-1 or PD-L1 checkpoint inhibitor therapy and were ineligible for a cisplatin-containing regimen.62 Of the 89 patients who received treatment with enfortumab vedotin, the confirmed ORR was 52% (95% CI, 41%–62%), with 20% of patients having a complete response. A total of 55% of patients had grade ≥3 AEs, with neutropenia, maculopapular rash, and fatigue being the most common. Four deaths were considered to be related to treatment, caused by acute kidney injury, metabolic acidosis, multiple organ dysfunction, and pneumonitis. Data supporting second-line use of enfortumab vedotin post-platinum or other nonplatinum chemotherapy are more limited than those for post-ICIs, although the phase I EV-101 dose escalation/expansion study did include patients with pretreated metastatic urothelial carcinoma who had not previously received an ICI.63 Of the 23 patients in this category, 43.5% showed a clinical response to enfortumab vedotin treatment. Furthermore, the FDA indication for second-line enfortumab vedotin specifies that the therapy is “indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.”64 Based on these data, as well as NCCN panel consensus on the clinical utility of this agent in the second-line setting, enfortumab vedotin was added as a preferred treatment option both post-platinum or other chemotherapy and post-ICI (see BL-G 3 of 7, page 872). Post-platinum or other chemotherapy, the panel decided that use of enfortumab vedotin should reflect the FDA indication by adding a footnote detailing the specifications.

Sacituzumab Govitecan-hziy

Sacituzumab govitecan is another antibody–drug conjugate composed of an anti–Trop-2 humanized monoclonal antibody coupled to SN-38, the active metabolite of the topoisomerase 1 inhibitor irinotecan. Sacituzumab govitecan has been evaluated in cohort 1 (n=113) of the open-label phase II TROPHY-U-01 study.65 Patients within this cohort had locally advanced, unresectable, or metastatic urothelial carcinoma that had progressed following prior platinum-based and PD-1/PD-L1 checkpoint inhibitor therapy and were treated with sacituzumab govitecan. At a median follow-up of 9.1 months, ORR was 27% (95% CI, 19.5%–36.6%) and 77% of participants showed a decrease in measurable disease. Median DoR was 7.2 months (95% CI, 4.7–8.6 months), median PFS was 5.4 months (95% CI, 3.5–7.2 months), and median OS was 10.9 months (95% CI, 9.0–13.8 months). Key grade ≥3 treatment-related AEs were neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%). Six percent of patients in the study discontinued treatment as a result of trAEs. Sacituzumab govitecan is recommended as an “other recommended option” as subsequent-line therapy for patients who have previously received a platinum-based therapy and ICI, if eligible (see BL-G 4 of 7, page 873). Enfortumab vedotin is preferred over sacituzumab govitecan based on the higher-quality data supporting use of enfortumab vedotin in this setting. Results of phase III comparative trials with sacituzumab govitecan are awaited.

Conclusions

Recent updates to the NCCN Guidelines for Bladder Cancer include changes to the NMIBC treatment algorithms, reflecting panel consensus that treatment decision-making is increasingly based on AUA/SUO risk stratification. In addition, the panel added guidance on how to treat NMIBC in the event of a BCG shortage, a common challenge in current clinical practice. For systemic therapy, notable updates include new roles for ICIs in BCG-unresponsive NMIBC and adjuvant treatment of muscle-invasive bladder cancer postcystectomy. The role of ICIs for metastatic urothelial cancer also continues to evolve, with phase III trials providing stronger support for the use of avelumab as first-line maintenance therapy and pembrolizumab in the second-line, post-platinum setting. Conversely, negative results from other phase III trials have led to the removal of recommendations for durvalumab and atezolizumab in the second-line setting. Finally, antibody–drug conjugates are playing an increasingly important role in the treatment of metastatic urothelial cancer.

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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2022.

All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

  • 1.

    Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72:733.

  • 2.

    National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts. Bladder Cancer. Accessed April 27, 2022. Available at: https://seer.cancer.gov/statfacts/html/urinb.html

    • Search Google Scholar
    • Export Citation
  • 3.

    American Urological Association. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO joint guideline (2020). Accessed April 27, 2022. Available at: https://www.auanet.org/guidelines/bladder-cancer-non-muscle-invasive-guideline

    • Search Google Scholar
    • Export Citation
  • 4.

    Ritch CR, Velasquez MC, Kwon D, et al. Use and validation of the AUA/SUO risk grouping for nonmuscle invasive bladder cancer in a contemporary cohort. J Urol 2020;203:505511.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Ramírez-Backhaus M, Domínguez-Escrig J, Collado A, et al. Restaging transurethral resection of bladder tumor for high-risk stage Ta and T1 bladder cancer. Curr Urol Rep 2012;13:109114.

    • Crossref
    • PubMed
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