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Empowering Bladder Cancer Care: A Formal Partnership between IBCG and UroToday in the Era of Expanding Therapies

“Nothing in life is to be feared; it is only to be understood.” – Marie Curie

As we embark on 2024, we continue to see an explosion of research and clinical trials in bladder cancer. Every FDA approval is the fruit of thousands of hours of dedicated work by investigators, patients, research, and clinical teams. However, regulatory approval is only the first step in linking patients with new therapies. Without effective dissemination of knowledge and guidance, many patients will not receive evidence-based treatments and indeed may not even know their treatment options. The bladder cancer community needs timely information—not only formal guidelines and best practice recommendations, but also practical “nuggets” to help patients, clinicians, and healthcare organizations evaluate and choose treatments depending on both clinical and economic circumstances.

The International Bladder Cancer Group (IBCG) and UroToday have long served as leading sources of expertise, research, and education to support and carry out high-quality studies and disseminate data and insights to clinicians, patients, and policymakers around the world. The two organizations have partnered informally for decades, but the relationship has now evolved into a formal partnership. The aim is to synergize the strengths of both organizations and further empower patients and clinicians by providing the latest information and resources on bladder cancer. By formally partnering, IBCG and UroToday will work even more closely together to support and inform the bladder cancer community on clinical trial design and research, peer-reviewed publications, national and international guidelines, and conferences and symposia.

Established in 2006, the IBCG is an internationally recognized organization that is committed to optimizing bladder cancer patient care by identifying and filling global educational needs and gaps in knowledge. To achieve this aim, the IBCG emphasizes meticulous evaluation and leverages available data to support evidence-based treatment and management. The IBCG regularly holds meetings and consensus panel reviews and has authored numerous peer-reviewed papers that have been published in highly-ranked journals. In addition, the IBCG aims to distill information into practical “pearls” to help clinicians improve bladder cancer patient care. To that end, members work together to author guidelines and best practice recommendations that are widely read and cited by clinicians and regulators around the world. The IBCG's input is regularly cited by national and international guideline committees, and its work is cited by prestigious guidelines, including those from the American Urological Association (AUA) and the European Urological Association (EUA), as well as by the US Food and Drug Administration (FDA).

In recent years, the IBCG has expanded its membership to include experts in various aspects of bladder cancer care, including medical oncologists, radiation oncologists, statisticians, and researchers from a diverse array of countries. In 2021, the Health Services Research group, led by Dr. Stephen B. Williams, was established to serve as a collaborative resource for clinicians and researchers. Additionally, a newsletter under Chief Editor Dr. Fred Witjes was launched in 2022. Other recent projects include hosting the AUA-IBCG Bladder Cancer Forum in 2022 and 2023, partnering with the Chilean Urological Association to develop Chilean Bladder Cancer guidelines, and collaborating with the Global Society of Rare Genitourinary Tumors (GSRGT) to develop practice recommendations for variant urothelial cancer histotypes.

UroToday, for its part, is a premier global source of urology news and education that is regularly accessed by more than 500,000 urologists and healthcare professionals. UroToday’s overarching goal is to offer clinically relevant content that clinicians need to remain at the forefront of the dynamic field of GU oncology and urology. Established in 2003, UroToday’s web-based platform shares content on key areas of research and clinical practice, enabling researchers and clinicians to review original studies, case studies, peer-to-peer video and podcast discussions, and pertinent articles and commentaries. Its offerings have expanded over time to include curated, evergreen Centers of Excellence that span the full scope of urology and urologic oncology. The website also offers detailed conference presentation summaries, a databank of clinical trials in progress, and a list of and access to key peer-reviewed publications. In addition, UroToday reaches an estimated 1 million patients worldwide, helping them understand their diagnosis and options for evidence-based urologic and GU oncologic care.

For decades, UroToday and IBCG have informally partnered to create multimedia educational tools and publish and disseminate articles, reflecting a shared commitment to advancing knowledge in the field of bladder cancer. The new, formal partnership aspires to build on these efforts by focusing on several key goals, including 1) creating and disseminating bladder cancer educational materials for patients, 2) updating patients about opportunities to participate in clinical trials and other studies, and 3) advocating for patients in the United States and globally. These goals reflect a patient-centered ethos that is central to each organization’s philosophy. By working even more closely together, UroToday and IBCG also can reach even more patients and help them feel empowered to make informed choices about their care.

Such outreach and education have become increasingly vital as treatments for urothelial cancer continue to expand at an exponential pace. Just two months ago (December 15, 2023), the FDA approved enfortumab vedotin-ejfv in combination with pembrolizumab for the first-line treatment of locally advanced or metastatic urothelial cancer (la/mUC). The FDA already had approved this antibody-drug conjugate/PD-1 inhibitor combination for the first-line treatment of cisplatin-ineligible patients, but the expanded indication means that for the first time, we have approved an alternative to chemotherapy for all patients with la/mUC.

Clinical data on enfortumab vedotin-ejfv/pembrolizumab in urothelial cancer are a compelling highlight from 2023 and thus are worth reviewing here. The FDA’s expanded approval reflects a near-doubling in survival observed in the enfortumab vedotin/pembrolizumab arm of the randomized, open-label, phase 3 EV-302/KEYNOTE-A39 trial, which enrolled 886 patients with previously untreated la/mUC regardless of PD-L1 status. Median overall survival (OS) with enfortumab vedotin/pembrolizumab was 31.5 months (95% confidence interval [CI], 25.4 months-not estimable), compared with 16.1 months (95% CI, 13.9-18.3 months) in the platinum-based chemotherapy (gemcitabine plus either cisplatin or carboplatin) arm. This difference translated to a 53% reduction in risk of death with enfortumab/vedotin versus chemotherapy (hazard ratio [HR], 0.47; 95% CI, 0.38-0.58; P <.0001). Median progression-free survival (PFS) in EV-302/KEYNOTE-A39 was 12.5 months (95% CI, 10.4-16.6) in the enfortumab vedotin/pembrolizumab arm versus 6.3 months (95% CI, 6.2-6.5) in the chemotherapy arm, for a HR of 0.45 (95% CI, 0.38-0.54; P <.0001). These findings were presented in October at the 2023 European Society for Medical Oncology (ESMO) Congress in Madrid.1

The expanded FDA indication for enfortumab vedotin/pembrolizumab signifies a paradigm shift in the treatment of advanced urothelial cancer—for the first time, we have an effective treatment option for all comers that is more effective and less toxic than chemotherapy. This is just one of several bladder cancer developments of note from 2023. At ESMO, we also heard results from the phase 3 CheckMate-901 study, in which combination treatment with gemcitabine-cisplatin plus the PD-1 inhibitor nivolumab led to a 22% reduction in risk of death compared with gemcitabine-cisplatin monotherapy in patients with advanced urothelial cancer.2 Median OS times were 21.7 months (95% CI, 18.6-26.4 months) with combination treatment versus 18.9 months (95% CI, 14.7 22.4 months) with monotherapy (HR for death, 0.78, 95% CI, 0.63 to 0.96, P = .02). PFS was also significantly longer with the combination compared with chemotherapy alone (HR for progression or death, 0.72; 95% CI, 0.59 to 0.88; P = .001). Other secondary endpoints, including complete and objective response rates and duration of response, also favored the dual-agent regimen, which is now under priority review by the FDA.

In the non-muscle-invasive bladder cancer (NMIBC) space, investigators are evaluating checkpoint inhibitors, chemotherapy agents, antibody-drug conjugates, and other novel agents.3-5 Researchers also are studying the intravesical gemcitabine delivery system TAR 200 for the treatment of high-risk BCG-unresponsive NMIBC in patients who are cystectomy-ineligible or who elect not to undergo chemotherapy.6 This pretzel-shaped silicone device is inserted via catheter into the bladder, where it gradually releases gemcitabine at a controlled rate. It received a breakthrough therapy designation from the FDA in December 2023 based on the results of the ongoing phase 2b SunRISe-1 study, which compares TAR-200 plus cetrelimab versus TAR-200 alone or cetrelimab alone in patients who are ineligible for or decline to undergo cystectomy. Interim data from SunRISe-1 were presented at the 2023 AUA meeting, and subsequent findings were presented at ESMO 2023.7,8 A sibling device, TAR-210, which releases the fibroblast growth factor receptor (FGFR) inhibitor erdafinitib into the bladder, is being evaluated in patients with NMIBC who have select FGFR alterations.9

In 2023, we also saw updated results on the first gene therapy approved for treating bladder cancer. Nadofaragene firadenovec-vncg received FDA approval in December 2022 for the treatment of patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors (+Ta/T1).10 This approval was based on the findings of Study CS-003, a single-arm, multicenter trial of nadofaragene firadenovec administered every 3 months.11 Among 98 evaluable patients, 51% (95% CI, 41%-61%) had complete responses, median duration of response was 9.7 months, and 46% of responses lasted at least 1 year. At the 2023 Society of Urologic Oncology (SUO) annual meeting, researchers updated us that 26% of complete responders had remained free of high-grade recurrence at 36 months. Median duration of CR was 9.7 months (95% CI 9.2-24 months) and 34% of complete responses were maintained for at least 36 months.

Yet another gene therapy, cretostimogene grenadenorepvec (CG0070), has received an FDA Fast Track Designation and Breakthrough Therapy Designation for BCG-unresponsive NMIBC. Cretostimogene is in active clinical studies in several stages of bladder cancer. Results from an interim analysis of 66 patients in the BOND-003 phase 3 trial presented at SUO 2023 showed that patients treated with cretostimogene monotherapy had a complete response rate of 75.7%, and 74% of complete responders maintained their response
for at least 6 months.12 Minimal treatment-related adverse events were observed.

As bladder cancer research expands, the IBCG is working with the Society for Immunotherapy of Cancer (SITC) to create guidance on clinical trial design in NMIBC, MIBC, and la/mUC. Such guidance is vital to maximize the utility and generalizability of clinical trial findings, both for regulatory purposes and to guide clinical decision-making. However, clinical decisions are not always effective at a population level if they do not account for available healthcare resources. For example, if a new treatment approved in North America costs tens of thousands of dollars per patient and has 90% efficacy, while another available treatment has only 2% lower efficacy and costs a fraction of the price, then we want to educate providers that they can exert a much greater impact at the population level by choosing the more cost-effective treatment. Cost-benefit ratios matter in all clinical settings, but especially in countries and regions where healthcare resources are limited. A case in point is the newly approved enfortumab vedotin combination. Because it is costly, it clearly should be used, but clinicians and healthcare administrators will require education on how to decide between this and other therapies.

The partnership between IBCG and UroToday helps achieve such education and accomplish many other aims. Both organizations are leading sources of pragmatic tools to educate and guide the global bladder cancer community to improve bladder cancer treatment, survival, and quality of life for as many patients as possible. The FDA and other regulatory bodies routinely reference IBCG guidance, while UroToday has long amplified the voices of both patients and investigators who underscore the need for new therapies to reach the clinic. Given recent growth in the number of patients with bladder cancer and available treatments, is vital for us to continue to come together not only to develop research and guidelines but also to spread the message about the impact of urothelial cancer and new developments in the field. Having worked with IBCG since its founding in 2006, and with UroToday for more than 20 years, I am thrilled that the two organizations are now formally partnering. Video updates on this topic from UroToday’s Bladder Cancer Center of Excellence are forthcoming. Stay tuned, and I wish each of you a happy and productive 2024.

Written by: Ashish M. Kamat, MD, MBBS, Professor of Urology and Cancer Research and Wayne B. Duddleston Professor of Cancer Research at MD Anderson Cancer Center in Houston, Texas. Dr. Kamat serves as President of International Bladder Cancer Group, (IBCG), and Co-President of International Bladder Cancer Network.

References:

  1. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus Gemcitabine–Cisplatin in Advanced Urothelial Carcinoma. New Engl J Med. 2023;389(19):1778-1789. doi:
  2. Powles TB, Perez Valderrama B, Gupta S, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34(2):S:1340. doi: 10.1056/NEJMoa2309863
  3. Szabados BE, Martinez EN, Alvarez Marquez FJ, et al. 2363MO A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in non-urothelial, muscle invasive bladder cancer (ABACUS-2). Ann Oncol. 2023;34(2):S1201-02. doi: https://doi.org/10.1016/j.annonc.2023.09.1012
  4. Thibault C, Elaidi RT, Pouessel D, et al. 1059P NEMIO: A randomized phase I-II trial evaluating efficacy and safety of dose dense MVAC (ddMVAC) + durvalumab +/- tremelimumab as neoadjuvant treatment in patients with bladder muscle-invasive urothelial carcinoma. Ann Oncol. 2023;31(4):S723. doi: https://doi.org/10.1016/j.annonc.2020.08.1179
  5. Sridhar S, O’Donnell PH, Flaig TW, et al. 2365MO Study EV-103 cohort L: Perioperative treatment w/ enfortumab vedotin (EV) monotherapy in cisplatin (cis)-ineligible patients (pts) w/ muscle invasive bladder cancer (MIBC). doi: https://doi.org/10.1016/j.annonc.2023.09.1014
  6. Tyson MD, Morris D, Palou J, et al. Safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who refused or were unfit for curative-intent therapy: a phase 1 study. J Urol. (2023);209:890-900. https://doi.org/10.1097/JU.0000000000003195Tyson MD, Morris D, Palou J, et al. Safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who refused or were unfit for curative-intent therapy: a phase 1 study. J Urol. (2023);209:890-900. https://doi.org/10.1097/JU.0000000000003195
  7. Daneshmand S, Heijden MSvd, Jacob JM, et al. LBA02-03 first results from SunRISE-1 in patients with bcg unresponsive high-risk non–muscle-invasive bladder cancer receivinG TAR-200 in combination with cetrelimab, TAR-200, or cetrelimab alone. J Urol. 2023;209(sppl_4):e1187.doi: https://doi.org/10.1097/JU.0000000000003361.03
  8. Necchi A, Jacob JM, Daneshmand S, et al. LBA105 Results from SunRISe-1 in patients (Pts) with bacillus Calmette&#x2013;Gu&#xe9;rin (BCG)-unresponsive high-risk non&#x2013;muscle-invasive bladder cancer (HR NMIBC) receiving TAR-200 monotherapy. Ann Oncol. 2023;34:S1343-S1344. doi: https://doi.org/10.1016/j.annonc.2023.10.111.
  9. Vilaseca A, Guerrero F, Zainfeld D, et al. Safety and efficacy of the erdafitinib (erda) intravesical delivery system, TAR-210, in patients (pts) with non–muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC) harboring select FGFR mutations or fusions: Phase 1 first-in-human study. J Clin Oncol. 2023;41(6_suppl):TPS583-TPS583.
  10. U.S. Food and Drug Administration. FDA D.I.S.C.O. Burst Edition: FDA approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-adstiladrin-nadofaragene-firadenovec-vncg-patients-high-risk#:~:text=On%20December%2016%2C%202022%2C%20the,with%20or%20without%20papillary%20tumor Last updated January 20, 2023. Accessed January 30, 2024.
  11. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107-117.
  12. 12. Tyson MD. First results of BOND-003, a phase 3 study of intravesical cretostimogene grenadenorepvec monotherapy for patients with high-risk BCG-unresponsive NMIBC. Presented at the 24th annual Society for Urologic Oncology Annual Meeting, December 1, 2023. Available at: https://www.urotoday.com/conference-highlights/suo-2023/suo-2023-bladder-cancer/148306-suo-2023-late-breaking-abstract-first-results-from-bond-003-a-phase-3-study-of-intravesical-cretostimogene-grenadenorepvec-monotherapy-for-patients-with-high-risk-bcg-unresponsive-nmibc.htmlaspx. Accessed February 8, 2024.