A New Era in Bladder Cancer Research at MSK

MSK Clinical Trials for Patients with BCG-Naïve, BCG-Exposed, and BCG-Unresponsive Bladder Cancer

MSK Clinical Trials for Patients with BCG-Naïve, BCG-Exposed, and BCG-Unresponsive Bladder Cancer

Physician-scientists at Memorial Sloan Kettering Cancer Center (MSK) are conducting a range of clinical trials of promising new treatments for patients with non-muscle invasive bladder cancer (NMIBC).

Intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) has been the standard of care for patients with high-risk NMIBC since its approval by the U.S. Food and Drug Administration in 1990. However, BCG fails in up to 40% of these patients, with about half of the failures occurring within six months of diagnosis. Add in lower therapy completion rates due to toxicity and the continuing worldwide supply shortage, and it’s crystal clear there is an urgent, unmet need for more effective treatment options. (1)

“Today, there is growing excitement in bladder cancer research given the recent approvals of new  treatment options for patients with unresectable or metastatic disease after decades of no advances. Many of these new agents are now being tested in patients with earlier-stage disease,” (2)(3) —- said urologic surgeon Bernard Bochner, MD, FACS, the Sir Murray F. Brennan Endowed Chair in Surgery at MSK. “While these new agents are helping some early-stage patients, one-year disease-free rates are still modest. As a result, there are a myriad of studies seeking to improve on these numbers. We are at the beginning of a new era in bladder cancer research.”

This article provides highlights of five clinical trials at MSK testing promising new treatment options for patients with BCG-naïve, BCG-exposed, and BCG-unresponsive NMIBC.

Clinical Trials for BCG-Naïve Patients

  • Docetaxel plus gemcitabine versus BCG. The phase 3 BRIDGE trial (NCT05538663) is a national, multisite study testing BCG versus intravesical docetaxel plus gemcitabine as a first-line treatment in patients with BCG-naïve high-grade NMIBC. MSK urologic surgeon Eugene Pietzak, MD, the trial’s correlative science chair, collaborated on the study design with principal investigator Max Kates, MD, Division Director of Urologic Oncology at Johns Hopkins University. The BRIDGE trial seeks to enroll 870 patients, and MSK is one of the lead accruing sites.

“Gemcitabine, either alone or in combination with docetaxel, are among the most commonly given treatments when BCG doesn’t work,” said Dr. Pietzak. “While docetaxel and gemcitabine have demonstrated activity as single agents, the BRIDGE trial is the first randomized controlled trial to test them in combination versus BCG. We hope the results will be practice-changing and provide an alternative to BCG for first-line therapy in NMIBC.”

Learn more about the phase 3 BRIDGE trial at MSK.

  • BCG plus pembrolizumab for patients with high-risk NMIBC. Three large randomized controlled trials are currently testing BCG plus immune checkpoint inhibitors in more than 3,000 patients with NMIBC globally. This MSK-exclusive phase 2 study (NCT03504163) is specifically designed for the subset of patients with very high-risk T1 bladder cancer seeking an alternative to radical cystectomy, the preferred treatment option according to the National Comprehensive Cancer Network Guidelines.

The trial, led by principal investigator Dr. Bajorin in collaboration with co-investigator Dr. Pietzak, is also open to patients with high-grade non-muscle-invasive upper tract urothelial carcinoma (NMI-UTUC). Patients receive nine infusions of pembrolizumab over 48 weeks plus once-weekly BCG for six weeks. BCG intravesical treatments begin on the third week of pembrolizumab therapy, allowing the latter to prime T cells to enhance the effectiveness of BCG.

“The pharmaceutical company-sponsored trials are enrolling patients with less aggressive bladder cancer, but it stands to reason that the average, newly-diagnosed patient with NMIBC would choose BCG treatment and its proven effectiveness rate of 80% rather than accept the 12% to 15% risk of a major, immune-related adverse event associated with checkpoint inhibitor therapy,” said Dr. Pietzak. “Our MSK-exclusive trial focuses on the subset of patients with very high-risk NMIBC for whom a radical cystectomy is the standard recommended option because there’s such a high risk they’ll progress to muscle-invasive disease if treated with BCG alone. These patients are typically excluded from pharmaceutical company-sponsored trials.”

Learn more about MSK’s phase 2 trial of BCG plus pembrolizumab for high-risk NMIBC patients.

Clinical Trials for BCG-Exposed Patients

  • Gemcitabine plus BCG for patients with high-grade NMIBC. This MSK-exclusive phase 1/2 study (NCT04179162) builds on pioneering preclinical and clinical studies at MSK by urologic surgeon Guido Dalbagni, MD and genitourinary oncologist Dean Bajorin, MD developing gemcitabine as a intravesical chemotherapy. (4)(5) The hypothesis for the current study is that intravesical gemcitabine may work synergistically with BCG by favorably altering the tumor microenvironment.

The standard of care for patients with NMIBC that relapses after a first-line BCG is a second BCG treatment, yet only 50% will be disease-free at six months. In this study, patients receive alternating intravesical gemcitabine and BCG treatments to see if this approach will make the immune environment more receptive to BCG. “Gemcitabine also has direct anti-tumor effects and is very well tolerated because it’s selective to cancer cells rather than normal urothelium,” Dr. Pietzak added.

Principal investigator Dr. Pietzak and co-investigators Dr. Bochner and Dr. Dalbagni reported interim phase 1 results for the trial at the Society of Urologic Oncology 22nd Annual Meeting in 2021. All 20 patients completed the 10-week treatment regimen, and 19 patients (95%) had no disease recurrence at six months post-treatment. The minimum tolerable dose of gemcitabine was 2,000 mg twice weekly, and there were no dose-limiting toxicities or treatment-related grades 3-5 adverse events. (6)

Final phase 1 results will be presented at the AACR Special Conference in Cancer Research: Bladder Cancer: Transforming The Field, held May 17 to 24, 2024, in Charlotte, North Carolina.

At the same conference, Dr. Pietzak will also present findings from a further analysis of urine samples from patients who participated in the phase 1 study. “Our analysis confirmed the addition of intravesical gemcitabine to BCG favorably altered the tumor microenvironment based on changes in urinary cytokine and chemokine profiles,” Dr. Pietzak said.

“Our phase 2 study is ongoing and almost complete, with only five more patients needed to meet the recruitment goal of 43,” said Dr. Pietzak. “Compared to the 50% response rates we typically see with BCG alone, we’re observing response rates as high as 90% with gemcitabine plus BCG combination in this patient population.”

Based on promising results to date, the National Cancer Institute has approved a phase 3 randomized study of 300 patients with relapsed disease after the first BCG treatment: 150 patients will receive BCG, and 150 will receive gemcitabine plus BCG.

“MSK will lead the national study through the NCI’s cooperative group mechanism. We anticipate the trial will open in May 2025,” said Dr. Pietzak. “Given the strong phase 2 results so far, we anticipate phase 3 results will show gemcitabine plus BCG leads to significantly improved outcomes compared with BCG alone in BCG-exposed patients.”   

Learn more about MSK’s phase 1/2 study of gemcitabine plus BCG for BCG-exposed patients.

  • Erdafitinib in Patients with Recurrent FGFR3-Altered NMIBC. This phase 2 “window of opportunity” study (NCT04917809) is for patients with FGFR3-altered NMIBC that recurs after standard treatment with BCG or chemotherapy. A tumor sequencing analysis using MSK-IMPACT® (Integrated Mutation Profiling of Actionable Cancer Targets) found that about 80% of individuals with frequently recurring, low-grade, non-invasive tumors have an FGFR3 mutation. (7)

“Research by MSK investigators and others has shown that FGFR3-mutated bladder cancer is more likely to recur but less likely to invade the bladder,” said Dr. Pietzak. “As a result, patients with the mutation are less likely to undergo radical cystectomy but still experience a reduced quality of life due to frequent cystoscopies, transurethral resection of bladder tumors (TURBTs), and numerous intravesical treatments of BCG, gemcitabine, mitomycin, and sometimes a combination of gemcitabine and docetaxel.” 

In the present study, principal investigator Dr. Pietzak and colleagues are studying whether erdafitinib, an oral tyrosine kinase inhibitor recently approved for metastatic bladder cancer, (8) may shrink recurrent bladder tumors before surgery, capitalizing on the 14- to 21-day “window of opportunity” between diagnosis of recurrence and resection.

Dr. Pietzak, Dr. Bochner, and colleagues have found evidence that FGFR3 mutations are associated with an immunosuppressive tumor marker environment. (9) “Work by Dr. Bishoy Faltas at Weill Cornell Medicine has suggested that erdafitinib may reverse some of those immunosuppressive changes so that even if a patient doesn’t fully respond to erdafitinib, it may improve the odds they’ll respond better to a subsequent BCG or chemotherapy wash,” said Dr. Pietzak. “We are also investigating whether FGFR3 in urine may serve as a biomarker for recurrence, which may allow for fewer cystoscopies and TURBTs in this patient population.”

Another innovative approach the MSK investigators are considering is the TARIS drug delivery system developed by J&J Innovative Medicine. (10) The small, pretzel-shaped device delivers medication directly to bladder tumors, which may allow for higher, targeted doses of erdafitinib compared to the oral format.

Learn more about the MSK-exclusive “window of opportunity” phase 2 trial of erdafitinib for patients with recurrent NMIBC.

A Clinical Trial of a Novel Immunotherapy for BCG-Unresponsive Patients

  • MSK-exclusive trial of the novel immunotherapy 2141-V11. Principal investigator Dr. Bochner, and co-investigators Dr. Pietzak and genitourinary oncologist Jonathan Rosenberg, MD, Chief of the Genitourinary Oncology Service at MSK, are conducting an investigator-initiated trial of 2141-V11,  a novel, intravesical anti-CD40 agonist antibody.

2141-V11 was developed in collaboration with Jeffery Ravetch, MD, PhD, head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology at The Rockefeller University. “Through a chance meeting with Dr. Ravetch and learning about his work into developing an antibody with a unique mechanism for presenting tumor-associated proteins to the immune system, we started collaborating on applying the approach to bladder cancer,” said Dr. Bochner. “His preclinical work demonstrated the effectiveness of intravesical 2141-V11 treatment in mouse models of bladder cancer, forming the basis for our first-in-human phase 1/2 study at MSK.”

Dr. Ravetch’s lab studies pairs of activating and inhibitory molecules, known as Fc receptors, which are found on the surface of immune cells. Dr. Ravetch and colleagues discovered that antibodies bound to Fc receptors can coordinate the immune system’s effector responses. (11) Dr. Bochner said the 2141-V11 antibody contains engineered Fc domains that encourage dendritic cells to present tumor-associated proteins to the immune system for eradication more effectively.

The MSK-exclusive trial of intravesical 2141-V11 (NCT05126472) seeks to enroll a total of 25 patients with high-grade NMIBC that has not responded to standard treatment and who have elected not to undergo or are considered ineligible for radical cystectomy.

Dr. Bochner will present the first results from the 2141-V11 trial at the American Urological Association 2024 Annual Meeting in San Antonio, Texas, on May 3, 2024.

“We have established safety and we have observed some clear responses, but this is only the beginning of our efforts to determine how well it 2141-V11 may work for patients with BCG-unresponsive bladder cancer,” said Dr. Bochner.

“Dr. Ravetch has found even greater anti-tumor activity when 2141-V11 is combined with interleukin-15 in his continuing lab studies,” Dr. Bochner said. “As a result, we have been working with an outside company to develop a “supercharged” version of IL-15 and hope to open a trial of 2141-V11 plus the new IL-15 product later this year at MSK.”

Learn more about the MSK-exclusive trial of 2141-V11 for BCG-unresponsive NMIBC who are not candidates for radical cystectomy.

Access disclosures for Dr. Bochner, Dr. Pietzak, Dr. Dalbagni, Dr. Bajorin, and Dr. Rosenberg

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  1. Chu C, Pietzak E. Immune mechanisms and molecular therapeutic strategies to enhance immunotherapy in non-muscle invasive bladder cancer: Invited review for special issue “Seminar: Treatment Advances and Molecular Biology Insights in Urothelial Carcinoma”. Urol Oncol. 2023;41(10):398-409.
  2. U.S. Food and Drug Administration. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. December 15, 2023. Accessed April 14, 2024.
  3. U.S. Food and Drug Administration. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. March 6, 2024. Accessed April 14, 2024.
  4. Cozzi PJ, Bajorin DF, Tong W, et al. Toxicology and pharmacokinetics of intravesical gemcitabine: a preclinical study in dogs. Clin Cancer Res. 1999;5(9):2629-2637.
  5. Dalbagni G, Russo P, Sheinfeld J, et al. Phase I trial of intravesical gemcitabine in bacillus Calmette-Guérin-refractory transitional-cell carcinoma of the bladder. J Clin Oncol. 2002;20(15):3193-3198.
  6. Society of Urologic Oncology 22nd Annual Meeting Abstract 2246. A Phase I Clinical Trial of Intravesical Chemoimmunotherapy with Alternating Gemcitabine and Bacillus Calmette-Guerin for Non-Muscle Invasive Bladder Cancer (NCT04179162).
  7. Pietzak EJ, Bagrodia A, Cha EK, et al. Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets. Eur Urol. 2017;72(6):952-959.
  8. U.S. Food and Drug Administration. FDA approvaes erdafitinib for locally advanced or metastatic urothelial carcinoma. January 19, 2024. Accessed April 14, 2024.
  9. Damrauer JS, Roell KR, Smith MA, et al. Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non-Muscle-Invasive Bladder Cancer. Clin Cancer Res. 2021;27(16):4599-4609.
  10. Johnson & Johnson Innovative Medicine. Janseen Oncology Strengthens Disease Interception Focus with TARIS’ Unique Delivery System. Accessed April 14, 2024.
  11. Bournazos S, Ravetch JV. Diversification of IgG effector functions. Int Immunol. 2017;29(7):303-310.