American Urological Association (AUA) 2024 Annual Meeting Summary
During Friday’s plenary session, a debate-style discussion, moderated by Dr. Eila Skinner, highlighted patient selection for ileal neobladder vs. ileal conduit urinary reconstruction after radical cystectomy for bladder cancer. Dr. Anne Shuckman argued that there are few absolute contraindications for neobladder, including severe renal or hepatic dysfunction, compromised intestinal function (including inflammatory bowel disease), and urethral stricture disease. Notably, these contraindications do not include oft-referenced age and sex. Additionally, several retrospective studies have exhibited similar renal functional decline between continent diversion and ileal conduit urinary diversion following surgery, in addition to similar post-operative infectious complications. The rate of stoma-related complications, including retraction/stenosis, parastomal hernia, prolapse, and skin irritation are not to be understated. From a quality of life standpoint, there have been conflicting data in the literature when comparing neobladder vs. conduit. However, Dr. Mark Tyson argued that significant lifestyle advantages exist to neobladder reconstruction, including improved physical function, sexual function, as well as mental and social health related to positive body image. With an estimated long-term catheterization rate of 10% necessary for neobladder patients, voiding dysfunction is often over-emphasized during patient counseling.
Dr. Josh Meeks took the counterargument, citing patient expectations that their neobladder will be physiologically similar to their native bladder, can be a source of frustration. Neobladder function declines with time, characterized by worsening daytime continence and increased nocturnal incontinence. Notably, the rates of urinary incontinence or hypercontinence requiring catheterization are much higher in women, with nearly half of women relying on intermittent self-catheterization in longitudinal follow-up. Dr. Amy Luckenbaugh discussed that ileal conduit urinary diversion is associated with shorter operative time, shorter length of stay, as well as decreased post-operative complications and unplanned readmissions.
Ultimately, while we guide our patients through thoughtful education, our discussions regarding urinary diversion techniques should be fair, balanced, and patient-centered to improve patient outcomes and limit decisional regret.
On the heels of the FDA’s approval of ANKTIVA for BCG-unresponsive NMIBC, Dr. Patrick Soon-Shiong, Chairmen of ImmunityBio, provided a comprehensive discussion on next-generation immunotherapy for non-muscle-invasive bladder cancer (NMIBC). To frame the discussion, Dr. Soon-Shiong discussed mechanisms for BCG and immuno-oncologic (IO) failure. Through the expression of MHC on the surface of tumor cells, dendritic cells are trained to recognize BCG-infected bladder cancer cells to generate killer T cells. CD8+ memory T cells exhibit therapeutic failure upon loss of MHC expression on the cancer cell surface, a so-called “cold” tumor, with MHC-negative clonal selection resulting in T cell immune evasion.
Targeting MHC-negative cells is a novel therapeutic approach to overcoming acquired resistance to traditional chemotherapy and immunotherapy. Natural killer (NK) cells are programmed to identify MHC-negative tumor cells. As a result, gamma interferon is released and acts in a paracrine fashion to restore MHC on the tumor cell surface, effectively converting a “cold” tumor to a “hot” tumor. ANKTIVA (N-803) is an IL-15 receptor superagonist consisting of an IL-15 mutant fused with an IL-15 receptor alpha, which binds with high affinity to IL-15 receptors on NK, CD4+, and CD8+ T cells. Mimicking the role of a dendritic cell, intravesical instillation results in the generation of both memory and killer CD8+ T cells, leading to a durable response.
Based on results from the QUILT 3.032 trial, the drug has been FDA-approved when combined with BCG for BCG unresponsive NMIBC. To further parse out the additive effect of ANKTIVA over BCG alone in the combination trial, Dr. Soon-Shiong referenced data from QUILT 2.005, a randomized trial of BCG vs. BCG + ANKTIVA for BCG-naïve NMIBC. Accordingly, the complete response rate in Cohort A (CIS) at any time was 85% in the combination group and 61% in the BCG-alone group, with sustained complete response rates being higher for BCG + ANKTIVA (median duration not reached). Considering the global BCG shortage, ImmunityBio took the exciting step of partnering with the Serum Institute of India for large-scale BCG production.
On Sunday, Dr. Joseph Jacob presented results from Cohort 2 (TAR-200 alone) of the ongoing SunRISe-1 study in BCG unresponsive NMIBC. The complete response rates at 6 and 12 months were 75.7% and 61.9%, respectively, in the TAR-200 monotherapy group. Clinical response was characterized as rapid onset (98% of complete responses achieved at the first disease assessment at week 12) and durable (74.6% with an 18-month duration of response). The therapy was well tolerated, with mostly grade 1-2 toxicities and few treatment discontinuations.
Dr. Mark Tyson presented updated results from BOND-003, a phase 3 study of intravesical Cretostimogene Grenadenorepvec for BCG unresponsive NMIBC. In a cohort of 105 patients with BCG unresponsive CIS, the complete response rate at any time was 75.2%. Notably, 53.8% of patients achieved a complete response upon repeat induction, and there was a 96.7% progression-free survival rate at 12 months. The treatment was very well tolerated, with no grade ≥3 toxicities.
A new program titled “Clinical Trials in Progress” was introduced at AUA 2024, highlighting ongoing trial design, methodology, and eligibility criteria. The bladder cancer session was chaired by Drs. Bernard Bochner and Karim Chamie. Several randomized trials in the intermediate-risk NMIBC disease space were discussed, including MoonRISe-1 (Phase 3 study of TAR-210 vs. chemotherapy in FGFR altered tumors) and PIVOT-006 (Phase 3 study of Cretostimogene vs. surveillance). Three ongoing single-arm BCG unresponsive trials were presented: BOND-003 (Cretostimogene) Cohort P (papillary-only disease), Orion-BC (paclitaxel-hyaluronic acid), and SSANTROP (Sasanlimab + Sacituzumab).
Written by: Patrick J. Hensley, MD, Urologic Oncologist, University of Kentucky College of Medicine Lexington, KY, USA
Adapted from the International Bladder Cancer Group (IBCG) Newsletter 2024 Vol 2