Tollefson, Matthew K.

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.

Context.— In women, radical cystectomy includes removal of the bladder, uterus, fallopian tubes, ovaries, and anterior vaginal wall, yet contiguous extension of urothelial carcinoma to all pelvic organs is rare and routine removal may be unnecessary. Objective.— To study pelvic organ involvement in women at radical cystectomy and investigate oncologic outcomes. Design.— Women with bladder cancer who underwent radical cystectomy at the Mayo Clinic and University of Toronto (1980–2018) were evaluated. Cancer-specific survival (CSS) was estimated with the Kaplan-Meier method; comparisons were made with the log-rank test. Associations with CSS were evaluated with Cox proportional hazard modeling. Results.— A total of 70 women with pT4a and 83 with pT3b cancer were studied. Organs involved were vagina (n = 41 of 70; 58.6%), uterus (n = 26 of 54; 48.1%), cervix (n = 15 of 54; 27.8%), fallopian tubes (n = 10 of 58; 17.2%), and ovaries (n = 7 of 58; 12.1%); 22 of 58 patients (37.9%) had >1 organ involved. Of 70 with pT4a cancer, 64 were available for survival analysis by 3 pelvic organ groups: vaginal only, vaginal and/or cervical/uterine, and vaginal and/or cervical/uterine and/or fallopian tubes/ovarian involvement. Three-year CSS for vaginal involvement only was 39%; it was 14% if cervical/uterine involvement, and <1% if fallopian tube/ovarian involvement was included (P = .02). Among 20 women with pT4aN0/Nx and vaginal involvement only, 3-year CSS for vaginal involvement was 50%, whereas among 48 women with pT3bN0/Nx cancer, 3-year CSS was 58%, P = .70. Conclusions.— Isolated vaginal involvement should be separated from uterine and/or adnexal extension of urothelial carcinoma at pathologic staging. Direct ovarian extension is rare and routine removal may be unnecessary.

509 Background: Bladder cancer is a leading cause of cancer death in the United States. The histology in > 90% of cases is urothelial carcinoma (UC). Tumors may present either as non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Current standard of care for patients with high risk NMIBC includes transurethral resection of bladder tumor (TURBT) followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG). Meanwhile, patients with BCG unresponsive NMIBC or MIBC are recommended to undergo radical cystectomy (RC), which adversely impacts quality of life and is associated with significant morbidity. MV-NIS is an investigational oncolytic measles virus with an excellent clinical safety profile. This ongoing phase I clinical study is designed to test the safety, efficacy and identify the recommended phase 2 dose (RP2D) of intravesical MV-NIS in patients with NMIBC or MIBC who are scheduled for RC and not eligible for neoadjuvant chemotherapy. Methods: Bladder UC patients were evaluated for eligibility and provided informed consent prior to enrolling. To date 8 patients have been enrolled: 4 to the single dose safety cohort, and 4 to the multi-dose expansion cohort. Patients were administered intravesical ̃1x109 TCID50 MV-NIS once at least 1 week prior to RC (safety cohort), or twice at 4 and 2 weeks prior to RC (expansion cohort). Patients were closely monitored during the 2-hour instillation period. Tumor specimens from the pre-treatment TURBT and post-treatment RC were analyzed to determine pre- and post-treatment pathological stage and evaluate tumor killing and immune cell infiltrate. Results: Intravesical MV-NIS treatment was well tolerated in all patients. Only a single Adverse Event (AE) attributable to MV-NIS treatment (Grade 1 hematuria). AEs Grade > 2 were related to post-surgical complications. Tumor downstaging was observed in 4 of 8 patients. Among 4 patients in the expansion cohort, 2 had no residual disease (pT0). Central assessment of RC tissues showed significant inflammatory infiltrate in all treated bladder specimens. Detailed analyses are ongoing to characterize MV infection and immune infiltrate in bladder tissue. Conclusions: The higher-than-expected rate of tumor downstaging and pT0 pathology, paired with the significant immune infiltrate observed in post-treatment bladder tissue, provide compelling evidence that intravesical MV-NIS has clinical activity against UC. These results support the use of two doses of ̃1x109 TCID50 as the RP2D in future clinical studies for BCG unresponsive NMIBC or MIBC patients. MV-NIS induced inflammation may act synergistically with checkpoint blockade therapies. Clinical trial information: NCT03171493.

Abstract Background: Bladder cancer is a leading cause of cancer death in the United States1. The histology in > 90% of cases is urothelial carcinoma (UC). Tumors may present either as non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Current standard of care for patients with high risk NMIBC includes transurethral resection of bladder tumor (TURBT) followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG)2. Meanwhile, patients with BCG unresponsive NMIBC or MIBC are recommended to undergo radical cystectomy (RC), which adversely impacts quality of life and is associated with significant morbidity3. MV-NIS is an investigational oncolytic measles virus with an excellent clinical safety profile4. This ongoing phase I clinical study is designed to test the safety, efficacy and identify the recommended phase 2 dose (RP2D) of intravesical MV-NIS in patients with NMIBC or MIBC who are scheduled for RC and not eligible for neoadjuvant chemotherapy. Methods: Bladder UC patients were evaluated for eligibility and provided informed consent prior to enrolling. To date 8 patients have been enrolled: 4 to the single dose safety cohort, and 4 to the multi-dose expansion cohort. Patients were administered intravesical ~1x109 TCID50 MV-NIS once at least 1 week prior to RC (safety cohort), or twice at 4 and 2 weeks prior to RC (expansion cohort). Patients were closely monitored during the 2-hour instillation period. Tumor specimens from the pre-treatment TURBT and post-treatment RC were analyzed to determine pre- and post-treatment pathological stage and evaluate tumor killing and immune cell infiltrate. Results: Intravesical MV-NIS treatment was well tolerated in all patients. Only a single Adverse Event (AE) attributable to MV-NIS treatment (Grade 1 hematuria). AEs Grade>2 were related to post-surgical complications. Tumor downstaging was observed in 4 of 8 patients. Among 4 patients in the expansion cohort, 2 had no residual disease (pT0). Central assessment of RC tissues showed significant inflammatory infiltrate in all treated bladder specimens. Detailed analyses are ongoing to characterize MV infection and immune infiltrate in bladder tissue. Conclusions: The higher-than-expected rate of tumor downstaging and pT0 pathology, paired with the significant immune infiltrate observed in post-treatment bladder tissue, provide compelling evidence that intravesical MV-NIS has clinical activity against UC. These results support the use of two doses of ~1x109 TCID50 as the RP2D in future clinical studies for BCG unresponsive NMIBC or MIBC patients. MV-NIS induced inflammation may act synergistically with checkpoint blockade therapies. References 1. Siegel, R.L., Miller, K.D. & Jemal, A. CA Cancer J Clin 69, 7-34 (2019). 2. Knowles, M.A. & Hurst, C.D. Nature reviews. Cancer 15, 25-41 (2015). 3. Zakaria, A.S., et al. Can Urol Assoc J 8, 259-267 (2014). 4. Galanis, E., et al. Cancer research 75, 22-30 (2015). Citation Format: Tanner S. Miest, Bradley Leibovich, Stephen Bardot, Paul R. Young, Stephen A. Boorjian, Mark Gonzalgo, Loren Herrera-Hernandez, Matthew K. Tollefson, Jeffrey Karnes, Paige Nichols, Tessa Kroeninger, Rachel Graham, Carole Lahana, Monica Reckner, Alysha Newsom, Nandakumar Packiriswamy, Janice Anoka, Kah Whye Peng, Erol Wiegert, Alice Bexon, Shruthi Naik. Safety and efficacy of neoadjuvant intravesical oncolytic MV-NIS in patients with urothelial carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P190.