BCG Unresponsive NMIBC: What s Available?

BCG Unresponsive NMIBC: What s Available? Michael S. Cookson, MD, MMHC, FACS Professor and Chair Department of Urology University of Oklahoma TwiLer @uromc

Professional Practice Gap Gap 1: There is incomplete understanding of the definition of BCG unresponsive or BCG failure Gap 2: Management options for patients with BCG unresponsive NMIBC are not well understood and are currently evolving

Learning Objectives Upon completion of this session, participants will improve their competence and performance by being able to: 1. Recognize the definitions of BCG failure 2. Outline the management options for patients with BCG failure 3. Discuss future clinical trial in BCG failure patients

BCG Indications Any pa1ent with high risk NMIBC TaHG, T1, and all CIS; also op1on for mul1focal and recurrent and >3cm Ta LG Recurrent BCG naïve AKer BCG induc1on if no indica1on for cystectomy or medically unfit FDA approved for CIS and high risk Ta,T1 Chang SS et al. J Urol 2016: 196(4); 1021

Has Become U.S. Standard of Care SWOG 8507 - BCG Maintenance 2-year RFS 82% vs. 62% with/without p < 0.0001 maintenance 5-year RFS 60% vs. 41% with/without maintenance Lamm DL, et al. J Urol 2000; 163:1124

The Problem: Some Will Fail BCG Despite benefits of BCG, long-term disease-free and progression-free survival may be difficult to achieve 50% will recur aher inducion BCG, and while 20-30% may be salvaged with addiional BCG BCG failure may be lethal if untreated Key: To idenify those failures early Logan C, et al. BJU Int 2012; 110:12

Consider Extravesical Sites Retrospec4ve analysis of 110 pa4ents with high-risk disease and BCG NMIBC repeatedly treated with intravesical BCG 52% had UUT and/or urethral carcinoma 48% had intravesical recurrence alone Giannarini G, et al: Eur Urol 2014; 65(4):825

Importance of Prostatic Involvement BCG treatment failed in 62 high-risk cases; patients underwent cystectomy Prostatic urethra TCC most important predictor of muscle-invasive cancer Hazard ratio, 12.2 (2.2-65.5) P=.003 Sampling from the urethra in high-risk patients is essential! Huguet J, et al. Eur Urol 2005; 48:53

BCG Unresponsive Failure to achieve a disease free state 6 months after initial BCG therapy with either maintenance or retreatment at 3 months due to either rapidly recurrent or persistent high grade disease Time 0 BCG Induction Time: 3 months Tumor + Re-induction or Maintenance Time: 6 months Tumor + Herr HW. J Urol 169:1706-1708, 2003 Nieder AM, et al. Urology 66(S6A):108-125, 2005

Why is 6 Months Important? 6 months is the treatment period to identify high-risk tumors as truly refractory Herr HW and Dalbagni G. J Urol 169:1706-08, 2003

Defini&on: BCG Unresponsive Recurrent/persistent high grade urothelial carcinoma after completion of at least induction and one cycle maintenance BCG ( 5+2 ) for high grade Ta/T1 or CIS Never achieved CR or recurred within 6 months of last BCG dose T1HG at first evaluation after induction BCG at least 5 of 6 induction doses These patients are extremely unlikely to respond to further BCG Lerner S, et al, Bladder Cancer 1:29, 2015

High-grade disease T1 at the first evaluation following an induction BCG course BCG 5/6 3 mos cysto: HG T1 Persistent or recurrent CIS alone +/- Ta/T1 disease within 12 months of completion of adequate BCG therapy BCG 5/6 + BCG 2/3 or 2/6 CIS +/- Ta or T1 1 year of last BCG Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy Ta or T1 BCG 5/6 + BCG 2/3 or 2/6 6 mos of last BCG FDA 2018, Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

Novel Definition: Molecular Failure Goal: Incorporate marker (FISH) to predict BCG failure before it becomes clinically apparent 143 patients treated with BCG therapy followed prospectively for 2 years FISH assays collected at 6 weeks and 3 months Results of the FISH assays were correlated with clinical outcomes Kamat AM, et al. BJU Int. 2016; 117:754-760

Recurrence and Progression-Free Survival based on FISH Kamat AM, et al. BJU Int. 2016; 117:754-760

Novel Defini+on: Molecular Failure Result: FISH results correlated with recurrence Conclusion: Patients with an early positive FISH and a negative cystoscopy at 3 months should be considered molecular BCG failures and could enroll in prospective RCT s Kamat AM, et al. BJU Int. 2016; 117:754-760

For Certain High Risk, NMIBC: The Most Definitive Therapy

Treatment Dilemma Cystectomy recommended as a standard of care a3er BCG failure Cystectomy: high rate of cure if performed before progression to muscle invasion Supported by AUA, NCCN, EAU Guidelines Unfortunately, morbidity remains high And, many with high risk NMIBC who fail BCG are not candidates for cystectomy Babjuk M,et al.eur Urol 2014; 59: 21-25 Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Joint Guideline

Intravesical Therapy when BCG Fails BCG/IFN Valrubicin only FDA approved drug Gemcitabine Docetaxel Gemcitabine/MMC Gemcitabine/Docetaxel

Treatment Response Efficacy Endpoints: 6 mo CR of 50% in CIS 1 year Recurrence free survival of 30% 18 mo Recurrence free survival of 25% No home-runs in this space

BCG + IFN Multicenter Phase II: 1,007 patients (BCG naïve and failure At 24 months, 45% of BCG failure were disease-free Those with 2 or more prior courses of BCG or BCG-refractory had worse outcomes Rosevear, J Urol 2011; 186:817

Valrubicin: Pivotal Study Open-label, phase III trial 90 patients with CIS after prior IVe therapy 21% CR at 6 months 32% CR at 6 months if you consider that with low grade recurrences (10 pts) Overall progression was low But, only 8% remained NED at 30 months Steinberg G et al. J Urol. 2000;163:761-7.

Valrubicin: Take Home Message FDA-approved for patients with CIS who fail BCG and are unfit or unwilling to undergo a radical cystectomy Despite FDA approval, long-term DFS remains poor and highlights the need for additional bladder-conserving therapies

Gemcitabine Trials Inhibits DNA synthesis Introduced by Dalbagni (2002) as safe Efficacy demonstrated in multiple Phase II trials with BCG naïve and some failure patients Brooks NA & O Donnell MA: Indian J Urol. 2015; 31: 312-319

Gemcitabine: SWOG S0353 U.S. Phase II Trial 47 patients all failed least 2 prior courses of BCG 89% high risk (HG Ta, T1 and/or CIS); 60% CIS Received 2 grams in 100cc NS q week x 6 weeks and the q month x 10 months Results: Recurrence-free 3 months: 47% CR 12 months: 28% CR 24 months: 21% CR Skinner J Urol 190:1200, 2013

Taxane Trials Inhibits microtubule depolymerization Introduced in BCG failures by McKiernan (2006) with no dose-limiting toxicity at 75 mg Efficacy demonstrated in several Phase I / II studies, most with some form of maintenance Brooks NA & O Donnell MA: Indian J Urol. 2015; 31: 312-319

Docetaxel 54 patients All failed prior BCG 22 had only one prior course 83% high grade, 53% with CIS Recurrence-free Survival DFS at 12 months = 40% DFS at 36 months = 25% Barlow et al, J Urol 189:834, 2013

Paclitaxel - Nanoparticle albumin bound (Nab) Phase II study of 28 patients recurrent Tis, T1 and Ta who failed at least 1 cycle of BCG 6 weekly nab-paclitaxel 500 mg/100 ml, and monthly maintenance for 6 months CR 35% at 6 mo RFS 1 year: 35% RFS 2 years: 31% McKiernan et al, J Urol. 2014; 192:1633-8

Combina(on Gem/Docetaxel 45 patients treated over 5 years Induction only TaLG (4); TaHG (13)CIS (20); T1HG (8) Steinberg, et al Bladder Cancer 1:65, 2015

Hyperthermia Delivery of hyperthermic chemotherapy with temp 41-44 C Mechanism: -Direct cytotoxic effects -Enhanced penetration of chemo agent Hyperthermia Denatured Unfolded Protein Heat Shock Proteins Signal to Natural Killer Cells Cancer cell with Mitomycin C delivered at 43 C VasodilaCon Activated Heated Chemotherapy Agent Increased Intracellular Concentration of Chemotherapy Agent Damaged Impaired DNA Increased Permeability of Cell Membrane

MMC and Hyperthermia 160 patients: 129 (80.6%) BCG failures from a combined 10- year single center experience MMC induction plus maintenance Median F/U 75 months RFS: 60% (1 year) RFS: 47% (2 years) Progression to MIBC: 4.3% 6.3% discontinued due to side-effects Arends TJH et al. J Urol 2014

Hyperthermia Systems Synergo Intravesical microwave applicator 5 thermocouplers deliver hyperthermia to the bladder via direct contact Combat BRS Bladder Recirculation System External warmer van der Heijden AG et al. Eur Urol 2004 Souas A et al. Int J Hyperthermia 2014

Photodynamic Therapy PDT involves the administra5on of a photosensi5zing agent with ac5va5on of the agent by light at the appropriate wavelength 5 ALA HAL Radachlorin Phase 1 Trials Brooks NA & O Donnell MA: Indian J Urol. 2015; 31: 312-319

BCG BCG Unresponsive Unresponsive Clinical Trials Trials

BCG refractory or unresponsive CIS Initial CR rate of 50% at 6 months Durable response rate of 30% at 12 months and 25% at 18 months BCG refractory or unresponsive papillary disease: Recurrence-free rate of 30% at 12 months and 25% at 18 months FDA 2018, Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

BCG Unresponsive Ad-IFN (FKD/SUO Clinical CTC) Trials A Phase III, Open Label Study to Evaluate the Safety and Efficacy of INSTILADRIN (rad-ifn/syn3) Administered Intravesically to PaMents with High Grade, BCG Unresponsive, NMIBC PI Steve Boorjian Primary aim: To evaluate the incidence of HG Event-Free Survival at 12 months Treatment: Ad/IFN 3 x 1011 vp/ml, 135paMents; 35 responding paments at 12 months (RR 25.2%, 95% CI = [18.1%, 33.4%])

S1605: Phase 2 Trial of Atezolizumab Rationale: High risk NMIBC responds to immunotherapy PDL1 is expressed in NMIBC (Inman et al. Cancer 2007) Encouraging results in metastatic disease (Powles et al. Nature 2015, Rosenberg et al. Lancet 2016) Hypothesis: checkpoint molecules facilitate immune evasion in BCG-unresponsive NMIBC and this can be overcome with checkpoint inhibitors

Keynote-057: Phase 2 Pembrolizumab de Wit, R: (Abstract #8640),ESMO 2018

Keynote-057: Phase 2 Pembrolizumab de Wit, R: (Abstract #8640),ESMO 2018

Conclusions and Clinical Pearls BCG induction + maintenance is a standard for high risk NMIBC Despite BCG therapy, a subgroup of patient will be unresponsive BCG 5+2 is considered minimum adequate therapy for Ta/CIS BCG unresponsive disease HG T1 after BCG induction CIS within within 6 months of last BCG HG Ta/T1 within 6 months of last BCG

Conclusion and Clinical Pearls Conclusions and Clinical Pearls If > 1 year from BCG, a0empt BCG again If unresponsive to BCG: consider Radical Cystectomy If unwilling or unfit for radical cystectomy Clinical trial preferred If HG Ta, intravesical chemotherapy (gemcitabine) For CIS, consider valrubicin AnIcipate FDA approval of new agents in the very near future

Stephenson Stephenson Cancer at OU Cancer Health Sciences Center Center