BC G Unresponsive Non- Muscle Invasive Bladder Cancer Seth P. Lerner, MD, FACS Professor of Urology Beth and Dave Swalm Chair in Urologic Oncology ScoA Department of Urology Baylor College of Medicine, Houston, Texas InternaHonal Bladder cancer Update January 24, 2017
Disclosures Clinical trials Endo, FKD, VivenHa NCI/SWOG Roche/Genentech, JBL Advisory Board Ferring Consultant Biocancell, UroGen, Vaxiion 3
Learning Objec=ves To understand current status and outcomes with BCG To describe post BCG treatment states and specifically BCG unresponsive disease To understand current Guideline statements To understand which pahents should be treated with salvage radical cystectomy To apply appropriate decision making regarding the use of salvage intravesical therapy To be aware of clinical trial ophons 4
BCG Indica=ons Any pahent with high risk NMIBC TaHG, T1, Tis; mulhfocal and recurrent and >3cm TaLG First occurrence standard of care Recurrent BCG naïve BCG failure (induchon) if no indicahon for cystectomy or medically unfit FDA approved for CIS and high risk Ta,T1 5
Standard of Care SWOG 8507 - BCG Maintenance Recurrence- Free Survival 2 year RFS 82% vs. 62% p without < 0.0001 maintenance 5 year RFS 60% vs. 41% without maintenance Lamm, DL et al, J Urol 163:1124, 2000 6
Failure to Achieve a CR at 3 Months Status at 3 month cysto associated with outcome EORTC 30962 affirmed 3 years of maintenance as standard of care for high risk NMIBC Lerner, et al Secondary analysis of SWOG 8507 Urologic Oncology 27:155, 2007 7
Outcomes Following BCG Table 3 Multivariable analysis of disease-related variables and the associated risk of treatment failure in BCG failure patients with (A) any recurrent CIS or (B) recurrent pure papillary disease treated with intravesical BCG/IFN. (N denotes sample size) Note: # signifies that there was no significant difference between these two groups (A) Treatment Failure Level N HR 95% CI P-value Number of Prior BCG Courses 2 courses 43 2.74 1.54 4.86 <.01 1 courses 55 Ref Prior BCG Failure Interval <6 Months 47 2.59 1.26 5.35 <.01 # 6 12 Months 23 2.29 1.03 5.08 0.04 >12 Months 28 Ref Total 98 (B) Treatment Failure Kaplan-Meier plot of treatment success of intravesical BCG/IFN in BCG Failure patients with recurrent CIS stratified by prior BCG failure interval and number of prior BCG failures including number at-risk. Images in this article Both prior BCG therapy and interval from last BCG are independently associated with recurrence probability Steinberg, et al Bladder Cancer 2:215, 2016 8
FDA/AUA/SUO Guidance Urology 83:262, 2014 3/30/2015 10/26/2015 9
BCG Unresponsive high risk NMIBC Recurrent/persistent high grade urothelial carcinoma ajer complehon of at least induchon 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 evaluahon ajer induchon BCG at least 5 of 6 induchon doses These pahents are extremely unlikely to respond to further BCG Lerner et al, Bladder Cancer 1:29, 2015)
Consider Extravesical Sites RetrospecHve analysis of 110 pahents with high- risk disease and BCG NMIBC repeatedly treated with intravesical BCG, No maintenance 52% had UUT and/or urethral carcinoma 48% had intravesical recurrence alone 11
Biopsies of the Prosta=c Urethra TUR biopsies at 5 and 7 o clock adjacent to the verumontanum detect CIS Verumontanum P ducts CIS 12
Importance of Prosta=c Urethra BCG treatment failed in 62 high- risk cases; pahents underwent cystectomy ProstaHc urethra TCC most important predictor of muscle- invasive cancer Hazard raho, 12.2 (2.2-65.5) P =.003 Sampling from the urethra in high- risk pahents is essenhal T2 <T2 Huguet J, et al. Eur Urol. 2005;48:53-59. 13
Case 60yo male Prior history of NMIBC treated with BCG During workup for right ureter stricture PosiHve bladder wash cytology high grade Suspicious renal pelvis washing ureteroscopy negahve Cystoscopy no obvious papillary tumors Bladder biopsies - mulhfocal CIS of the bladder 14
Case (con=nued) ProstaHc urethra biopsies Duct and acinar CIS Minimal invasion peri- ductal soj Hssue RC + eplnd Path: Extensive bladder CIS pt0n0 (0/30) with CIS prostahc ducts/no invasion 1/25/17 15 Baylor College of Medicine
Cystectomy is the Standard of Care for Pa=ents Who are Medically Fit 16
Cystectomy is the Standard of Care for Pa=ents Who are Medically Fit ICUD 2012 The threat of progression remains real but comfortably low enough within the first 6 months of inihahng BCG to consider alternahves to cystectomy for those pahents unfit or not willing to undergo this standard management ophon (LOE 2, Grade B). In the case of any BCG non- response or failure, cystectomy is recommended (LOE 2a, Grade A). 17
Early vs. Delayed Cystectomy 105 pts, T1G3 with at least 2 risk factors CIS, large tumor, mulhfocality) 51 refused cystectomy and treated with BCG. All ulhmately had a delayed cystectomy (avg 11 months later) Cystectomy done at first sign of recurrence T1 or TIS or T2 (34%) Ø 5 yr CSS 83% vs. 67% Ganzinger Eur Urol 53:146, 2008 18
Cystectomy in BCG Failure for CIS Long- term cancer control rates ophmal with RC n=52 with CIS only at the =me of RC All pahent underwent extended LND to IMA No pahent had lymph node metastasis 5- and 10- year RFS rates were 94% and 90%, Zahnder, et al BJU Int. 2014 Jan
When BCG Fails the PaHent BCG/IFN Valrubicin only FDA approved drug Gemcitabine OpHmized MMC Gem/MMC Gem/Docetaxel Clinical trial 20
BCG plus Interferon Alpha MulHcenter phase II trial 213 pahents with CIS Ø PaHents with 2 or more prior courses of BCG or BCG- refractory did worse Rosevear, JUrol 186:817, 2011 21
Valrubicin 80 pahents with CIS 39% had at least 2 prior courses of BCG Received 6 or 9 weeks of Valstar 35% NED at 3 months THINK (posihve cytology allowed) CR at 6 months 18% 7% disease free at 2 years Dinney et al Urol Onc 31:1635,2013
Gemcitabine SWOG S0353 47 pahents all failed 2 courses BCG 89% high risk, 60% CIS 6 weekly treatments 2g in 100cc, then monthly x 12 Results: Ø 47% NED at 3 months Ø 28% conhnuously disease- free at 12 mos Skinner J Urol 190:1200, 2013 23
Docetaxel 54 pahents All failed prior BCG 22 had only one prior course 83% high grade, 53% with CIS Recurrence- free Survival Barlow et al, J Urol 189:834, 2013
Device- assisted Chemotherapy Synergo microwave with MMC 1 51 pahents with CIS 34 failed prior BCG, 17 refractory (not reported separately) CR at 3 months 88% 22/45 (49%) recurred with median f/u 22 months 6 cystectomies ElectromoHve MMC (EMDA) promising US trials in BCG- recurrent pahents in planning phase 1 Witjes et al World J Urol 2009;27:319 25
Combina=on Chemotherapy 1g gemcitabine, then 40 mg MMC (sequenhal, 90 min each) 47 pahents - 76% intermed/high risk, 55% CIS - 17 no prior BCG (10 immunocompromised) - 55% >2 prior courses BCG 68% CR at 3 months 48 % NED at 1 year 38% NED at 2 years (20-25% for HG/CIS) CIS All pa=ents High grade Lighroot AJ, Urol Oncol 32:35, e15 2014
Gemcitabine/Docetaxel 45 pahents treated over 5 years InducHon only TaLG (4); TaHG (13) CIS (20); T1HG (8) 66% 54% 33% Steinberg, et al Bladder Cancer 1:65, 2015 27
Dra] FDA Guidance November 2016 28
Clinical Trial Design FDA Guidance Randomizing pahents with BCG- unresponsive disease to a minimally effechve drug as a concurrent control raises ethical concerns. Because effechve drugs are not available and the alternahve treatment is cystectomy, single- arm trials of pahents with BCG unresponsive CIS disease with or without papillary disease are appropriate. Primary endpoint should be complete response in pahents with CIS 29
Clinical Trials Ad- IFN gene therapy (FKD) SUO- CTC Viccinium (VivenHa) Atezolizumab (SWOG S1605 - Roche/GNE) Pembrolizumab (Merck) ABI- 009 Phase I/II (AADi LLC) Cabazitaxel, gemcitabine, and cisplahn Phase I (Columbia) BGJ 398 FGFR targeted therapy (MSKCC) ChemoXRT for T1 (RTOG 0926) 30
Ad- IFN (FKD/SUOCTC) A Phase III, Open Label Study to Evaluate the Safety and Efficacy of INSTILADRIN (rad- IFN/ Syn3) Administered Intravesically to PaHents with High Grade, BCG Unresponsive, NMIBC PI - Boorjian Primary aim: To evaluate the incidence of HG Event- Free Survival at 12 months Treatment: Ad/IFN 3 x 1011 vp/ml135 pahents; 35 responding pahents at 12 months (RR 25.2%, 95% CI = [18.1%, 33.4%])
Ad- IFN (FKD/SUOCTC) Intravesical dosing at 3 month intervals x 4; mos 1,4,7,10 Responding pahents may conhnue treatment year 2
S1605: Phase 2 trial of Atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer. (PI Peter Black) Rationale: High risk NMIBC responds to immunotherapy PDL1 is expressed in NMIBC 1 Encouraging results in metastatic disease 2,3 Hypothesis: checkpoint molecules facilitate immune evasion in BCG-unresponsive NMIBC and this can be overcome with checkpoint inhibitors 1 Inman et al, Cancer 2007 2 Powles et al, Nature 2015 3 Rosenberg, Lancet 2016
Study Scheme BCG unresponsive Ta/T1/Tis (TURBT) Atezolizumab Atezolizumab Atezolizumab q 3 weeks Atezolizumab registration within 6 weeks of TURBT start therapy within 5 days of registration cysto cytol Atezolizumab Atezolizumab Atezolizumab Atezolizumab cysto biopsy cytol Atezolizumab maintenance q3wks for 9 cycles q 3 weeks 9 weeks* CR @ 21 weeks* (=6 months post TURBT) surveillance for 18 months RFS @ 18 months * time is relative to first dose of atezolizumab
Take Home Message High risk disease any high grade Ta or T1 and any CIS BCG standard of care Maintenance therapy improves recurrence and progression- free survival No role for Interferon in BCG naïve pahents May be beneficial as salvage therapy 35
Take Home Message BCG Failure and Unresponsive states are high risk for understaging and progression to muscle invasive disease Radical cystectomy has a high probability of long term cancer control Intravesical therapy and clinical trials of new agents are appropriate for those pahents who do not need immediate cystectomy, refuse or are medically unfit for cystectomy 36
Aims & Scope Editors-in-Chief Seth P. Lerner Scott Department of Urology Baylor College of Medicine Houston, Texas, USA Email: blc@iospress.com Dan Theodorescu University of Colorado Cancer Center Aurora, Colorado, USA Email: blc@iospress.com To view the full Editorial Board, please visit: www.iospress.com/bladdercancer/?tab=editorial-board Bladder Cancer Bladder Cancer is an international multidisciplinary journal to facilitate progress in understanding the epidemiology/etiology, genetics, molecular correlates, pathogenesis, pharmacology, ethics, diagnosis and treatment of tumors of the bladder and upper urinary tract. The journal publishes research reports, reviews, short communications, and lettersto-the-editor. In addition, the journal will also have a News and Views section for timely commentary. The journal is dedicated to providing an open forum for original research in basic science, translational research and clinical medicine that will expedite our fundamental understanding and improve treatment of tumors of the bladder and upper urinary tract. Journal Information ISSN 2352-3727 (print) ISSN 2352-3735 (online) The first issue (1:1) to be published in 2015 Open Access author fees waived for 2015 and 2016 In 2015 and 2016 freely available online Call for Papers Submit Your Article Submit manuscripts electronically via the mstracker online submission system at: http://mstracker.com/submit1.php?jc=blc For detailed author instructions please visit our website: www.iospress.com/bladder-cancer/?tab= submission-of-manuscripts www.iospress.com/bladder-cancer