Optimising the management of non-muscle invasive bladder cancer from diagnosis to cure. Dr Richard Savdie Uro-Oncology Fellow BSc MBBS FRACS

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1 Optimising the management of non-muscle invasive bladder cancer from diagnosis to cure Dr Richard Savdie Uro-Oncology Fellow BSc MBBS FRACS Objectives 1. Explore best practice diagnostic techniques 2. Define the patient most at risk of recurrence and progression 3. Optimising intravesical therapies 4. Update on BCG refractory disease in 2015

2 NMIBC 70,000 new cases of bladder cancer in the US annually. 15,000 deaths 70% of all new cases are NMIBC Most expensive cancer to treat from diagnosis to death Canadian Cancer Statistics 2015, predicted Initial evaluation for NMIBC has not changed much Haematuria work up Flexible Cystoscopy TURBT

progression to muscle invasive cancer at a rate of 25% to

3 Recurrence remains high Progression is a life threatening event High risk NMIBC carries a high probability of progression to muscle invasive cancer at a rate of 25% to 50% within 5 years of diagnosis. 15 year follow up for High Risk NMIBC:

4 Carcinoma in situ Without treatment, 54% of patients will progress to muscle invasive disease With BCG treatment, approximately 10-20% of complete responders eventually progress to muscle-invasive disease, compared with 66% of non-responders Losa et al J Urol 2000 Making the diagnosis. What s new in the guidelines on NMIBC 2015?

5 2015 update Monopoly vs Bipolar resection Bipolar cause less diathermy artefact No difference in obturator kick, bleeding, operative time, hyponatremia RCT, single centre, 147 patients Venkatramani et al J Urol June 2014

6 Mild cautery artifact Severe cautery artifact 2015 update

7 Prostatic urethral biopsy When? : (1) in positive cytology, negative cystoscopy (2) In the setting of high risk disease Why? Important predictor of muscle invasive disease Huguet et al Eur Urol 2005 showed it was the only predictor of muscle invasive disease in those failing BCG and going on to cystectomy Recommend resecting at 5 and 7 O clock from BN to Veru Random bladder biopsies should be taken systematically

8 2015 update Repeat TURBT reduces recurrence rates Sfakianos et al J Urol 2014 n = 1021, retrospective review of those who had BCG for NMIBC (MSK) Graph image Recurrence rates at 3 mo: Single TURBT - 43% ; Repeat TURBT - 9.6%. Recommend within 6 weeks for high risk pts (High grade Ta, any T1)

Repeat TURBT improves progression free survival Sfakianos JUrol 2014 Divrik et al Eur Urol 2010 Experience at TURBT influences recurrence rate When compared to

9 Repeat TURBT improves progression free survival Sfakianos JUrol 2014 Divrik et al Eur Urol 2010 Experience at TURBT influences recurrence rate When compared to experienced surgeons, younger surgeons more likely to: leave residual tumour ( OR 7.5) lack muscle in the specimen (OR 8.5) Mariappan Eur Urol 2010 Mariappan BJUI 2012

10 Importance of muscle in the specimen Chamie K et al, Cancer 2014

Photodynamic diagnostic cystoscopy (Fluorescence)( HAL) Richards et al J Urol 2014 PDD cystoscopy metaanalysis Prospective pooled data :1345 patients PDD detected significantly more tumours than WL

11 Photodynamic diagnostic cystoscopy (Fluorescence)( HAL) Richards et al J Urol 2014 PDD cystoscopy metaanalysis Prospective pooled data :1345 patients PDD detected significantly more tumours than WL Ta tumors (14.7%, p<0.001) CIS lesions (40.8%, p<0.001) In 26.7% of cases, CIS detected by FC alone (p<0.001) Recurrences significantly lower with FC 34.5% vs 45.4% (p=0.006) Burger M et al Eur Urol 2013

12 Narrow Band Imaging (NBI) Olympus technology Enhances view of blood vessels and therefore tumours because of their increased microvasculature NBI improves recurrence free survival Herr H Eur Urol 2015

13 Pathology reporting Importance of consistency among reporters Standard terminology Grade 1,2,3 vs LG/HG (use both) Mention of muscle

14 Urinary markers are not yet recommended to replace cytology and cystoscopy in surveillance of NMIBC Defining the patient most at risk of recurrence and progression

15 EAU guidelines 2015 risk stratification Task #4: The revised European Association of Urology Guidelines includes multifocal, frequently recurrent, large volume (>3cm) TaG1,G2 disease in the high risk category for progression. There was consensus that these patients have approximately half the progression compared to TaHG and thus should remain in EAU intermediate risk category.

Risk stratification: AUA Group Features Low Risk small volume, low grade Ta Low risk with concerning features High risk Multifocal /large volume, LGTa, and or

16 Risk stratification: AUA Group Features Low Risk small volume, low grade Ta Low risk with concerning features High risk Multifocal /large volume, LGTa, and or recurrent Initial patient with HG Ta, T1, or CIS High risk with concerning features patient with HG Ta, T1, or CIS that has recurred after initial therapy EORTC risk tables

17 EORTC bladder calculator CUETO risk calculator for BCG treated

18 Residual disease at repeat TURBT Herr J Urol 2007 LVI in the tumour specimen Significantly lower DSS if present in TURBT Streeper BJUI 2009

High risk features on TURBT Andius et al Urology 2007 121 patients T1 disease Median F/U 15 yrs in those surviving Vasc invasion and solid tumour most significant

19 High risk features on TURBT Andius et al Urology patients T1 disease Median F/U 15 yrs in those surviving Vasc invasion and solid tumour most significant prognostic factors Variant histology does worse micropapillary, plasmocytoid, nested, sarcomatoid, squamous and adeno variants of urothelial carcinoma Black et al Urol Oncol 2009

20 Micropapillary T1 does not respond to BCG as well 40 patients 75 % recurred 45% progressed to T2 Median time to progression 8 months Willis et al 2014

Guidelines EAU and AUA Delayed vs Early cystectomy in recurrent high risk NMIBC Included both noninvasive and invasive disease Rationale for early : Problem of

21 Guidelines EAU and AUA Delayed vs Early cystectomy in recurrent high risk NMIBC Included both noninvasive and invasive disease Rationale for early : Problem of Under staging :27-51% of patients being upstaged to muscleinvasive tumour at RC Late failures: poor prognosis Excellent survival rates for T1/Tis Herr J Urol 2001

22 Management summary Optimisation of Intravesical therapies

A single, immediate post operative instillation of intravesical chemotherapy Three large meta-analyses of collectively over 7000 patients have shown the reduction in recurrence over TURBT alone MMC,

23 A single, immediate post operative instillation of intravesical chemotherapy Three large meta-analyses of collectively over 7000 patients have shown the reduction in recurrence over TURBT alone MMC, epirubicin and doxorubicin have all shown benefit with no difference between groups Which subgroup benefits most not known, but some evidence it is the low risk Sylvester J Urol 2004 Abern J NAtl Compr Canc Netw 2013 Perlis Eur Urol 2013 BCG refractory disease

24 Reduced dose BCG and interferon multicenter phase II trial : 213 patients Rosevear et al J Urol 2014 Improving BCG delivery The presence of leukocyturia, non-visible haematuria or asymptomatic bacteriuria is not a contraindication for BCG application, and antibiotic prophylaxis is not necessary in these cases Herr HW. Outpatient urological procedures in antibiotic-naive patients with bladder cancer with asymptomatic bacteriuria. BJU Int 2012 Dec;110(11 pt B):E Herr HW. Intravesical bacillus Calmette-Guérin outcomes in patients with bladder cancer and asymptomatic bacteriuria. J Urol 2012 Feb;187(2):435-7.

25 BCG strain The EORTC meta-analysis suggested no large differences in efficacy between various BCG strains [162]. Recently published smaller studies without maintenance demonstrated some differences between strains. This clearly needs further evaluation in prospective trials Sylvester J Urol 2002 Improving BCG delivery In their meta-analysis, Böhle et al. concluded that at least one year of maintenance BCG is required to obtain superiority of BCG over MMC for prevention of recurrence or progression (LE: 1a).

26 Improving BCG delivery In a RCT of 1,355 patients, the EORTC has shown that when BCG is given at full dose, 3 years maintenance reduces the recurrence rate compared to one year in highbut not in intermediate-risk patients. There were no differences in progression or overall survival. In the 3-year arm, however, 36.1% of patients did not complete the 3- years schedule (LE: 1b) Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU Cancers Group randomized study of maintenance bacillus Calmette-Guérin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol 2013 Potential causes of BCG failure postulated Host immune incompetence Inadequate TUR or occult invasive disease Resistant or non-antigenic tumour Inadequate treatment schedule Inadequate dose: too few CFUs Inadequate contact or dwell time Excess BCG inducing immunosuppression

27 Intravesical therapies after BCG failure Chemotherapy Immunotherapy Valrubicin Gemcytabine MCNA BCG +/- IFN Docetaxel Mitomycin Historical Treatment of BCG failure Dinney C

28 Cytokines and BCG response Can differentiate those who are responding and those who are not. Responders shown to have higher levels of BCG induced cytokines after induction Magnitude of cytokine response correlates with recurrence rate and time to recurrence Changes in Il-2, Il-6 and Il-8 4 hours after BCG injection

Tumour immune microenvironment predicted response Th2 vs. Th1 lymphocyte polarization of the tumor immune microenvironment.

29 Predicting response to BCG in CIS BCG is a Th1-polarizing immunotherapy correlate the pretreatment immunologic tumor microenvironment (Th1 or Th2) with response to therapy IHC used to assess Th1vs Th2 on tumour tissue obtained at biopsy Tumour immune microenvironment predicted response Th2 vs. Th1 lymphocyte polarization of the tumor immune microenvironment. (G/T ratio = GATA-3+ lymphocytes/t-bet+ lymphocytes) among BCG responders and nonresponders. AUC 0.94 Nunez-Nateras Urol Oncol 2014

30 Improving MMC delivery 40 mg in 20 ml sterile water Fasting, limit water intake Au et al JNCI 2001 Level 1b Sodium bicarbonate 1.3 gm morning prior to treatment to alkalinise urine 60 min dwell time vs 30 mins? (LE 3) Hyperthermia or EMDA (LE 2b) Hyperthermia Lammers et al Eur URol 2011

31 Hyperthermia 160 patients : 129 ( 80.6%) BCG failures collected over 10 years MMC induction plus maintenance Median followup 75 months RFS: 60% (1yr) ; 47% (2 yrs) Progression to MIBC : 4.3% (cf 17% 5yr progression in high risk group) 6.3% discontinued due to AEs Arends J Urol 2014 EMDA (Electro-motive Drug administration)

32 BCG and MMC sequenced therapy Di Stasi Lancet Oncology 2006 EMDA vs PD MMC vs TURBT alone Di Stasi Lancet 2011

33 Clinical trials in NMIBC A multitude of clinical trials in NMIBC

34 Building on the success of BCG Bioniche - Mycobacterial Cell Wall-Nucleic Acid Complex BCG vaccination: PRIME - Trial recombinant BCG e.g. van Rhijn and Rentsch: lysteriolysin BCG + Mitomycin sequential e.g. EMDA Di Stasi 2006 concomitant e.g Svatek 2014 MMC followed by BCG in same session - potentiation? Efficacy and safety of MCNA in patients with NMIBC at high risk for recurrence and progression after failed BCG Intravesical MCNA weekly for 6 weeks then 3 weekly at 3, 6, 12, 18 and 24 months Primary endpoint is DFS at 1 year 129 patients; 91 CIS, with or without papillary, 38 papillary only 107 BCG-refractory: 68 received >1 induction course Median Follow up 34.7 months Morales et al J Urol 2014

35 Mycobacterial cell wall complex ( Urocidin) 1 yr DFS Papillary 35.1% CIS 21% 2 yr DFS - 19% Papillary 32% Durable response: 32.7 months in responders PFS 77.7% at 3 yrs MCNA well tolerated with few AEs Morales et al J Urol 2014

Immunotherapy checkpoint inhibitors anti-pd1/pdl1 industry-led and co-operative group trials Phase I (safety) trial of Pembrolizumab in combination with BCG in high risk NMIBC (NCT02324582) Phase II

Atezolizumab+ + + + Phase$2$trial$of$Atezolizumab$in$BCGGunresponsive$NMIBC$ q+3+weeks+ registrahon+within++ 6+weeks+of+TURBT+ start+therapy+within++ 5+days+of+registraHon++ Atezolizumab+ cysto+

38 Immunotherapy checkpoint inhibitors anti-pd1/pdl1 industry-led and co-operative group trials Phase I (safety) trial of Pembrolizumab in combination with BCG in high risk NMIBC (NCT ) Phase II trial of Atezolizumab ( MPDL 3280A ) Pre cystectomy neoadjuvant Rx Endpoints : Intratumoral CD3 T cell density, Path T0 rate BCG+ unresponsive+ Ta/T1/Tis+ (TURBT)+ + + Atezolizumab+ Atezolizumab+ + Atezolizumab Phase$2$trial$of$Atezolizumab$in$BCGGunresponsive$NMIBC$ q+3+weeks+ registrahon+within++ 6+weeks+of+TURBT+ start+therapy+within++ 5+days+of+registraHon++ Atezolizumab+ cysto+ cytol+ + 9+weeks*+ Atezolizumab+ Atezolizumab+ + Atezolizumab+ q+3+weeks+ Atezolizumab+ cysto+ biopsy+ cytol+ Atezolizumab+ maintenance+ q3wks+for++ 9+cycles+ CR$@$$ 21$weeks*$ (=6$months$post$TURBT)$ surveillance+ for+18+ months+ RFS$@$18$ months$ *+Hme+is+relaHve+to+first+dose+of+atezolizumab+

A Randomized, Prospective, Phase II Study to Determine the Efficacy of Bacillus Calmette-Guerin (BCG) Given in Combination With PANVAC[TM] Versus BCG Given Alone in Adults With High Grade NMIBC Who

39 A Randomized, Prospective, Phase II Study to Determine the Efficacy of Bacillus Calmette-Guerin (BCG) Given in Combination With PANVAC[TM] Versus BCG Given Alone in Adults With High Grade NMIBC Who Failed at Least 1 Induction Course of BCG PANVAC, has been shown to induce a CD4 and CD8 antigenspecific immune response against the tumor-associated antigens (TAAs), carcinoembryonic antigen (CEA) and mucin-1 (MUC-1) Phase II : Dec Jan 2019 Disease free survival PANVAC + TICE vs TICE alone ( SWOG protocol induction +maintenance) Hyper-Branched Polyglycerol UBC initiated Sitka Biopharma Currently in Trial design for phase 1/2

rad-ifnα2b (Instiladrin ) Currently in phase 2

$refractory NMIBC Phase 2b, Trial of$ Intermediate-Risk Superficial Bladder Cancer

that carries the gene for the diphtheria toxin

40 rad-ifnα2b (Instiladrin ) Currently in phase 2 trials (NCT ) RFS after 4 cycles in BCG refractory NMIBC Phase 2b, Trial of Intravesical DTA-H19/PEI in Patients With Intermediate-Risk Superficial Bladder Cancer DTA-H19, is a doubled stranded DNA plasmid that carries the gene for the diphtheria toxin A (DT-A) chain under the regulation of the H19 promoter sequence.

41 Questions?

Management of High-Risk Non-Muscle Invasive Bladder Cancer. Seth P. Lerner, MD, FACS

Management of High-Risk Non-Muscle Invasive Bladder Cancer Seth P. Lerner, MD, FACS Professor of Urology, Beth and Dave Swalm Chair in Urologic Oncology, Scott Department of Urology, Baylor College of