[PPT] - Case-Based Discussion: Non-Muscle Invasive Bladder Cancer Se Seth PowerPoint Presentation

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Case-Based Discussion: Non-Muscle Invasive Bladder Cancer

Se Seth P. . Lerner MD; Gu Gui Go Godoy MD, , MPH; Jennifer Taylor MD, , MPH Urologic Oncology 13 September 2019

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Disclosures

S. Lerner
Clinical trials: Endo, FKD, JBL (SWOG), Roche/Genentech (SWOG), UroGen, Viventia
Consultant: BioCancell, UroGen, Vaxiion, Verity
Advisory Board: BioCancell, Ferring, miR Scientific, QED Therapeutics, UroGen
Honoraria: MSD Korea, Dava Oncology, Nucleix
G. Godoy
Clinical trials:
J. Taylor
Clinical trials: Photocure

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CASE 1

73yo man with gross hematuria

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CASE 1

1 ppd x 20 years, quit 1991
PMHx: Htn, DM (well-controlled)

>TURBT

Tumor was 3.4 x 3.0cm on CT scan, "large" by

endoscopic estimate.

Staging studies negative for adenopathy or metastasis
Path: HG T1 (neg MP) + CIS

>Re-TURBT

Path: pT0

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AUA NMIBC Risk Groups

TABLE 4: AUA Risk Stratification for Non-Muscle Invasive Bladder Cancer Low Risk Intermediate Risk High Risk LGa solitary Ta ≤ 3cm Recurrence within 1 year, LG Ta HG T1 PUNLMPb Solitary LG Ta > 3cm Any recurrent, HG Ta LG Ta, multifocal HG Ta, >3cm (or multifocal) HGc Ta, ≤ 3cm Any CISd LG T1 Any BCG failure in HG patient Any variant histology Any LVIe Any HG prostatic urethral involvement

aLG = low grade; bPUNLMP = papillary urothelial neoplasm of low malignant potential; cHG = high grade; dCIS=carcinoma in situ; eLVI = lymphovascular invasion

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CASE 1

AUA NMIBC Risk Group HIGH
AUA guidelines

Should consider perioperative intravesical chemotherapy Should give induction intravesical therapy (MMC/BCG) 3 years maintenance BCG if response with induction

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High-Risk NMIBC

BCG is first choice intravesical agent
What about in time of shortage??

https://www.bcan.org/2019-bcg-shortage-bladder-cancer/ https://www.auanet.org/about-us/bcg-shortage-info

Joint statement from AUA, SUO, AACU, LUGPA, BCAN

https://www.bcan.org/wp-content/uploads/2019/05/BCAN-Letter-Re-BCG-Shortage-for-Web.pdf

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Joint Statement: BCG for High Risk

For patients with high-risk NMIBC, high-grade T1 and CIS

patients receiving induction therapy, they should be prioritized ed for use e of full-stren ength BCG. If not available, these patients and other high-risk patients should be given a reduced 1/2 to 1/3 dose, if feasible.

If supply exists for maintenance therapy for patients with

NMIBC, every attempt should be made to use 1/3 dose BCG and limit dose to one year.

In the event of BCG supply shortage, maintenance therapy

should not be given and BCG-naïve patients with high-risk disease should be prioritized for induction BCG.

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BCG Supply

Connaught strain (Sanofi Pasteur) off line since 2012

then closed permanently in 2017

Merck manufactures Tice in a single plant in US for

global distribution in 70 countries

US market was 28 percent of the total product
increased production by more than 100 percent
In late 2016, at full capacity enables approximately 600,000

to 870,000 vials annually

January, 2019 begins allocation distribution

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Joint Statement-February 19, 2019

BCG should not be used for low-risk disease.
Intravesical chemotherapy first-line option for patients

with intermediate-risk NMIBC.

An alternative intravesical chemotherapy should be used for

second line intermediate risk disease

Patients with high-risk NMIBC prioritized for full-strength
BCG. If not available, dose reduce to 1/2 to 1/3
If supply exists for maintenance therapy for patients with

NMIBC, every attempt should be made to use 1/3 dose BCG and limit dose to one year.

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Joint Statement-February 19, 2019

BCG supply shortage: maintenance therapy should not

be given and prioritize induction for BCG-naïve patients with high-risk disease.

If BCG is not available: alternative chemotherapy
ptions include mitomycin gemcitabine, epirubicin,

docetaxel, valrubicin or sequential gemcitabine/docetaxel or gemcitabine/mitomycin

Consider RC T1HG + CIS, LVI, P urethra, variant

histology.

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BCG Supply – Merck Update

Producing TICE-BCG to the full extent of its manufacturing

capacity remains a top priority

Merck continues to explore alternatives that could potentially

increase production capacity in the future; however, this takes time due to the complexity of the manufacturing process.

Merck continues to work collaboratively with regulators,

including the FDA and European health authorities, as well as medical societies and patient advocacy networks, including the AUA, and BCAN; and healthcare practitioners.

Personal communication 08/6/2019

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BCG Dose Reduction

Sometimes less is better
An appropriate cytokine response can be

achieved with as little as 1/100 of a standard dose

Dose reduce in face of toxicity rather than

abandon potentially effective therapy

– 1/2, 1/3, 1/10, 1/30, 1/100

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EORTC 30962

No significant increase in toxicity with 3 years
vs. one year
Study did not meet pre-defined endpoint of

10% difference in recurrence rate (RR)

There was a difference in RR at the extremes

– 1 year vs. 3 year

Full Dose-3yrs had the highest disease-free

rate at 5 yrs while 1/3 Dose-1yr had the lowest

But…is low dose is better than no dose?

Oddens, et al Eur Urol 63:462, 2013

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AUA Split Dosing Policy

Split dosing is now supported by new HCPCS code

J9030 allowing billing for 1/mg BCG and replaces J9031 (1 vial/BCG) & became effective 7/01/2019.

But billing for 2+ patients for split vial use is not

approved by carriers as of 8/3/2019 – personal communication Neal Shore

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FDA

CBER has been diligently working with Merck to enable the

TICE BCG coming back on the market as soon as possible.

CBER has posted the shortage situation on its website as well as

in CBER communications to the public.

Recommend that BCAN or other advocacy group might want to

engage with any BCG manufacturer who would be interested to come to the US market.

FDA would certainly be willing to engage and communicate

with advocacy organizations in this regard.

Personal communication Chana Weinstock July 2019

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FDA – Clinical trials

No change in eligibility for BCG unresponsive disease defined as

patients who have received doses as specified in the FDA guidance with approved BCG strains.

Patients treated with lower doses of BCG and experiencing recurrent

NMIBC would not be considered as having received “adequate BCG treatment” and would not meet the definition of BCG unresponsive disease.

Despite these patients not meeting criteria for BCG unresponsive

disease, evaluation of these patients and their responses on study may still have clinical merit and whether these patients are included in trial is at the sponsor’s discretion.

Personal communication Chana Weinstock July 2019

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BCG Phylogeny and Rationale for Strain Differences

Rationale for Strain evaluation: Differences in genotype/phenotype between BCG substrains could influence antitumor efficacy.

BCG Connaught (n=71) BCG Tice (n=60) Recurrence-free survival (%) Rentsch, et al. European Urology 2015

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Health Canada

Verity
Russian strain produced by Serum Institute of India
File to supply BCG in Canada has been reviewed and

company optimistic about approval - expect answer within 30-60 days

Verity has made initial contact with FDA and plans to

set a date to review the Canadian file

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S1602 (Prime) Trial Schema

Randomize CIS, TA high grade, or T1 high grade urothelial bladder cancer Prime: intradermal BCG (Tokyo strain 100 µl at 0.5 mg /ml) + Intravesical BCG (Tokyo strain 80 mg/dose) Intravesical BCG (Tokyo strain 80 mg/dose) Intravesical BCG TICE (50 mg/dose) Treatment includes induction weekly for 6 weeks then maintenance with 3 weekly instillations at months 3, 6 and every 6 months to 3 years Merck agrees to supply Tice

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Back to CASE 1

Pt completed induction BCG, 6 doses, full-strength,

well-tolerated Cysto #1 without recurrence, cytology negative

Fluorescence cystoscopy available with flexible

cystoscope (Storz/Photocure), FDA approved spring 2018

Pt received maintenance BCG, 3 doses, full-strength

Cysto #2 with suspicious papillary tumor and erythema >TURBT

Path: HG Ta + CIS

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Treatment failure

BCG-unresponsive: new definition, 2015

must receive adequate BCG (5 of 6 doses induction)
HG T1 at first evaluation after adequate induction
Persistent/recurrent HG disease within 6

6 months of 2 courses of BCG (“5 + 2”)

iBCG (5/6 doses) and either [repeat iBCG 5/6] or [mBCG 2/3]
Our patient is now qualified as BCG-unresponsive

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HG Ta HG T1 Tis

(-) cysto, (-) cytology

maintenance BCG

(+) cysto and/or (+) cytology

HG Ta, Tis repeat induction BCG HG T1 UNRESPONSIVE

induction BCG

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Treatment failure

BCG-unresponsive: revised definition, FDA 2018

Recurrent CIS +/- Ta or T1 within 12 months of completion
f adequate BCG - (“5+2”)
Recurrent/persistent high grade Ta or T1 within 6 months of

completion of adequate BCG – no change

T1HG at first evaluation after induction BCG – at least 5 of 6

induction doses – no change

“Flexibility” in use of 6 and 12 month time

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What are options now?

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AUA Guidelines 2016

In a high-risk patient with persistent or recurrent disease within one year following treatment with two induction cycles of BCG or BCG maintenance, a clinician should offer radical cystectomy.

(Moderate Recommendation; Evidence Strength: Grade C)

Cystectomy is Standard of Care

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105 pts, T1G3 with at least 2 risk factors
CIS, large tumor, multifocality)
51 refused cystectomy and treated with BCG. All

ultimately had a delayed cystectomy (avg 11 months later)

Cystectomy done at first sign
f recurrence
T1 or TIS or T2 (34%)

Ø 5 yr CSS 83% vs. 67%

Ganzinger Eur Urol 53:146, 2008

Early vs. Delayed Cystectomy

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Alternatives (to Cystectomy) when BCG Fails the Patient

BCG/IFN – patients treated w/induction only
BCG unresponsive

– Valrubicin – only FDA approved drug – Gemcitabine – Optimized MMC – MMC + Heat or Microwave – Gem/MMC – Gem/Docetaxel

Clinical trial

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Valrubicin

80 patients with CIS

39% had at least 2 prior courses of BCG

Received 6 or 9 weeks of Valrubicin
35% NED at 3 months

(positive cytology allowed)

CR at 6 months 18%
4% disease-free at 2 years

Dinney et al Urol Onc 31:1635,2013

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Gemcitabine

SWOG S0353

47 patients all failed 2 courses BCG
89% high risk, 60% CIS
6 weekly treatments 2g in 100cc, then monthly x 12

*Alkalinize with NaHCO3 po

Results:

Ø 47% NED at 3 months Ø 28% continuously disease-free at 12 mos

Skinner J Urol 190:1200, 2013

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Docetaxel

Long term results of Phase I and II trials
54 patients BCG unresponsive
32 (59%)initial CR and 18 received

maintenance

Barlow et al J Urol 189:834, 2013

Recurrence-free survival With and without maintenance

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45 patients treated over 5 years
Induction only
TaLG (4); TaHG (13) CIS (20);

T1HG (8)

Steinberg, et al Bladder Cancer 1:65, 2015

66% 54% 33%

Hopkins – 33 patients
42% 2 year HG RFS

Fig.4

Kaplan-Meier plots of A) HG-RFS vs. DFS B) HG-RFS by HG vs LG pathology at therapy initiation C)

Milbar, et al Bladder Cancer 3:293, 2017

Gemcitabine/Docetaxel

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Device-assisted Chemotherapy

Synergo microwave with MMC1

51 patients 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

Electromotive MMC (EMDA) promising
US trials in BCG-recurrent patients in planning

phase

1 Witjes et al World J Urol 2009;27:319

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Clinical Trial Design FDA Guidance

Randomizing patients with BCG-unresponsive

disease to a minimally effective drug as a concurrent control raises ethical concerns.

Because effective drugs are not available and the

alternative treatment is cystectomy, single-arm trials of patients with BCG unresponsive CIS disease with or without papillary disease are appropriate.

Primary endpoint should be complete response

and durability in patients with CIS

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VICINIUM: A UNIQUE MECHANISM OF ACTION FOR TREATING HIGH-GRADE NMIBC

EpCAM (the target) is overexpressed in

>98% of high grade NMIBCs*, minimal expression on healthy bladder tissue

Stable, genetically engineered peptide

linker allows fusion protein to remain intact until internalized by cancer cell

Anti-EpCAM Ab fragment delivers toxin

that kills tumor cells by blocking protein synthesis

* Data generated in prior EBIO studies using internal antibody 5

Presented by Rian Dickstein AUA 2018

Vicinium – Antibody-drug Conjugate

Toxin is is a truncated form of Pseudomonas exotoxin A

Induction: twice weekly x 6 Maintenance: every other week up to 24 months

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Time point

Phase 3 Pooled CRR (95% CI) Phase 2 Pooled CRR (95% CI) 3-months 39% (29%, 49%) 40% (26%, 56%) 6-months 27% (18%, 37%) 27% (15%, 42%) 9-months 20% (12%, 29%) 18% (8%, 32%) 12-months 14% (7%, 23%) 16% (7%, 30%) CRR – Complete response rate

Courtesy Gary Steinberg

Preliminary Phase 3 CRR vs Phase 2 CRR

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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 NMIBC1
Encouraging results in metastatic disease2,3
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

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surveillance for 18 mo. BCG unresponsive Ta/T1/Tis (TURBT)

Atezolizumab

cysto cytol

Atezolizumab Atezolizumab Atezolizumab cysto biopsy cytol Atezolizumab Atezolizumab

Study Scheme

Atezolizumab

Atezolizumab maintenance q3wks for 9 cycles

RFS @ 18 months q 3 weeks CR @ 25 weeks* (=6 months post TURBT) q 3 weeks 13 wks*

registration within

6 weeks of TURBT

start therapy within

5 days of registration

* time is relative to first dose of atezolizumab

Atezolizumab Atezolizumab

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Patient Disposition: Cohort A CIS ± Papillary Disease

aIncludes patients in cohort A with CIS at baseline who at month 3 also had CIS ± papillary tumor. bIncludes all patients with any high-risk papillary disease (HG Ta or any T1, ± CIS) or progression beyond T1 at

assessment.

Median follow-up in cohort A:

14.0 months (range, 4.0-26.3 months)

Treatment ongoing in 32 (31.1%) patients

Cohort A (with CIS) N = 103 Ongoing n = 32 Treated N = 103 Discontinued, n = 71 Persistent disease,a n = 32 Recurrent disease,b n = 27 All AEs, n = 7 Drug-related AEs, n = 5 Physician decision, n = 3 Protocol violation, n = 1 Patient withdrawal, n = 1

de Wit KN057 ESMO 2018

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Response N = 103 N % 95% CI CR 40/41 38.8/40.2 29.4-48.9/30.6-50.4 Non-CR 57 55.3 45.2-65.1 Persistentb 47/41-6 45.6 35.8-55.7 NMIBC stage progressionc 9 8.7 4.1-15.9 Non-bladder malignancyd 1 1.0 0.0-5.3 Progression to T2 ― Nonevaluablee 6/4 5.8/3.9 2.2-12.2/1.1-9.7

Overall Response Rate at Month 3a

ESMO Nov 2018 vs GUASCO Feb 2019

aSummary of overall responses of high-risk NMIBC per central assessment at month 3 in all patients who received ≥1 dose of trial treatment, had baseline evaluations, and also had ≥1

postbaseline disease assessment. bDefined as patients with CIS at baseline who at month 3 also had CIS ± papillary tumor. cIncrease in stage from CIS and/or high-grade Ta at baseline to T1

disease. dDefined as presence of lesions suspicious for locally advanced or metastatic bladder cancer on imaging. dPatient developed new liver lesions on imaging and was later found to have a

second primary malignancy of pancreatic cancer. Subsequent review of the baseline scan showed subtle findings that, in retrospect, could be attributed to pancreatic cancer. ePatients whose protocol-specified efficacy assessments were missing or who discontinued from the trial for reasons other than PD are considered not evaluable for efficacy. Database cutoff: July 18, 2018.

54% maintain CR at 9 months

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Take Home Message

BCG Unresponsive state is unlikely to

respond to additional BCG ± IFN and is associated with increased risk for progression to muscle invasive disease

Radical cystectomy has a high probability
f long term cancer control and is

standard of care per current Guidelines

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Take Home Message

FDA in collaboration with multiple

stakeholders has defined a registration pathway via a single arm trial design with efficacy determined by initial and durable CR for CIS

Intravesical therapy and clinical trials of new

agents are appropriate for those patients who do not need immediate cystectomy, refuse or are medically unfit for cystectomy

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CASE 2

76yo woman with gross hematuria
No tobacco history

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CASE 2

3 tumors: 3-4cm, 3-4cm, 1cm (below)
Small papillary fronds seen emanating from U.O.
Diagnostic ureteroscopy done to clear distal ureter

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CASE 2

Path: all LG Ta
Staging studies negative

TABLE 4: AUA Risk Stratification for Non-Muscle Invasive Bladder Cancer Low Risk Intermediate Risk High Risk LGa solitary Ta ≤ 3cm Recurrence within 1 year, LG Ta HG T1 PUNLMPb Solitary LG Ta > 3cm Any recurrent, HG Ta LG Ta, multifocal HG Ta, >3cm (or multifocal) HGc Ta, ≤ 3cm Any CISd LG T1 Any BCG failure in HG patient Any variant histology Any LVIe Any HG prostatic urethral involvement

aLG = low grade; bPUNLMP = papillary urothelial neoplasm of low malignant potential; cHG =

high grade; dCIS=carcinoma in situ; eLVI = lymphovascular invasion

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CASE 2

AUA NMIBC Risk Group INTERMEDIATE
AUA guidelines (2016)

Should consider perioperative intravesical chemotherapy Should consider induction intravesical therapy (MMC/BCG) 1 year maintenance BCG if response with induction

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CASE 2

What to do in BCG shortage??
Joint statement

Intravesical chemotherapy should be used as the first-line option for patients with intermediate-risk NMIBC. Patients with recurrent/multifocal low-grade Ta lesions who require intravesical therapy should receive intravesical chemotherapy such as mitomycin, gemcitabine, epirubicin or docetaxel instead of BCG. If BCG would be administered as second-line therapy for patients with intermediate-risk NMIBC, an alternative intravesical chemotherapy should be used rather than BCG in the setting of this BCG shortage.

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Gem vs. MMC slides

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