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
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
CASE 1 • 73yo man with gross hematuria 3
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 4
AUA NMIBC Risk Groups TABLE 4: AUA Risk Stratification for Non-Muscle Invasive Bladder Cancer Low Risk Intermediate Risk High Risk LG a solitary Ta ≤ 3cm Recurrence within 1 year, LG Ta HG T1 PUNLMP b Solitary LG Ta > 3cm Any recurrent, HG Ta LG Ta, multifocal HG Ta, >3cm (or multifocal) HG c Ta, ≤ 3cm Any CIS d LG T1 Any BCG failure in HG patient Any variant histology Any LVI e Any HG prostatic urethral involvement a LG = low grade; b PUNLMP = papillary urothelial neoplasm of low malignant potential; c HG = high grade; d CIS=carcinoma in situ; e LVI = lymphovascular invasion 5
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 6
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 7
Joint Statement: BCG for High Risk For patients with high-risk NMIBC, high-grade T1 and CIS • patients receiving induction therapy, they should be ength BCG . If not available, prioritized ed for use e of full-stren 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. 8
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
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.
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 options include mitomycin gemcitabine, epirubicin, docetaxel, valrubicin or sequential gemcitabine/docetaxel or gemcitabine/mitomycin • Consider RC T1HG + CIS, LVI, P urethra, variant histology.
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
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
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
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
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
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
BCG Phylogeny and Rationale for Strain Differences Rationale for Strain evaluation : Differences in genotype/phenotype between BCG substrains could influence antitumor efficacy. Recurrence-free survival (%) BCG Connaught (n=71) BCG Tice (n=60) Rentsch, et al. European Urology 2015
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
S1602 (Prime) Trial Schema Intravesical BCG TICE (50 mg/dose) CIS, TA high grade, or T1 Intravesical BCG Randomize high grade urothelial bladder (Tokyo strain 80 mg/dose) cancer Prime : intradermal BCG (Tokyo strain 100 µl at 0.5 mg /ml) + Intravesical BCG (Tokyo strain 80 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 M erck agrees to supply Tice
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 • 21
Treatment failure BCG- unresponsive : new definition, 2015 must receive adequate BCG (5 of 6 doses induction) • HG T1 at first evaluation after adequate induction • 6 months of 2 Persistent/recurrent HG disease within 6 • 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 22
(-) cysto, maintenance BCG (-) cytology HG Ta induction HG T1 BCG repeat Tis HG Ta, Tis induction BCG (+) cysto and/or (+) cytology UNRESPONSIVE HG T1 23
Treatment failure BCG- unresponsive : revised definition, FDA 2018 Recurrent CIS +/- Ta or T1 within 12 months of completion • of 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 • 24
What are options now? 25
Recommend
More recommend
