Update of Definitions, End Points and Design of NMIBC Trials. IBCG - - PowerPoint PPT Presentation

Update of Definitions, End Points and Design of NMIBC Trials. IBCG Kamat A et al: J Clin Oncol. 2016 Jun 1;

34(16): 1935–1944. Don Lamm, MD Perspectives in Urology, PCP. November 14, 2019

Definitions of BCG Failure

• Adequate BCG treatment: SWOG 3 wk maintenance, at least

5/6 induction and 2/3 maintenance

• BCG refractory: increased grade or stage at 3 months or

persistence/recurrence at 6.

• BCG relapse: NED at 6, within 6 months of BCG, i.e maint.
• BCG intolerant: unable to receive BCG due to side effects
• BCG unresponsive: highest risk refractory or relapsing and

unable to receive BCG

Causes of BCG Failure

• Upper tract seeding
• Unrecognized prostatic urethral Urothelial Carcinoma (UC)
• Resistant clones of UC
• Immunosuppression: PD-1, PD-L1, Tregs, M2-like tumor

associated macrophages ( TAMs), Bone Morphogenic Protein 4 (BMAP4), myeloid -derived suppressor cells (M-DSCs), group 2 lymphoid cells (ILC2), IL-13, ↓NK cells ↓ IL-17+ mast cells….

BCG Maintenance 10 Year RFS: 3 wk v monthly v 6wk only

3m 3w 1m 0m

3 m 3 w 0 m 1 m

Available Salvage Options

• Mitomycin C: 40mg/20cc
• Doxorubicin: 50mg/25cc
• Doxorubicin > Mitomycin C
• Gemcitabine: 400mg/20cc
• Docetaxel: 40mg/20cc
• Valrubicin: 800mg/50cc
• Combinations: Gem/docetaxel, Gem/MMC

Potential Future Options

• Vicinium: EpCAM antibody fragment fused to

Pseudomonas Exotoxin A

• Imiquimod: Interferon inducer
• Immune Checkpoint Inhibiters
• Other immunotherapies, e.g. KLH
• Viral/gene treatments
• Adstilladrin- interferon gamma
• CG0070- GMCSF
• Vaccinia

Salvage Experience in High Risk NMIBC/BCG Failure

Rx

N 1yr RFS 2yr RFS Repeat BCG>1yr 116 43% Valrubicin- CIS 113 16.4% Gem- 30 21% 58 28% 21% Doce 18 50% 22% 54 40% 25% Abraxane 28 36% Gem/Doce 41 54% 34% Gem/MMC 47 48% 38% Chemo 43-45C >300 44-92% 49-69%

Hassler M: Current Opinion in Urology. 29(3):239-246, May 2019

BCG versus BCG plus IFN⍺

• Cochrane meta analysis: 5

randomized trials, 1231 patients show no clear evidence of difference in time to recurrence ( Cochrane Database Syst

• Rev. 2017 Mar; 2017(3):

CD012112.

• Our study of 680 BCG naïve

patients showed no advantage of adding interferon (Nepple, 2010)

Nepple K: J Urol. 184:1915-19, 2010

Salvage Experience in High Risk NMIBC/BCG Failure

Rx

N 1yr RFS 2yr RFS Repeat BCG>1yr 116 43% Valrubicin- CIS 113 16.4% Gem- 30 21% 58 28% 21% Doce 18 50% 22% 54 40% 25% Abraxane 28 36% Gem/Doce 41 54% 34% Gem/MMC 47 48% 38% Chemo 43-45C >300 44-92% 49-69%

Hassler M: Current Opinion in Urology. 29(3):239-246, May 2019

Salvage Gemcitabine and Docetaxel Combination Chemotherapy After BCG Failure in Non-Muscle Invasive Bladder Cancer Patients

Mounica Rao, University of Arizona, College of Medicine - Phoenix Mentor: Donald Lamm, MD, BCG Oncology, University of Arizona, College of Medicine - Phoenix

Gemcitabine/Docetaxel

Author Year N Steinberg R 2015 45 Milbar N 2017 34 Rao/Lamm 2019 53 DFS 1 yr DFS 2 yr 54% 34% 42% 24% 74% 56%

U Iowa and Hopkins: 1000mg Gem/50cc, 37.5mg/50cc Doce at room temperature. U Arizona: 200mg/10cc Gem, 20mg Doce/10cc Doce at 43C

N Engl J Med. 2018 Jan 18;378(3):230-240 HIPEC: 90 min intraperitoneal perfusion Cisplatin at 40C after debulking ovarian CA “Hyperthermia increases drug penetration, chemosensitivity, by DNA repair inhibition, apoptosis, NK cells and inhibits angiogenesis.”

Vicinium

• Monoclonal Ab fragment to Epcam, expressed on 98%
• f urothelial carcinoma cells
• Linked to pseudomonas exotoxin A
• Currently in “Phase 3” (historically controlled) clinical

trial

• Favorable side effect profile
• In 45 BCG failure patients with CIS, one year CRR: 16%

25% in those receiving 7-10 BCG instillations

Instiladrin: (now Adstiladrin) Adenovirus with recombinant IFN⍺/Syn3

Shore N et al: J Clin Oncol. 2017, 20;35:3410

• 40 with BCG refractory or relapsed HG UC
• Single intravesical instillation of 1 or 3 x10^11 viral particles/ml
• Responders again treated at 4, 7 and 10 months
• Primary end point: High grade UC free at one year
• 35% recurrence free at 1 year, with good tolerance

85 y/o man with 23yr Hx Bladder CA, now with recurrent CIS

• Gross hematuria, “golf ball” sized tumor
• resected. No post op chemo or other Rx

after 12 repeat resections/20 yrs.

• 2013: dysuria, nocturia x8. CIS> BCG x6
• CIS bladder and prostate resected> gem/

doce

• Severe dysuria, nocturia x20, CIS persists
• CG0070 x6> Dysuria resolves, N x2-3, Bx

neg

• Symptomatic response persists, at one

year Cytology positive, Bx bladder clear, prostate positive for ductal CIS

• Chemoradiation therapy for invasive UC

prostate, cysto and cytology negative

Oncolytic Virus: CG0070

• CG0070, a conditionally replicating oncolytic adenovirus (Ad5)with a

retinoblastoma (Rb) E2F-1 promotor and human GMCSF gene

• Designed to attack and lyse tumor cells, releasing tumor antigen and

stimulating immune response with GMCSF

• Our experience with 15 patients, all with CIS +/- Ta,T1, UC post BCG
• Results: 1 yr DFS 47%; 2yr DFS 40%
• Pre (2.5 yr) and post (2.5 yr) Rx recurrence reduced from 32 to 13

(P<0.01)

• Well tolerated and in some markedly reducing irritative CIS symptoms

Salvage Experience in High Risk NMIBC/BCG Failure

Rx

N 1yr RFS 2yr RFS Repeat BCG>1yr 116 43% Valrubicin- CIS 113 16% Gemcitabine 88 21%-28% 21% Docetaxel 72 40-50% 22-25% Abraxane 28 36% Gem/Doce 41 54% 34% Gem/MMC 47 48% 38% Chemo 43-45C >300 44-92% 49-69% Gem/Doce 43C 60 74% 56% CG0070 15 53% (CIS) 43% Adstiladrin 40 35% Vicinium 45 16% (CIS)

Improving MMC Treatment: Concentration and Hyperthermia

Slide courtesy/modification of M. O’Donnell

Clinical Trials

• NanoDoce: NMIBC/MIBC injected into base of resection

and instilled weekly. Animal studies show penetration into detrusor, immune response. Lamm: Phoenix, Hopkins and N. Carolina

• Rapamycin 0.5mg/day to reduce recurrence. Svatek: San

Antonio (Metformin, inthibits mTOR as well)

• Atezolizumab in BCG unresponsive NMIBC. Black: SWOG
• Durvalumab/BCG/RT in BCG failures: Hahn: Hoosier Ca Res

Network

• Durvalumab/Oportuzumab Monatox (Vicinium) in BCG

failures: Agarwal: NCI

• Phase 2 Synergo MMC hyperthermia in CIS

Conclusions

• BCG Salvage and Alternatives are increasingly important

with the world-wide BCG shortage

• Immunotherapy, e.g PD-1/L1, now a major advance M+ UC is

being extensively studied in NMIBC

• Hyperthermia improves chemotherapy and is under-used
• Combination intravesical chemotherapy improves efficacy

and can likely be improved with simple hyperthermia

• Gemcitabine>docetaxel is highly effective and inexpensive
• New modalities- adenovirus with GMCSF or Ifn, specific

targeted toxins and many new options are hopefully coming

BCG Failure: Conclusions

• Check for upper tract and prostatic urethra UC; biopsy for CIS
• Use 3 week maintenance BCG; HG recurrence is failure on Rx
• HG rec 1 or more years after BCG often responds to BCG
• There is nothing physiologic about room temperature chemo
• Combination chemo> single agent. Gemcitabine>docetaxel
• New agents are greatly needed, now more than ever with BCG

shortage: Vicinium, Adstiladrin, CG0070, Immune check point blockers, etc.

Thank You!