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 3 w 3m 3w 0 m 1m 0m 3 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 Nepple K: J Urol. 184:1915-19, 2010 interferon (Nepple, 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 DFS 1 yr DFS 2 yr Author Year N 54% 34% Steinberg R 2015 45 42% 24% Milbar N 2017 34 74% 56% Rao/Lamm 2019 53 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% of 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!