Inhibitors in NMIBC Seth P. Lerner, MD, FACS Professor, Scott - PowerPoint PPT Presentation

There is a Role for Check Point Inhibitors in NMIBC Seth P. Lerner, MD, FACS Professor, Scott Department of Urology Beth and Dave Swalm Chair in Urologic Oncology Baylor College of Medicine 4 th FOIU July 3-5, 2018

Financial and Other Disclosures  Off-label use of drugs, devices, or other agents: none  Data from IRB-approved human research is presented I have the following financial interests or Disclosure code relationships to disclose: FKD S Roche/Genentech S JBL S Viventia S BioCancell, Nucleix, QED, UroGen C UroGen, Vaxiion C 2

BCG Mechanism of Action Redelman-Sidi et al, Nat Rev Urol 2014

Urinary IFN-  Response to Adding IFN-  and Decreasing BCG 10000 MB (ng/12 hrs) 1000 IFN-  100 10 M1 M2 M3 M4 M5 M6 M7 M8 M9 I1 I2 I3 I4 I5 I6 I7 I8 M10 M12 M11 BCG 1/3 BCG 1/10 BCG +IFN-  Response +IFN- 

SWOG 8507 - Recurrence-Free Survival p < 0.0001 Lamm, DL et al, J Urol 163:1124, 2000 6

SWOG 8507 – Worsening-Free Survival p = 0.04 Lamm, DL et al, J Urol 163:1124, 2000 7

Pre-existing BCG-specific immunity improves anti-tumor response in patients Patients with Clinical high-risk bladder TURBT BCG therapy outcome? tumor PPD test + + + 100 + 90 + + + 80 Recurrence-free survival (%) + + 70 + 60 50 + + + + 40 30 20 + Censored 10 PPD + (n=23) PPD - (n=32) * 0 0 10 20 30 40 50 60 Time until recurrence (months) (slide courtesy of R Svatek) Biot, C., et al. Sci Transl Med 2012

Subcutaneous immunization prior to intravesical challenge results in rapid bladder T cell infiltration at 1st intravesical instillation BCG s.c. Repeated * Weeks 1 to 4 -21 0 7 14 21 33-35 Single * Week 1 -21 0 33-35 Single * Week 4 0 21 33-35 Instillation: PBS BCG BCG PBS BCG BCG BCG Week(s) of treatment: W1-4 W1-4 W1 W1-4 W1-4 W1 W4 Ø BCG s.c. 21 days prior to (slide courtesy of R Svatek) instillation Biot, C., et al. Sci Transl Med 2012

SWOG 1602 (PRIME) A Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming for BCG- Naïve High -Grade Non-Muscle Invasive Bladder Cancer Intravesical TICE BCG induction and maintenance (50 mg/dose) BCG- naïve Intravesical Tokyo BCG induction and PPD high risk maintenance (80 mg/dose) Negative NMIBC Prime: intradermal BCG (Tokyo strain 100 µl at 0.5 mg /ml) + Intravesical Tokyo BCG induction and maintenance (80 mg/dose) PI: Robert Svatek, UT San Antonio

“BCG Unresponsive ” high risk NMIBC • Recurrent/persistent high grade urothelial carcinoma after completion of at least induction and one cycle maintenance BCG (“ 5+2 ” ) for high grade Ta/T1 or CIS – Never achieved CR or recurred within 6 months of last BCG dose • T1HG at first evaluation after induction BCG – at least 5 of 6 induction doses • These patients are “extremely unlikely” to respond to further BCG Lerner et al, Bladder Cancer 1:29, 2015 )

Clinical Trial Design – BCG Unresponsive • 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 12 FDA final guidance February 2018

The Cancer Immunity Cycle 13 Chen DS, Mellman I. Immunity 2013;39:1 – 10

Rationale for CPI efficacy of immunotherapy in pre-clinical data non-muscle from syngeneic invasive bladder mouse models cancer (BCG) expression of PD-L1 efficacy of PD-L1 in Ta, T1 and CIS and PD-1 inhibitors previously treated in advanced with BCG bladder cancer

Pre-Clinical Data MB-49 Orthotopic model – Avelumab treated Vandeveer, et al Cancer Immunol Res 4:452, 2016

PD-L1 Expression NMIBC A – Negative B – Membranous staining C,D – BCG granuloma Inman, et al Cancer 109:1499, 2007 16

CPI in NMIBC Clinical Trials • BCG +/- Durvalumab (NCT 03528694) • Ph II Durvalumab BCG unresponsive CIS (NCT 02901548) • Durvalumab + Viccinium prior BCG treatment ( NCI n=40) (NCT 03258593) • ADAPT Durvalumab+/- BCG+XRT BCG relapsing (NCT 03317158) • Durvalumab BCG unresponsive CIS (NCT 02901548)

CPI in NMIBC Clinical Trials • BCG and Pembro (NCT 02808143 and 02324582) • Pembro first line for CIS (NCT 03504163) • Keynote 057 – Pembro BCG unresponsive (NCT 02625961) • Ph I/II marker lesion Pembro intravesical or intravenous (NCT03167151)

CPI in NMIBC Clinical Trials • Atezolizumab alone or + BCG (NCT 02792192) • SWOG 1605 Atezolizumab BCG unresponsive (NCT 02844816) • Nivolumab +/- BMS 986205 (IDO inhibitor) in BCG unresponsive (n=436) (NCT 03519256)

S1605: Phase II trial of Atezolizumab in BCG- unresponsive high risk NMIBC Atezolizumab Atezolizumab Atezolizumab Atezolizumab Atezolizumab Atezolizumab Atezolizumab Atezolizumab Atezolizumab Atezolizumab maintenance q3wks for 9 cycles BCG cysto cysto surveillance unresponsive biopsy cytol for 18 mo. Ta/T1/Tis cytol q 3 weeks q 3 weeks (TURBT) CR @ 25 weeks* RFS @ 18 13 weeks* (=6 months post TURBT) months • registration within * time is relative to first dose of atezolizumab 60 daysof TURBT • start therapy within 5 days of registration PI: Black & Singh (Lerner) ECOG/ACRIN: T Bivalacqua Alliance: M Woods CCTG: W Kassouf

KEYNOTE-057: Phase II trial of Pembrolizumab in BCG unresponsive high risk NMIBC Primary Eligibility endpoint Cohort 1 • DFS (all-comers • high risk NMIBC and PD-L1+) CIS ± (T1, HGTa, CIS) Secondary Ta or T1 endpoints • urothelial • DFS (12 wk, 6 or mixed and 12 mo) histology pembro safety • PFS (12 wk, 6 2 Cohorts 200 mg Q3w follow-up • BCG- mo, 12 mo) • CR unresponsive • DOR • ECOG status Exploratory Ta or T1 0, 1, or 2 endpoints • Safety • Hemoglobin • PK profile Cohort 2 >9 g/dL • Biomarkers Target enrollment: 260

HCRN 16-243 ADAPT-BLADDER Trial – Phase 1 (n = 3-42 patients) DLT < 0/3 or 1/6 Proceed to pts cohorts 2a/2b BCG- DLT limit Durvalumab unresponsive DLT > 2/6 pts Close (3+3, n=3-6) exceeded NMIBC Durvalumab + BCG DLT < 5/12 pts RP2D (6+3+3, n=12) Reduce BCG to 1/3 rd dose BCG Full-dose BCG BCG- unrepsonsive 1/3 rd dose DLT > 2/6, > 4/9, or > DLT limit BCG dose NMIBC Close 5/12 pts exceeded Tested? BCG Durvalumab + EBRT DLT < 5/12 pts RP2D Cohort 1 (6+3+3, n=12) Cohort 2a Cohort 2b DLT limit DLT > 2/6, > 4/9, or > Close 5/12 pts exceeded Courtesy Noah Hahn

HCRN 16-243 ADAPT-BLADDER Trial – Phase 2 (n = 144 patients) (All patients treated at RP2D) Durvalumab + BCG 6m RFS (n=48) Int/High Risk Durvalumab + EBRT BCG- 6m RFS (n=48) relapsing NMIBC RESIDUAL BCG Durvalumab 6m RFS NMIBC (n=48) (n~28) *Randomize 1:1 to activated arms (additional arms may activate in the future) **1:1 randomization to Durvalumab + EBRT vs all other activated arms only at radiation qualified sites Courtesy Noah Hahn

Conclusions • NMIBC is an immune sensitive cancer • Urologists have been using BCG vaccine as intravesical immunotherapy for 3 decades • We now have an understanding of the biology of the immune response to BCG and the role of checkpoint inhibition • Clinical trials testing monoclonal antibodies targeting immune checkpoints are moving into NMIBC disease states