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

There is a Role for Check Point Inhibitors in NMIBC

4th FOIU July 3-5, 2018

Seth P. Lerner, MD, FACS Professor, Scott Department of Urology Beth and Dave Swalm Chair in Urologic Oncology Baylor College of Medicine

Financial and Other Disclosures

• Off-label use of drugs, devices, or other agents: none
• Data from IRB-approved human research is presented

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I have the following financial interests or relationships to disclose: Disclosure code FKD S Roche/Genentech S JBL S Viventia S BioCancell, Nucleix, QED, UroGen C UroGen, Vaxiion C

Redelman-Sidi et al, Nat Rev Urol 2014

BCG Mechanism of Action

Urinary IFN- Response to Adding IFN-  and Decreasing BCG

1/3 BCG +IFN-  BCG Response 10 100 1000 10000

IFN-  (ng/12 hrs)

I1 I2 I3 I4 I5 I6 I7 I8 M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12

MB

1/10 BCG +IFN- 

6

Lamm, DL et al, J Urol 163:1124, 2000

p < 0.0001

SWOG 8507 - Recurrence-Free Survival

7

Lamm, DL et al, J Urol 163:1124, 2000

p = 0.04

SWOG 8507 – Worsening-Free Survival

Pre-existing BCG-specific immunity improves anti-tumor response in patients

PPD + (n=23) PPD - (n=32) *

+ Censored

Time until recurrence (months) 10 20 30 40 50 60 10 20 30 40 50 60 70 80 90 100 Recurrence-free survival (%)

+ + + + + + + + + + + + + +

Patients with high-risk bladder tumor PPD test TURBT BCG therapy Clinical

• utcome?

Biot, C., et al. Sci Transl Med 2012

(slide courtesy of R Svatek)

Subcutaneous immunization prior to intravesical challenge results in rapid bladder T cell infiltration at 1st intravesical instillation

Repeated

Weeks 1 to 4

7 14 21

BCG s.c.

33-35

Single

Week 1

Single

Week 4

• 21

*

33-35

• 21

*

33-35

*

21

Instillation: PBS BCG BCG BCG BCG PBS Week(s) of treatment: W1-4 W1-4 W1-4 W1 W4 W1-4 Ø BCG s.c. 21 days prior to instillation BCG W1 Biot, C., et al. Sci Transl Med 2012

(slide courtesy of R Svatek)

SWOG 1602 (PRIME)

BCG-naïve high risk NMIBC PPD Negative Prime: intradermal BCG (Tokyo strain 100 µl at 0.5 mg /ml) + Intravesical Tokyo BCG induction and maintenance (80 mg/dose) Intravesical Tokyo BCG induction and maintenance (80 mg/dose) Intravesical TICE BCG induction and maintenance (50 mg/dose)

PI: Robert Svatek, UT San Antonio

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

“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

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FDA final guidance February 2018

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Chen DS, Mellman I. Immunity 2013;39:1–10

The Cancer Immunity Cycle

Rationale for CPI

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

Pre-Clinical Data

MB-49 Orthotopic model – Avelumab treated

Vandeveer, et al Cancer Immunol Res 4:452, 2016

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PD-L1 Expression NMIBC

Inman, et al Cancer 109:1499, 2007

A – Negative B – Membranous staining C,D – BCG granuloma

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)

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

cysto cytol

Atezolizumab Atezolizumab Atezolizumab

cysto biopsy cytol

Atezolizumab Atezolizumab Atezolizumab

Atezolizumab maintenance q3wks for 9 cycles

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

• registration within

60 daysof TURBT

• start therapy within

5 days of registration

* time is relative to first dose of atezolizumab

Atezolizumab

S1605: Phase II trial of Atezolizumab in BCG- unresponsive high risk NMIBC

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

• DFS (all-comers

and PD-L1+)

• DFS (12 wk, 6

and 12 mo)

• PFS (12 wk, 6

mo, 12 mo)

• CR
• DOR
• Safety
• PK profile
• Biomarkers

Eligibility

• high risk NMIBC

(T1, HGTa, CIS)

• urothelial
• r mixed

histology

• BCG-

unresponsive

• ECOG status

0, 1, or 2

• Hemoglobin

>9 g/dL

Primary endpoint Secondary endpoints Exploratory endpoints

Target enrollment: 260

CIS ± Ta or T1 safety follow-up

2 Cohorts

Ta or T1

Cohort 1 Cohort 2

pembro 200 mg Q3w

BCG- unrepsonsive NMIBC Durvalumab + BCG

(6+3+3, n=12)

RP2D BCG- unresponsive NMIBC Durvalumab

(3+3, n=3-6)

DLT > 2/6 pts DLT < 5/12 pts DLT > 2/6, > 4/9, or > 5/12 pts DLT limit exceeded Full-dose BCG 1/3rd dose BCG Reduce BCG to 1/3rd dose BCG BCG dose Tested? Close DLT < 0/3 or 1/6 pts DLT limit exceeded Close Proceed to cohorts 2a/2b Durvalumab + EBRT

(6+3+3, n=12)

RP2D DLT < 5/12 pts DLT > 2/6, > 4/9, or > 5/12 pts DLT limit exceeded Close Cohort 1 Cohort 2a Cohort 2b

HCRN 16-243 ADAPT-BLADDER Trial – Phase 1 (n = 3-42 patients)

Courtesy Noah Hahn

*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

Durvalumab + BCG

(n=48)

6m RFS Int/High Risk BCG- relapsing NMIBC Durvalumab + EBRT

(n=48)

6m RFS BCG

(n=48)

6m RFS Durvalumab

(n~28)

RESIDUAL NMIBC (All patients treated at RP2D)

HCRN 16-243 ADAPT-BLADDER Trial – Phase 2 (n = 144 patients)

Courtesy Noah Hahn

• 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

Conclusions