Safety, Efficacy, and Immune Correlates of Alternative Doses and - - PowerPoint PPT Presentation

Safety, Efficacy, and Immune Correlates of Alternative Doses and Schedules of Entinostat Combined With Pembrolizumab in Patients With Advanced Solid Tumors – Results From SNDX-275-0141 Phase I Trial

Anthony Tolcher1,7, Michael L. Meyers2, Dmitry Gabrilovich3, Fang Wang3, Jane Trepel4, Min-Jung Lee4, Emmett Schmitt5, Christine Quaranto6, Serap Sankoh6, David Tamang6, Peter Ordentlich6

1START, San Antonio, TX, 2Syndax Pharmaceuticals, Inc., New York, NY, 3The Wistar Institute,

Philadelphia, PA, 4National Cancer Institute, National Institutes of Health, Bethesda, MD, 5Merck & Co., Inc., Kenilworth, NJ, 6Syndax Pharmaceuticals, Inc., Waltham, MA,

7 Current Affiliation: NEXT Oncology, San Antonio TX

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Disclosure Information: AACR Annual Meeting 2018 Anthony W. Tolcher MD, FRCPC, FACP

I have the following financial relationships to disclose:

• Grant/Research support from Syndax for the conduct of this study
• Employee of: Past Employment at START, now NEXT Oncology
• I will discuss the following off label use and/or investigational use in my

presentation: Combination of entinostat and pembrolizumab

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Immune Checkpoint Inhibitors & Entinostat Target Complementary Immunosuppression Mechanisms in the Tumor Microenvironment

• 1. Orillion A, et al. Clin Cancer Res. 2017;23(17):5187-5201. 2. Johnson M, et al. SITC, 2017. 3. Gandhi L, et al. SITC, 2017.
• Entinostat – oral, class I selective

histone deacetylase inhibitor

• Has demonstrated potent

immunomodulatory activity by inhibition of myeloid-derived suppressor cell (MDSC) function1

• Encouraging preliminary data of the

combination of entinostat plus pembrolizumab in PD-1 pretreated patients have been reported:

– Melanoma: 4 of 13 responders (31% ORR)2 – NSCLC: 3 of 31 responders (10% ORR)3

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Overview of Study 0141 Design and Schedule of Blood Samples

Objectives

• Cardiac safety, PK, safety/tolerability

(ECG/ 24 hour Holter monitor)

• Immune correlatives

Part 1

ARM A Entinostat 1mg daily (Days 1-5 every 7 days) + pembrolizumab 200 mg Q3W (N=10) ARM C Entinostat 10 mg QoW + pembrolizumab 200 mg Q3W (N=10) ARM B Entinostat 5 mg weekly* + pembrolizumab 200 mg Q3W (N=10)

Objectives

• Safety/tolerability, PK, efficacy
• Impact on immune correlatives

Part 2

Double Blind 2 Wks Timepoints for blood sampling

Pre- dose Day 14 Day 15 Pre- dose

Patients with advanced solid tumors

R A N D O M I Z E Entinostat 15mg Single dose (N=15) Placebo Single dose (N=15) R A N D O M I Z E

* 5 mg weekly is the dose being used in all ongoing Phase 2 PD-1 combination trials as well as E2112.

Alternative doses were hypothesis generating

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Baseline Demographics of Treatment Arms Are Similar

Arm A 1 mg Days 1-5 every 7 (N=8) Arm B 5 mg weekly (N=9) Arm C 10 mg QoW (N=9) Total (N=26)

Age (years), median (range) 59.5 (22 - 68) 56.0 (44 -75) 65.0 (41-70) 60.5 (22-75) Sex, n (%) Male 2 ( 25.0) 2 ( 22.2) 3 ( 33.3) 7 ( 26.9) Female 6 ( 75.0) 7 ( 77.8) 6 ( 66.7) 19 ( 73.1) ECOG Performance Status, n (%) 2 ( 25.0) 3 ( 33.3) 3 ( 33.3) 8 ( 30.8) 1 6 ( 75.0) 6 ( 66.7) 6 ( 66.7) 18 ( 69.2) Tumor Type, n (%) Breast (all HR+) 4 ( 50.0) 4 ( 44.4) 3 ( 33.3) 11 ( 42.3) Prostate 0 ( 0.0) 2 ( 22.2) 2 ( 22.2) 4 ( 15.4) Ovarian 1 ( 12.5) 0 ( 0.0) 1 ( 11.1) 2 ( 7.7) Other 3 ( 37.5) 3 (33.3) 3 ( 33.3) 9 ( 34.6)

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Principal Biomarker Correlates

Hypothesis: Myeloid Derived Suppressor Cells Mediate Resistance to PD1 axis targeting

• Determine the effect on MDSC population in blood after exposure to

entinostat or placebo in the lead-in portion of the study

• Determine the effect of MDSC population in blood after exposure to

continuous entinostat amongst three administration schedules

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Day 1

Sample (before dosing)

Day 1 Day 14

• 15 mg entinostat
• Placebo

Randomize: Randomize:

• Arm A – 1 mg entinostat, Days 1-5 every 7 days
• Arm B – 5 mg entinostat weekly
• Arm C – 10 mg entinostat every other week

All arms receive pembrolizumab 200 mg Q3W Sample Sample Sample (before dosing)

Day 15 Immune (MDSC) Biomarkers Were Analyzed at Four Timepoints

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Lead-in Shows MDSCs Are Significantly Lowered by Entinostat Treatment Compared to Placebo

* Unpaired t-test.

• After a single entinostat dose, MDSC cell frequency was

significantly decreased in patients who received entinostat compared to placebo

• No statistical difference was observed in frequency of

NK, T cell, or B cell populations in patients receiving entinostat relative to the placebo control

Lin-/CD14+/HLA-DRlow/neg

• 60
• 30

30 60

MDSC

p = 0.0039*

MDSC Change, %

(Post-dose – Pre-dose) Placebo Entinostat

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Lead-in Shows MDSCs Are Significantly Lowered by Entinostat Treatment Compared to Placebo

** Paired t-test.

Pre-dose Post-dose

10 20 30 Entinostat

p = 0.0069**

MDSC (% Cells) 10 20 30 Placebo

p = 0.636**

MDSC (% Cells)

Pre-dose Post-dose

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In Part 2, Continuous Dosing Maintains Observed Decrease in MDSCs – (141) C1D15

Entinostat Dosing Arms:

• Arm A: 1 mg Days 1-5 every 7 days
• Arm B: 5 mg once weekly
• Arm C: 10 mg once every other week

Placebo Primed

1 mg 5 mg 10 mg

• 60
• 30

30 60 MDSC Change, %

(Post-dose – Pre-dose)

Dose Group

Entinostat Primed

1 mg 5 mg 10 mg

• 60
• 30

30 60 Dose Group MDSC Change, %

(Post-dose – Pre-dose)

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Entinostat Pharmacokinetics Contribute to Durable Exposure

• Entinostat exposure during the first cycle of treatment increases in a dose dependent manner over the first cycle
• f treatment by both Cmax and AUC
• Peak exposure generally occurs within 1 hour of dosing, with a residual exposure tail persisting up to 15 days.

1 mg 5 mg 10 mg 15 mg Cmax ng/mL 9 52 118 253 AUC(cycle1) ng*hr/mL 1040 1366 2432 6359 1 mg 5 mg 10 mg 15 mg 200 400 600 800

Cmax

Dose Arms Time (hrs)

0.1 1 10 100 1000

Entinostat PK

15 mg (-0140) 10 mg (-0141) 5 mg (-0141) 1 mg (-0141)

Entinostat Cp (ng/mL)

1 mg 5 mg 10 mg 15 mg 5000 10000 15000 20000

AUC(Cycle 1)

ng*hr/mL Dose Arms ng/mL

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A Similar Safety Profile Is Observed As Previously Reported1,2 – Grade 3/4 Related Adverse Events

• No notable differences in the safety

profile were observed among the 3 arms

• The overall safety profile observed in

this study was consistent with previously reported experience of entinostat combined with pembrolizumab1,2

Total (N=26)

Subjects With At Least One Grade >= 3 Related Treatment-Emergent Adverse Event 10 (38.5) Neutrophil count decreased 5 ( 19.2) White blood cell count decreased 3 ( 11.5) Lymphocyte count decreased 2 ( 7.7) Anemia 1 ( 3.8) Arthralgia 1 ( 3.8) Colitis 1 ( 3.8) Hyperglycemia 1 ( 3.8) Neutropenia 1 ( 3.8) Vomiting 1 ( 3.8)

1Johnson M, et al. SITC, 2017. 2Gandhi L, et al. SITC, 2017.

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Entinostat + Pembrolizumab Shows Promising Activity In Patients with Heavily Pretreated Cancers

Encouraging activity:

• 3 PRs (ORR = 11.5%)

in endometrial, HR+ BC, uterine leiomyosarcoma

• 2 SDs > 6 months

(HR+ BC)

• 19 (73.1%) and 11

(42.3%) patients on study for 12 and 24 weeks respectively

5 10 15 20 25 30 35 40 45 50 55 60 65 70

Endometrial Breast Ovarian Breast Breast Breast Breast Breast Breast Prostate Prostate Uterine NSCLC Left Parotid gland Distal appendix Ovarian Osteosarcoma neck

Time on Study (Weeks)

10 mg QoW 5 mg QW 1 mg 5 of 7

Breast Uterine Breast Breast Breast Cervical Prostate Prostate Lung PR (Partial Response) SD (Stable Disease) PD (Progressive Disease) Non-CR/Non-PD Ongoing at Data Cutoff

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Conclusions

• Consistent with previous reports, entinostat treatment results in

reductions in circulating MDSCs

• No notable differences in the safety profile were observed among the

3 arms, and the overall safety profile was consistent with previously reported experience of entinostat combined with pembrolizumab

• The combination of entinostat and pembrolizumab continues to show

promising activity in patients with heavily pretreated cancers

• This trial supports continued study of entinostat 5 mg weekly, the

schedule being used in other entinostat/pembrolizumab studies and in the ongoing Phase III E2112 entinostat/exemestane study

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Acknowledgements

• We thank the patients and their families/caregivers
• START study staff

This study was sponsored by Syndax Pharmaceuticals, Inc., in collaboration with Merck & Co., Inc., Kenilworth, NJ