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 Tolcher 1,7 , Michael L. Meyers 2 , Dmitry Gabrilovich 3 , Fang Wang 3 , Jane Trepel 4 , Min-Jung Lee 4 , Emmett Schmitt 5 , Christine Quaranto 6 , Serap Sankoh 6 , David Tamang 6 , Peter Ordentlich 6 1 START, San Antonio, TX, 2 Syndax Pharmaceuticals, Inc., New York, NY, 3 The Wistar Institute, Philadelphia, PA, 4 National Cancer Institute, National Institutes of Health, Bethesda, MD, 5 Merck & Co., Inc., Kenilworth, NJ, 6 Syndax Pharmaceuticals, Inc., Waltham, MA, 7 Current Affiliation: NEXT Oncology, San Antonio TX

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 2

Immune Checkpoint Inhibitors & Entinostat Target Complementary Immunosuppression Mechanisms in the Tumor Microenvironment  Entinostat – oral, class I selective histone deacetylase inhibitor  Has demonstrated potent immunomodulatory activity by inhibition of myeloid-derived suppressor cell (MDSC) function 1  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 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. 3

Overview of Study 0141 Design and Schedule of Blood Samples Alternative doses were hypothesis generating Part 1 Part 2 Double Blind ARM A Entinostat 1mg daily (Days 1-5 every 7 days) Entinostat 15mg R R + pembrolizumab 200 mg Q3W Single dose A A (N=10) (N=15) N N Patients ARM B D D Entinostat 5 mg weekly* 2 Wks with advanced O O + pembrolizumab 200 mg Q3W M M solid tumors (N=10) I I Placebo Z Z Single dose ARM C E E (N=15) Entinostat 10 mg QoW + pembrolizumab 200 mg Q3W (N=10) Timepoints for Pre- Day Pre- Day 14 dose dose 15 blood sampling Objectives Objectives  Cardiac safety, PK, safety/tolerability  Safety/tolerability, PK, efficacy (ECG/ 24 hour Holter monitor)  Impact on immune correlatives  Immune correlatives 4 * 5 mg weekly is the dose being used in all ongoing Phase 2 PD-1 combination trials as well as E2112.

Baseline Demographics of Treatment Arms Are Similar Arm A 1 mg Days 1-5 Arm B Arm C every 7 5 mg weekly 10 mg QoW Total (N=8) (N=9) (N=9) (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 (%) 0 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) 5

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 6

Immune (MDSC) Biomarkers Were Analyzed at Four Timepoints Sample Sample Sample Sample (before dosing) (before dosing) Day 1 Day 14 Day 1 Day 15 Randomize: Randomize:  15 mg entinostat  Arm A – 1 mg entinostat, Days 1-5 every 7 days  Placebo  Arm B – 5 mg entinostat weekly  Arm C – 10 mg entinostat every other week All arms receive pembrolizumab 200 mg Q3W 7

Lead-in Shows MDSCs Are Significantly Lowered by Entinostat Treatment Compared to Placebo MDSC Lin - /CD14 + /HLA-DR low/neg 60  After a single entinostat dose, MDSC cell frequency was p = 0.0039* significantly decreased in patients who received entinostat compared to placebo 30 MDSC Change, % (Post-dose – Pre-dose)  No statistical difference was observed in frequency of NK, T cell, or B cell populations in patients receiving 0 entinostat relative to the placebo control -30 -60 Placebo Entinostat 8 * Unpaired t-test.

Lead-in Shows MDSCs Are Significantly Lowered by Entinostat Treatment Compared to Placebo Entinostat Placebo 30 30 20 20 (% Cells) (% Cells) MDSC MDSC 10 10 p = 0.0069 ** p = 0.636 ** 0 0 Pre-dose Post-dose Pre-dose Post-dose 9 ** Paired t-test.

In Part 2, Continuous Dosing Maintains Observed Decrease in MDSCs – (141) C1D15 Placebo Primed Entinostat Primed 60 60 MDSC Change, % MDSC Change, % (Post-dose – Pre-dose) (Post-dose – Pre-dose) 30 30 0 0 -30 -30 -60 -60 1 mg 5 mg 10 mg 1 mg 5 mg 10 mg Dose Group Dose Group 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 10

Entinostat Pharmacokinetics Contribute to Durable Exposure 1 mg 5 mg 10 mg 15 mg AUC (Cycle 1) C max C max ng/mL 9 52 118 253 20000 800 AUC (cycle1) ng*hr/mL 1040 1366 2432 6359 Entinostat PK 15000 600 1000 15 mg (-0140) Entinostat C p (ng/mL) ng*hr/mL 10 mg (-0141) ng/mL 100 10000 5 mg (-0141) 400 1 mg (-0141) 10 5000 200 1 0.1 0 0 1 mg 5 mg 10 mg 15 mg 1 mg 5 mg 10 mg 15 mg Time (hrs) Dose Arms Dose Arms  Entinostat exposure during the first cycle of treatment increases in a dose dependent manner over the first cycle of treatment by both C max and AUC 11  Peak exposure generally occurs within 1 hour of dosing, with a residual exposure tail persisting up to 15 days.

A Similar Safety Profile Is Observed As Previously Reported 1,2 – Grade 3/4 Related Adverse Events  No notable differences in the safety Total (N=26) profile were observed among the 3 arms Subjects With At Least One Grade >= 3 10 (38.5) Related Treatment-Emergent Adverse Event  The overall safety profile observed in Neutrophil count decreased 5 ( 19.2) this study was consistent with previously White blood cell count decreased 3 ( 11.5) reported experience of entinostat combined with pembrolizumab 1,2 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) 12 1 Johnson M, et al. SITC, 2017. 2 Gandhi L, et al. SITC, 2017.

Entinostat + Pembrolizumab Shows Promising Activity In Patients with Heavily Pretreated Cancers Endometrial 10 mg QoW Breast Ovarian Encouraging activity: Breast Breast  3 PRs (ORR = 11.5%) Prostate NSCLC in endometrial, HR+ Uterine Prostate BC, uterine Breast leiomyosarcoma Uterine 5 mg QW Cervical  2 SDs > 6 months Breast Prostate (HR+ BC) Prostate  19 (73.1%) and 11 Lung Breast (42.3%) patients on Breast study for 12 and 24 Breast 1 mg 5 of 7 Left Parotid gland weeks respectively Breast PR (Partial Response) Distal appendix Ovarian SD (Stable Disease) Breast PD (Progressive Disease) Osteosarcoma neck Non-CR/Non-PD Breast Ongoing at Data Cutoff 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 13 Time on Study (Weeks)

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 14

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 15