Efficacy/safety of entinostat (ENT) and pembrolizumab ...€¦ · Efficacy/safety of entinostat (ENT) and pembrolizumab (PEMBRO) in NSCLC patients previously treated with anti -PD-(L)1

Efficacy/safety of entinostat (ENT) and pembrolizumab (PEMBRO) in NSCLC patients previously treated with anti-PD-(L)1 therapyMatthew D. Hellmann1, Pasi A. Jänne2, Mateusz Opyrchal3, Navid Hafez4, Luis E. Raez5, Dmitry

Gabrilovich6, Fang Wang6, Peter Ordentlich7, Susan Brouwer7, Serap Sankoh7, Emmett Schmidt8, Michael L. Meyers7, Suresh S. Ramalingam9

1Memorial Sloan Kettering Cancer Center, New York, USA, 2Dana-Farber Cancer Institute, Boston, MA, USA, 3Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA, 4Yale Cancer Center, New Haven, CT, USA, 5Memorial Cancer Institute, Pembroke Pines, FL, USA, 6The Wistar Institute, Philadelphia, PA, USA, 7Syndax Pharmaceuticals, Inc., Waltham, MA, USA, 8Merck & Co., Inc., Kenilworth, NJ, USA, 9The

Winship Cancer Institute of Emory University, Atlanta, GA, USA

Matthew Hellmann, Memorial Sloan Kettering Cancer Center, New York, USA

DISCLOSURES

M. Hellmann: Consulting for Syndax, Merck, AstraZeneca, BMS, Roche/Genentech, Mirati, Janssen, Shattuck Labs, and Nektar.

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ENCORE-601: ENT + PEMBRO in PD-(L)1-Pretreated NSCLC

• Entinostat (ENT) is an oral class I-selective histone deacetylase inhibitor2

• ENT leads to downregulation of immunosuppressive cell types in the tumor microenvironment2

• Synergy with anti-PD1 inhibition in preclinical models2

• Promising activity shown in combination with pembrolizumab in patients with melanoma and lung cancer3,4

NSCLC, non-small cell lung cancer.1. Zimmer L, et al. Eur J Cancer. 2017;75:47-55. 2. Orillion A, et al. Clin Cancer Res. 2017;23:5187-5201. 3. Agarwala SS, et al. Presented at ASCO 2018. Abstract 9530. 4. Gandhi L, et al. Presented at ASCO 2018. Abstract 9036.

Treatment options are limited for patients with NSCLC whose disease has progressed on anti-PD-(L)1 therapy1

3


ALK, anaplastic lymphoma kinase; CRC, colorectal cancer; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; ENT, entinostat; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PEMBRO, pembrolizumab; PFS, progression-free survival; PO, orally; RECIST, Response Evaluation Criteria in Solid Tumors; QW, once a week; Q3W, every 3 weeks.

Phase 2 Primary Endpoint • ORR (irRECIST)Phase 2 Secondary Endpoints• PFS, OS, safety & tolerability

Phase 1b:

Phase 2: ENT 5 mg PO QW +

PEMBRO 200 mg IV Q3W

MismatchRepair-Proficient CRCAnti-PD-1/PD-L1-naive

NSCLCAnti-PD-1/PD-L1–naive

MelanomaProgressing on

Anti-PD-1/PD-L1

NSCLCProgressing on

Anti-PD-1/PD-L1

Dose & safety confirmation

Inclusion Criteria:• Recurrent or metastatic NSCLC, measurable by RECIST 1.1• Prior progression on anti-PD(L1) treatment• Prior chemotherapy in the advanced/metastatic setting• Prior ALK or EGFR treatment if indicated• ECOG Performance Status < 2• Willingness to baseline and on-Tx biopsy and blood samples

76 patients enrolled (72 efficacy evaluable*), last patient enrolled December 2017• Sample size was based on single proportion binomial test, assuming a

true ORR of 15% & lower threshold of 5%, with 90% power and a 1-sided significance level of 5%.

*4 patients were non-evaluable due to withdrawal of consent or discontinuations for administrative reasons prior to the first tumor assessment.

ENCORE-601: Open-label study evaluating ENT + PEMBRO in patients with recurrent or metastatic NSCLC and prior progression on anti-PD-1/PD-L1 therapy

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Demographics N=76Male, % 53%

Median age (range) 67 yrs (30-85)

ECOG Performance Status, %

Grade 0 / Grade 1 / Missing 28% / 71% / 1%

Current/Former Smoker 88%

PD-L1 Expression (N=60)

≥50% 15%

1%-49% 43%

<1% 42%

Data not available for 16 patients

PD-(L)1 history N=76Best Response on Prior Anti-PD-(L)1, %

Complete Response 1%

Partial Response 7%

Stable Disease 45%

Disease Progression 37%

Unknown 11%

Duration on Prior Anti-PD-(L)1

Median 5.3 months

Time from Prior Anti-PD-(L)1 to Study Therapy

Median 2.2 months

PD-(L)1 as immediate prior therapy, n (%) 47 (62%)

Patient baseline demographics and PD-(L)1 history

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ECOG, Eastern Cooperative Oncology Group.


• Objective response rate with ENT + PEMBRO was 10% (7 of 72, 95% CI: 4-19%)– Prespecified ORR target not reached; median duration of response was 5.3 months– An additional 50% of patients achieved disease stabilization

• Experience similar in PD1-pretreated melanoma (ORR = 18%)1

CI, confidence interval; ENT, entinostat; PEMBRO, pembrolizumab; PD, progressive disease; PR, partial response; SD, stable disease.1. Gandhi L, et al. Presented at ASCO 2018. Abstract 9036.

Time to last scan (weeks)

Perc

ent c

hang

e re

lativ

e to

bas

elin

e

Cha

nge

from

bas

elin

e (%

)Durable responses were observed in patients who experienced progression on prior anti-PD(L)1 therapy

6

PD SD PR Confirmed

75%65%

50%

35%

20%

5%

-10%

-25%

-40%

-55%

-70%

-85%

-100%

0 6 12 18 24 30 36 42 48 54 60 66 72 78

-100

-75

-50

-25

0

25

50

75

100mPFS = 2.8 months (95% CI: 2.1-4.1)


(++)(-)

Time, Months

Treatment Duration:ENT + PEMBROPrior Treatment

Pembro

Pembro

Nivo

Nivo

Nivo

Nivo

Nivo

<1% 1-49% ≥50%

PD-L1 Status

Partial Response Stable Disease UnknownBest Response on Prior PD-(L)1

Ongoing ENT + PEMBRO Treatment

Responses observed regardless of prior treatment history or PD-L1 status

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PD-L1 Status

(+)

(-)

(-)

(-)

(++)

(-)

(-)

(+)

-18 -12 -6 -3 0 3 6 9 1512 18 21-39 -36 -33 -30 -27 -24 -21 -9-15

Chemo Chemo

Chemo

Chemo

Chemo, chemotherapy; ENT, entinostat; Nivo, nivolumab; PEMBRO, pembrolizumab.


32

1

18

4 4

19

115

159

12

9

3

95

3

1

4

4

1

1

7

0

5

10

15

20

25

30

35

40

45

50

AE, adverse event; irAE, immune-related adverse event.

• 7 patients (9.2%) experienced Grade 3/4 related irAEs– pneumonitis, 3; colitis, 3;

hyperthyroidism, 1• 23 patients (30.3%) experienced

other Grade 3/4 related AEs• 11 patients (14%) discontinued

a study drug due to a treatment-related AE

• 13 patients (17%) required a dose reduction of study drug, of which 11 remained on study

Tota

l Pat

ient

s W

ith a

n Ev

ent,

%

GeneralDisorders

Metabolism and Nutrition Disorders

Gastrointestinal Disorders

Respiratory Disorders Investigations

Blood and Lymphatic

System Disorders

Grade 1-2 Grade 3-4

Treatment-related adverse events occurring in ≥ 10% of patients for All Grade or ≥ 2 patients for Grade 3/4

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*Age, sex, ECOG and visceral involvement.ECOG, Eastern Cooperative Oncology Group; ENT, entinostat; PEMBRO, pembrolizumab.1. Krieg C, et al. Nat Med. 2018;24:144-153.

Biomarkers: Identifying factors that may predict response to ENT + PEMBRO

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• No significant association of response with – Smoking status – PD-L1 expression – Prior PD-(L)1 treatment history– Other baseline characteristics*

• Peripheral monocyte frequency as a predictor of anti-tumor immune response has been previously shown1

– An association of monocyte levels with response was observed and further explored

Extensive analysis of baseline demographic features, blood, tissue


High* 19 12 8 6 5 2 1 0Low* 46 22 6 2 1 0

100

0 10 20 30 40 50 60 70Time to event (weeks)

PFS

(%)

+ CENSORED

Higher baseline levels of peripheral CD14+CD16-HLA-DRHI classical monocytes are associated with ORR and PFS benefits

10

20

80

40

60

0

• 26% of patients in the monocyte high group (5 of 19) are ongoing and 2% of patients in the monocyte low group (1 of 46) are ongoing.

*High / low defined by midpoint (13.1% of live PBMCs / ml) of range of peripheral monocyte values from available samples.CI, confidence interval; NE, not estimable; ORR, objective response rate, mPFS, median progression-free survival.

mPFS (95% CI) ORR (95% CI)

MonocyteHigh 5.3 months (1.3-NE) 21.1% (6.1-45.6)

MonocyteLow 2.7 months (1.5-4.1) 6.5% (1.4-17.9)


*% change from baseline was measured at C2D15 (5 wks).MDSCs, myeloid-derived suppressor cells.

Reduced circulating MDSCs (CD14+HLA-DRneg/low) associated with clinical responses

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• Circulating MDSC cell reduction consistent with hypothesized entinostat MOA• Trend in increased CD8+ T cells observed in responding patients

25.0%, n=6 -18.3%, n=34-10.5%, n=30-65.3%, n=6

CD8 T cells

% C

hang

efr

om B

asel

ine*

PR non-PR

400

300

200

100

0

-100

M-MDSCs

% C

hang

efr

om B

asel

ine* 1500

300

200

100

0

PR non-PR-100


Conclusions: ENT + PEMBRO in PD-(L)1 Pre-treated NSCLC

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• ENT + PEMBRO demonstrated anti-tumor activity (ORR 10%) in patients with NSCLC who have progressed on prior PD-(L)1 blockade– Prespecified ORR target not reached; may represent clinically meaningful activity– An additional 50% of patients achieved disease stabilization

• Most patients tolerated the therapy well

• Responses to ENT+ PEMBRO were independent of baseline PD-L1 expression

• Exploratory biomarker analyses identified baseline levels of peripheral classical monocytes as potential predictors of clinical benefit

• Future trial designs prospectively incorporating biomarkers for patient selection are under discussion

ENT, entinostat; ORR, objective response rate; NSCLC, non-small cell lung cancer; PEMBRO, pembrolizumab.


• The authors thank the patients and their families, investigators and study staff. • We acknowledge prior contributions to this study by Leena Gandhi, MD at New York University.

Acknowledgements

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This study was sponsored by Syndax Pharmaceuticals, Inc., in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Editorial assistance was provided by BluPrint Oncology, LLC. This assistance was funded by Syndax Pharmaceuticals, Inc.

Efficacy/safety of entinostat (ENT) and pembrolizumab ...€¦ · Efficacy/safety of entinostat (ENT) and pembrolizumab (PEMBRO) in NSCLC patients previously treated with anti -PD-(L)1

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