Merck Oncology Overview

The Development of MSI-H Cancer Therapy
Development of Anti-Cancer Drugs Forum
Tokyo , Japan, 18, February 2017
Andrew Joe, MD
Executive Director, Late Stage Oncology
Merck & Co., Inc., Rahway, NJ USA

PD-L1 and PD-L2 Block T Cells from Attacking
Cancer Cells•

PD-1 is an antigen expressed on
the surface of activated T-cells•

PD-1 interacts with its ligands
PD-L1 and PD-L2 expressed oncancer and surrounding cells•This inhibits activation of Tlymphocytes and prevents ananti-tumor immune response

PD-1 inhibition with Keytruda reactivates T cells to attack andkill cancer cells
2Pembrolizumab is a Humanized IgG4, High-Affinity
Anti-PD-1 Blocking Antibody

 No cytotoxic (ADCC/CDC) activity
 Low occurrence of anti-drug antibodies and no impact onpharmacokinetics

Presented by: Antoni Ribas ASCO 2013
3

KEYTRUDA Development ProgramFirst anti-PD-1 to market in the US

 Approvals in Melanoma, Non-Small Cell Lung Cancer, (1L and 2L+ PD-L1+), Recurrent or
Metastatic Head and Neck Squamous Cell Carcinoma

 Demonstrated overall survival- vs. ipilimumab in melanoma- vs. docetaxel in 2L+ PD-L1+ NSCLC- vs chemo in previously treated patients with advanced bladder cancer

 Data in first line NSCLC for both Monotherapy and in Combination with chemotherapy
 Clinical activity in more than 20 different tumor types
 More than 30 ongoing registration-enabling studies
 5 FDA Breakthrough Designations
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Keytruda Monotherapy Has Shown Activity in 20 Tumors

Change From Baseline in Tumor Size, %100

Melanoma1100

NSCLC2100H&N31000000-100-100-100-100100

NHL PMBCL8Mesothelioma9

Ovarian10

Gastric6

100000-100-100-100SCLC11

Esophageal12

NPC1300-100-100-100-10000-100-100-100ER+/HER2– BC17

Cervical18

Thyroid19

100100100

100000000-100-100-100-100-100-100100

Salivary20

1. Daud A et al. ASCO 2015; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al. ASCO 2015; 4. Plimack E et al. ASCO 2015; 5. Nanda R et al. SABCS 2014; 6. Bang YJ et al.
ASCO 2015 ; 7. Moskowitz C et al. ASH 2014; 8. Zinzani PL et al. ASH 2015; 9. Alley EA et al. AACR 2015; 10. Varga A et al. ASCO 2015; 11. Ott PA et al. 2015 ASCO; 12. Doi Tet al. ASCO 2015; 13. Hsu C et al. ECC 2015; 14. Ott PA et al. ECC 2015; 15. Bang Y-J et al. ECC 2015; 16. O’Neil B et al. ECC 2015; 17. Rugo HS et al. SABCS 2015;
18. Frenel JS et al. ASCO 2016; 19. Mehnert JM et al. ASCO 2016; 20. Cohen R et al. ASCO 2016.
5cHL7

Anal1400

Colorectal161000100100

TNBC5100100

Biliary Tract15100100100100

Urothelial4

Pembrolizumab Late Development Program• Clinicaltrials are
ongoing incommon,
uncommon,and rarecancers

Melanoma

1L (KN006)
2L (KN002)
Adjuvant (KN053/054)
1L + T-Vec (Amgen)
1L + IDO-1 (Incyte)

NSCLC

1L (KN024)
1L (KN042)
1L + pemetrexed non sq (KN189)
1L + pacitaxel sq(KN407)
2/3L (KN010)
Adjuvant (KN091)

Gastrointestinal

1L Gastric + chemo (KN062)
2L Gastric (KN061)
3L Gastric (KN059)
2L Esophageal (KN181)
3L Esophageal (KN180)
1L CRC MSI-high (KN177)
3L CRC MSI-high (KN164)

Hepatocellular
2L (KN224)
2L (KN240)

Head and Neck

1L + chemo/cetuximab (KN048)
2L (KN040)
3L (KN055)
2L Nasopharyngeal (KN122)

Hematological Malignancies
3L HL (KN087)
rrHL + brent. ved. (KN204)
2L NHL rrPMBCL (KN170)
1L MM + len/dex (KN185)
3L rrMM + pom/dex (KN183)

Bladder

1L (KN052)
1L (KN361)
2L NIBC (KN057)
2L (KN045)

Triple Negative Breast
2L+ (KN086)
2L/3L (KN119)

Other
2L Advanced Cancers (KN158)
2L Ovarian (KN100)
2L Prostate (KN199)
1L Renal Cell Carcinoma (KN427)
1L + Axitinib Renal Cell Carcinoma (KN426)
6

Biomarker Program to Identify Cancers Likelyto Respond to Pembrolizumab Therapy
Ligandexpression ontumor

PD-L1 Expression

Immunogenic
microenvironment

Increased antigen
presentation dueto high DNA
mutation load

Immune-Related
Gene Expression(GEP) Signature

DNA Mismatch
Repair Deficiency(MSI-H), DNA
Polymerase
mutation, others

Goal is to identify patients most likely to benefit fromtreatment
7

KEYNOTE (KN) 016• Demonstration of clinical efficacy in a biomarkerdefined population

8

MSI-H Cancer Has a High Mutational Burden• Mismatch repair (MMR) deficiency refers to deficiency in proteins
responsible for DNA MMR: MSH2, MSH6, MLH1, PMS2.

• MMR deficiency leads to the MSI-H phenotype.
• MMR deficient/MSI-H cancers harbor thousands of mutations (i.e.,high mutational burden; hypermutated phenotype).

Microsatellite
Instability

DNA mutations lead toprotein neo-antigens,detected as ‘foreign’ &recognized by T-cells

9Rationale and Hypothesis• Hypothesis: Pembrolizumab is effectivein treating any MSI-H cancer– MSI-H cancer, regardless of tumor
histology, is associated with a highmutational burden (hypermutatedphenotype)– High mutational burden leads to highneoantigen expression– High neoantigen expression leads toautologous immune recognition ofcancer cells– By blocking PD-1 on tumor
neoantigen-specific T cells,
pembrolizumab can activate antitumor immune responses

Jonathan C. Dudley et al. Clin Cancer
Res 2016;22:813-820

10Biological Rationale for Tumor-Agnostic Approach• PD-1 blockade withpembrolizumab canrestore effective antitumor immunity in MSI-Hcancer, regardless ofcancer type11

Pembrolizumab Therapy of MSI-H Cancer• MSI-H cancer represents a unique, biomarker-identified
disease with a common immunobiology• MSI-H cancers are readily identifiable using locallyavailable assays (e.g., PCR, IHC)

• MSI-H – associated with worse prognosis in advanced
CRC; limited data in MSI-H gastric and endometrial
cancer – worse prognosis (or unclear association withprognosis) in advanced-stage disease12Ongoing Clinical Studies• A Phase II Study of Pembrolizumab (MK-3475) as
Monotherapy in Subjects With Previously Treated Locally
Advanced Unresectable or Metastatic (Stage IV)
Mismatched Repair Deficient or Microsatellite InstabilityHigh Colorectal Carcinoma (KEYNOTE-164)– Locally confirmed MMR deficient or MSI status• A Clinical Trial of Pembrolizumab (MK-3475) Evaluating
Predictive Biomarkers in Subjects With Advanced Solid
Tumors (KEYNOTE 158)
– Any advanced solid tumor, with the exception of colorectal
carcinoma (CRC), which is Microsatellite Instability (MSI)High (MSI-H)
32Conclusions• There is a strong biological rationale for anti-PD-1
pembrolizumab therapy of MSI cancer, regardless oftumor histology• Clinical trials have demonstrated durable clinical efficacy
of pembrolizumab for the treatment of MSI-H colorectal
and non-colorectal cancer• Challenges in drug development for a tumor-agnosticindication– Study design for providing evidence of clinical efficacy (vstraditional randomized controlled studies)– Identification of study population
33