Considerations In Development Of Pembrolizumab In MSI-H .

CONSIDERATIONS IN DEVELOPMENT OFPEMBROLIZUMAB IN MSI-H CANCERSDecember 2017Christine K. Gause, Ph.DExecutive Director, Biostatistics.

Microsatellite Instability-High Cancer - USPIKEYTRUDA is indicated for the treatment of adult and pediatric patients withunresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repairdeficient solid tumors that have progressed following prior treatment and who have nosatisfactory alternative treatment options, or colorectal cancer that has progressed following treatment with afluoropyrimidine, oxaliplatin, and irinotecan2

Biomarker Program to Identify Cancers Likely to Respond toPembrolizumab TherapyLigandexpression ontumorImmunogenicmicroenvironmentIncreased antigenpresentation dueto high DNAmutation loadPD-L1 ExpressionImmune-RelatedGene Expression(GEP) SignatureDNA Mismatch RepairDeficiency (MSI-H),DNA Polymerasemutation, othersGoal is to identify patients most likely to benefit from treatment

MSI-H Cancer Has a High Mutational BurdenMismatch 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).MicrosatelliteInstabilityDNA mutations lead toprotein neo-antigens,detected as ‘foreign’ &recognized by T-cells

Rationale and HypothesisHypothesis: Pembrolizumab is effective in treating any MSIH cancer MSI-H cancer, regardless of tumor histology, isassociated with a high mutational burden (hypermutatedphenotype) High mutational burden leads to high neoantigenexpression High neoantigen expression leads to autologous immunerecognition of cancer cells By blocking PD-1 on tumor neoantigen-specific T cells,pembrolizumab can activate anti-tumor immuneresponsesJonathan C. Dudley et al. Clin Cancer Res2016;22:813-820

Biological Rationale for Tumor-Agnostic Approach PD-1 blockade with pembrolizumab canrestore effective anti-tumor immunity inMSI-H cancer, regardless of cancer type

KEYNOTE (KN) 016 Investigator-Initiated TrialMSD-sponsored, investigator-initiated trial at Johns Hopkins University – detection of efficacysignal in a biomarker-defined population

MSI-H Tumor Phenotype Associated with Efficacy in Colorectal andNon-Colorectal Patients Treated with PembrolizumabPhase 2 Study of MK-3475 in Patients With Microsatellite Unstable (MSI) Tumors Initiated in 2013, sponsored by Johns Hopkins- Sidney Kimmel Comprehensive Cancer Center in collaboration with MSDColorectal CancersCohort ADeficient inMismatch Repair(n 40)Cohort BProficient inMismatch Repair(n 25) MSI-H identified by IHC (deficiency of MLH1, MSH2, MSH6, or PMS2),or by PCR (instability in 2 loci)Non-Colorectal CancersCohort CDeficient inMismatch Repair(n 40) Primary endpoint: ORR Secondary endpoints: PFS by RECIST v1.1, and OSLe D et al, NEJM 2015; Diaz L et al, ASCO 2016

Global Phase 2 Studies KEYNOTE-164 and KEYNOTE-158:Study DesignKEYNOTE-164a/158b(MSI-H CRC/non-CRC) Age 18 years Locally confirmedMSI-H by PCR or IHC Previously treatedc ECOG PS 0-1 Measurable disease(RECIST v1.1) Life expectancy 3 months Adequate organ functionaHistologicallyPembrolizumab200 mgQ3WTreated for 2 years,35 treatments, oruntil PD,unacceptable AEs,or study withdrawalconfirmed, advanced, unresctable or metastatic CRC; previous treatment with approved therapies includingfluoropyrimidine, oxaliplatin, and irinotecan.bHistologically or cytologically confirmed, advanced, incurable non-CRC solid tumor; patients must have progressed on orbe intolerant to standard therapies.c 2 prior therapies and 1 prior therapy for MSI-H CRC and non-CRC, respectively.Clinicaltrials.gov: NCT02460198 and NCT02628067Survivalfollow-upPrimary end point:ORR (RECIST v1.1,central review)Secondary end points:DOR, PFS, OS, safety

Ongoing Clinical StudiesA Phase II Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects WithPreviously Treated Locally Advanced Unresectable or Metastatic (Stage IV)Mismatched Repair Deficient or Microsatellite Instability-High Colorectal Carcinoma(KEYNOTE-164) Locally confirmed MMR deficient or MSI statusA Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers inSubjects With Advanced Solid Tumors (KEYNOTE 158) Any advanced solid tumor, with the exception of colorectal carcinoma (CRC), which isMicrosatellite Instability (MSI)-High (MSI-H)

Overview of Trials Included in MSI-HStudyDesign and Patient PopulationKEYNOTE-016NCT01876511 prospective, investigator-initiated 6 sites patients with CRC and other tumorsKEYNOTE-164NCT02460198 prospective international multi-center NOTE-158NCT02628067 retrospectively identified patients with PD-L1positive gastric, bladder, or triple-negativebreast cancer retrospectively identified patients with PD-L1positive esophageal, biliary, breast,endometrial, or CRC prospective international multi-centerenrollment of patients with MSI-H/dMMRnon-CRC retrospectively identified patients who wereenrolled in specific rare tumor non-CRCcohortsNumber ofpatients28 CRC30 non-CRC61Prior therapy CRC: 2 priorregimens Non-CRC: 1 priorregimenPrior fluoropyrimidine,oxaliplatin, andirinotecan /- antiVEGF/EGFR mAb6 1 prior regimen5 1 prior regimen19 1 prior regimen11

Tumor Agnostic ApproachPrevalence of MSI-H prohibits conduct of randomized controlled trials by tumor typeLooking for a consistent, durable treatment effect which supports utility ofpembrolizumab across multiple tumor types Primary efficacy endpoint across trials: ORR Key secondary efficacy endpoint: Duration of responseAnalysis approach: Pooled across all trials and across all tumor types to examineconsistency of effect12

Pooled ORR Results for Patients with MSI-H/dMMR CancerN 149Objective response rateORR (95% CI)Complete response ratePartial response rate39.6% (31.7, 47.9)7.4%32.2%Response durationMedian in months (range)% with duration 6 monthsNR (1.6 , 22.7 )78%Source: USPI13

Pooled DOR Results for Patients with MSI-H/dMMR CancerMedian DOR (mos): Not reached (1.6 - 22.7 )Number (KM %) responders 6 mos: 46 (78%)Confirmed responses are durable14

Results by Tumor Type for Patients with MSI-H/dMMR CancerObjective response rateCRCNon-CRCEndometrial cancerBiliary cancerGastric or GE junction cancerPancreatic cancerSmall intestinal cancerDOR rangeN90n (%)32 (36%)95% CI(26%, 46%)(months)(1.6 , 22.7 )5927 (46%)(33%, 59%)(1.9 , 22.1 )145 (36%)(13%, 65%)(4.2 , 17.3 )113 (27%)(6%, 61%)(11.6 , 19.6 )95 (56%)(21%, 86%)(5.8 , 22.1 )65 (83%)(36%, 100%)(2.6 , 9.2 )83 (38%)(9%, 76%)(1.9 , 9.1 )CR complete response; PR partial response; SD stable disease; PD progressive disease; NE not evaluable.Source: USPI15

Results by Tumor Type for Patients with MSI-H/dMMR Cancer(continued)Objective response rateNon-CRC (continued)Breast cancerProstate cancerBladder cancerEsophageal cancerSarcomaThyroid cancerRetroperitoneal adenocarcinomaSmall cell lung cancerRenal cell cancer95% CI(33%, 59%)DOR rangeN59n (%)27 (46%)2PR, PR(7.6, 15.9)2PR, SD9.8 1NE1PR1PD1NE1PR7.5 1CR8.9 1PD(months)(1.9 , 22.1 )18.2 CR complete response; PR partial response; SD stable disease; PD progressive disease; NE not evaluable.Source: USPI16

Pembrolizumab Addresses Unmet Need in MSI-H/dMMR CancerPopulation MSI-H cancer represents a unique, biomarker-identified disease with a commonimmunobiology MSI-H cancers are readily identifiable using locally available assays (e.g., PCR, IHC) The low prevalence of the MSI-H phenotype in uncommon or rare cancers preclude RCTs forindividual types of MSI-H cancers Pembrolizumab addresses an unmet medical need with a favorable benefit risk profile inpreviously treated patients with advanced MSI-H cancer

ConclusionsThere is a strong biological rationale for anti-PD-1 pembrolizumab therapy of MSIcancer, regardless of tumor histologyClinical trials have demonstrated durable clinical efficacy of pembrolizumab for thetreatment of MSI-H colorectal and non-colorectal cancerChallenges in drug development for a tumor-agnostic indications Study design for providing evidence of clinical efficacy - Low prevalence ofbiomarker in uncommon or rare cancers may prevent conduct of RCTs forindividual tumor types defined by biomarker in a timely manner Identification of study population

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Histologically or cytologically confirmed, advanced, incurable non- CRC solid tumor; patients must have progressed on or be intolerant to standard therapies. c 2 prior therapies and 1 prior therapy for MSI-H CRC and non-CRC, respectively. Clinicaltrials.gov: NCT02460198 and NCT02628067 KEYNOTE-164 a /158 b (MSI-H CRC/non-CRC) Age .