IntroductionTreatments in

Oncology

-Chemotherapy-Radiotherapy-Surgery-Biologics

Lesterhuls WJ, et al2 and Kirkwood JM, et al. J Clin Oncol. 2008;26(20):3445-3455.

Biologic treatments

Direct

Immune mediated

VaccinesBacterialILInmunoglobulins

Immunology and tumors

Tumoral Changes

Normal Tissue

I.S. ResponseTolerance

I.S Response

Adaptative

Innate

Immunity

•Humoral Immunity: Lack

•Celular Immunity: Correct

•Citotoxic T Cells

•NK

•Antineoplasic chemokines

Overview of tumor-specif ic immune response and components targeted by individual immunotherapies

How it works?

IMMUNE CHECKPOINTS

Anti CTLA4

<br />Durable clinical responses are seen with anti-CTLA-4 treatment

Presented By Lawrence Fong at 2014 ASCO Annual Meeting

-All AEs were higher in ipilimumab+DTIC (AST and ALT , diarrhea, pruritus and rash)-Grade 3 or 4 adverse events occurred in 56.3% with ipilimumab+DTIC vs 27.5% twith DTIC p<0.001 (gastrointestinal . -The most common AE was immune related (77%)

OS

PFS

DURATION OF RESPONSE

Side effect does not depend on dose

Response is independent on

dose

Anti-PD-1 antibody(MK-3475- Pembrolizumab

Anti-PD-1L antibody(MPDL3280A)

N: 834p

•Phase III•AdvancedMelanoma.

•Received no more than

one previous systemic therapy

R1:1:1

Pembrolizumab 10mg/Kg every 2w

Pembrolizumab 10mg/Kg every 3w

Ipilimumab 3mg/Kg every 3w

EP1:

•PFS •OS

Keynote-006

Nivo 2W

Nivo 3W Ipi 3W

ORR 34% 33% 11.9%

CR: 5% 6% 1%

mTimes to response

86d 85d 87d

mTime to exposure

164d 151d 50d

AE G3-5 13% 10% 19%

Fatigue 20% 19% 15%

Diarrhea 16% 14% 22%

RashPrurito

15%14%

13%14%

15%25%

InmuneRelated AE

Nivo 2W

Nivo 3W

Ipi 3W

Hypothyroidism 10% 8.7% 2%

Hyperthyroidism 7% 3% 3%

Colitis 2% 4% 8%

Hepatitis 1% 2% 1%

Hypophysis 0.4% 0.7% 2%

Pneumonitis 0.4% 2% 0.4%

Uveitis 0.4% 1% 0%

MyositisNephritis

00

1%0.4%

0.4%0.4%

mPFS: 5.5m for 2W (95% [CI], 3.4m to 6.9m) 4.1m for 3W (95% CI, 2.9m to 6.9m)2.8m for IPI (95% CI, 2.8m to 2.9m).

HR for PFS :0.58 (95% CI, 0.46 to 0.72; P<0.001) 2-

week regimen and

0.58 (95% CI, 0.47 to 0.72; P<0.001) 3-week regimen

1Y survival :

74.1% (2W)HR: 0.63; 95% CI, 0.47 to 0.83; P<0.0005),

68.4% (3W)HR: 0.69; 95% CI, 0.52 to 0.90; P = 0.0036),

58.2% for ipilimumab

Combination

ORR: 52%-61% vs 10%-11%DCR: 65%-73% vs 20%-46%

Select Adverse Events and Their Management with Immunomodulatory Medication (IMM), According to Organ Category

•N: 140p->117p•Phase 2 Trial•Multicentric

•2 or more treatments •SQ-NSCLC EIII-IV

•Disiase mesurable by image

NIVOLUMAB 3mg/KgEvery 2 weeks (1 cicle)

Objectives

-EP1:Objective response (IRC)

-EP2: Objective response Investigator assessed (IA)

-Other EP: PK, exposure efficacy and safety,

tolerability, PFS, OS

* Treatment after progression was permitted if a patient had investigatorassessed clinical benefi t (continuing disease or symptomcontrol despite radiographic progression), stable performance status, and was tolerating nivolumab.

•PD *•Unacceptable toxiciy

Responses:

IRC IA

CR 0 1% (1p)

PR 15% (17p) 12% (14p)

SD 26% (30p) 32%

ORR: 13%-15%Disease control 41%-45%

•1-year survival rate was 41% and mOS was 8.2 months•26%p SD-> 6 months •Responses were independent of PD-L1 status

CheckMate-017(Nivolumab vs Docetaxel)

Nivolumab improved OS by

41% versus docetaxel (9.2 vs 6.0 months; HR = 0.59; 95% CI, 0.44-0.79; P = .00025).

The manufacturer of nivolumab is

working on publication and

presentation of the study data.

N: 272pPre-treated Advanced

or M1 SC NSCLC

N: 135Nivolumab 3mg/Kg IV

every 2w

R

N: 137Docetaxel 75mg/m2 IV every 3

weeks

Renal Cancer

Phase 2 study

Progression-free survival

Presented By Robert Motzer at 2014 ASCO Annual Meeting

Slide 13

Presented By Robert Motzer at 2014 ASCO Annual Meeting

Duration of response

Presented By Robert Motzer at 2014 ASCO Annual Meeting

Overall survival

Presented By Robert Motzer at 2014 ASCO Annual Meeting

Biomarkers

PD/PD-L1 in Tumor cells??

PD/PD-L1 in TIL??

Cut off %??

Biomarkers

Response Biomarkers