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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