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Transcript of CCO immune checkpoint_inhibitors_in_cancer_care
Immune Checkpoint Inhibitors in Cancer Care: Expert Panel Discussions
This program is supported by an educational grant from Genentech.
Not an official event of the 2015 ASCO Annual Meeting. Not sponsored or endorsed by ASCO or Conquer Cancer Foundation.
clinicaloptions.com/oncologyImmune Checkpoint Inhibitors
About These Slides
Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (email [email protected])
DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
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Faculty
Program Director:Antoni Ribas, MD, PhDProfessorDepartment of Medicine and Hematology-OncologyUniversity of California, Los AngelesLos Angeles, California
Joaquim Bellmunt, MD, PhDDirector, Bladder Cancer CenterDana-Farber Cancer InstituteAssociate Professor, Harvard Medical SchoolBoston, Massachusetts
Charles G. Drake, MD, PhDProfessor, Immunology, Urology, and OncologyCo-Director, Multidisciplinary Prostate Cancer ClinicJohns Hopkins UniversityBaltimore, Maryland
Leora Horn, MD, MSc, FRCPCAssociate Professor of MedicineClinical Director, Thoracic Oncology Research ProgramAssistant Director, Education Development ProgramVanderbilt Ingram Cancer CenterNashville, Tennessee
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Faculty Disclosures
Antoni Ribas, MD, PhD, has disclosed that he has served as a consultant for Amgen, GlaxoSmithKline, Merck, and Millennium and has ownership interest in cCAM-Bio, Compugen, Flexus Bio, and Kite Pharma.
Joaquim Bellmunt, MD, PhD, has no real or apparent conflicts of interest to report.
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Faculty Disclosures
Charles G. Drake, MD, PhD, has disclosed that he has received royalties from Amplimmune and Bristol-Myers Squibb; consulting fees from Amplimmune, Bristol-Myers Squibb, Compugen, Dendreon, F-star, ImmuneXcite, Lilly, MedImmune, NexImmune, Merck, Potenza, Novartis, Roche/Genentech, sanofi-aventis, and Vesuvius; and funds for research support from Aduro Biotech, Bristol-Myers Squibb, and Janssen.
Leora Horn, MD, MSc, FRCPC, has disclosed that she has received consulting fees from Genentech and Merck.
Antoni Ribas, MD, PhDProfessorDepartment of Medicine and Hematology-OncologyUniversity of California, Los AngelesLos Angeles, California
Overview of Immune Checkpoint Blockade
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Active immunotherapy
Adoptive cell transferimmunotherapy
IL-2IFNIL-15IL-21
Peptide vaccineDC vaccineGenetic vaccine
OX40
CD137
CD40
PD-1
CTLA-4
T cell cloningTCR or CAR
genetic engineering
General Approaches for Cancer Immunotherapy
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CTLA-4: A Brake to the Immune Response to Melanoma
Antigen-MHC : TCR B7 : CD28
B7 : CTLA-4
Modified from Jedd Wolchock, Memorial Sloan Kettering Cancer Center.
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Pts at Risk, nIpilimumab 1861 839 370 254 192 170 120 26 15 5 0
Pro
po
rtio
n A
live
0
0.2
0.4
0.6
0.8
1.0
Mos
0 12 24 36 48 60 72 84 96 108 120
Median OS: 11.4 mos (95% CI: 10.7-12.1)
IpilimumabCensored
Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24. Schadendorf D, et al. J Clin Oncol. 2015;[Epub ahead of print].
Ipilimumab: Pooled Survival Analysis From Phase II/III Trials in Advanced Melanoma
3-yr OS rate: 22% (95% CI: 20-24)
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CTLA-4 and PD-1/L1 Checkpoint Blockade
Ribas A. N Engl J Med. 2012;366:2517-2519.
Priming phase (lymph node)
Effector phase (peripheral tissue)
T-cell migration
Dendritic cell
T cell
MHC TCR
B7
CD28
CTLA-4
T cell Cancercell
MHCTCR
PD-1
PD-L1
T cellCancer
cellDendritic
cellT cell
B7
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100
80
60
40
20
0
CheckMate 066 and KEYNOTE 006: OS
1. Robert C, et al. N Engl J Med. 2015;372:320-330. 2. Robert C, et al. N Engl J Med. 2015;[Epub ahead of print].
OS
(%
)
0 3 6 9 12 15 18Mos
HR for death: 0.42 (99.79% CI: 0.25-0.73; P < .001)
Nivolumab Dacarbazine
Not reached10.8 mos (9.3-12.1)
mOS (95% CI)
Dacarbazine
Nivolumab
Nivolumab vs DTIC in BRAF-negative, previously untreated melanoma[1]
Pembrolizumab vs Ipilimumab in Advanced Melanoma[2]
100
80
60
40
20
0
OS
(%
)
2 4Mos
Ipilimumab
Pembrolizumab q2w
Pembrolizumab q3w
0 8 106 14 1612 18
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Clinical Activity of Pembrolizumab
Baseline: April 13, 2012
72-yr-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab
April 9, 2013
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Inhibiting PD-1–Mediated Adaptive Immune Resistance
TCRMHC
Melanoma cell
PD-1PD-L1
Interferons
Taube JM, et al. Sci Transl Med. 2012;4:127ra37. Tumeh PC, et al. Nature. 2014;515:568-571.
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Inhibiting PD-1–Mediated Adaptive Immune Resistance
Taube JM, et al. Sci Transl Med. 2012;4:127ra37. Tumeh PC, et al. Nature. 2014;515:568-571.
TCRMHC
Melanoma cell
PD-1PD-L1
Interferons
Anti–PD-1Anti–PD-L1
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TCRMHC
Melanoma cell
PD-1PD-L1
Interferons
Responder Progression
MHC
Melanoma cell
PD-L1
Tumeh PC, et al. Nature. 2014;515:568-571.
PD-1 and PD-L1 Expression in Response to CD8 Infiltration and Adaptive Immune Resistance
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Predicting Responses in a Validation Set From Gustave RoussyPt CD8+ Density, Invasive
Margin Before TreatmentPredicted Probability
of ResponseBlinded
PredictionClinical Response
(RECIST 1.1)
1 58 0.35 Progression Progression
2 159 0.37 Progression Progression
3 329 0.40 Progression Progression
4 341 0.41 Progression Progression
5 2120 0.75 Response Stable
6 5466 0.98 Response Progression
7 2211 0.76 Response Response
8 3810 0.92 Response Response
9 4294 0.95 Response Response
10 4948 0.97 Response Response
11 5565 0.98 Response Response
12 6004 0.99 Response Response
13 5951 0.99 Response Complete response
14 7230 0.99 Response Complete response
15 6320 0.99 Response Complete response
Tumeh PC, et al. Nature. 2014;515:568-571.
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Clinical Development of Anti–PD-1 Checkpoint Inhibitors in Solid Tumors
Antibody Molecule Development Stage
Nivolumab Fully human IgG4
Approved (US): advanced melanoma after previous therapy, advanced squamous NSCLC
after CTPhase III multiple tumors (NSCLC, melanoma,
RCC, HNSCC, GBM, gastric)
Pembrolizumab Humanized IgG4
Approved (US): advanced melanoma after previous therapy
Phase III multiple tumors (HNSCC, NSCLC, melanoma, bladder, gastric/GE)
Pidilizumab Humanized IgG1 Phase II multiple tumors (pancreatic, CRC,
RCC, prostate, CNS)
AMP-224Fc-PD-L2 fusion
protein Phase I
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Clinical Development of Anti–PD-L1 Checkpoint Inhibitors in Solid Tumors
Antibody Molecule Development Stage
MEDI4736(durvalumab)
Engineered human IgG1
Phase III multiple tumors (NSCLC, HNSCC)
MPDL3280A(atezolizumab)
Engineered human IgG1
Phase III multiple tumors (NSCLC, bladder, RCC, TNBC)
MSB0010718C(avelumab)
Fully human IgG1 Phase III (NSCLC)
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Clinical Development of Other Immune Checkpoint Inhibitors in Solid TumorsTarget Antibody Molecule Development Stage
CTLA-4
Ipilimumab Humanized IgG1
Approved: advanced melanomaPhase III multiple tumors
(melanoma, NSCLC, SCLC, CRPC, GBM, RCC)
Tremelimumab Fully human IgG2Phase III multiple tumors
(HNSCC, NSCLC)
IDO
INCB024360Small-molecule
inhibitorPhase II multiple tumors
(ovarian, melanoma)
NLG919Small-molecule
inhibitorPhase I
B7-H3 MGA271Humanized IgG1kappa
Phase I
LAG-3 BMS-986016 --- Phase I
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Anti–PD-1/anti–PD-L1
Generate T cells:
+ Anti–CTLA-4+ Immune-activating antibodies or cytokines+ TLR agonists or oncolytic viruses+ IDO or macrophage inhibitors+ Targeted therapies
Bring T cells into tumors:
VaccinesTCR-engineered ACTCAR-engineered ACT
Management of Cancer in the Post Anti–PD-1/L1 Era
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Summary
CTLA-4 blockade can induce long-lasting responses in a subset of patients with metastatic melanoma
PD-1 blockade induces responses by releasing a checkpoint (brake) that limits immune responses to melanoma
When CD8+ T cells blocked by PD-1 are not present in tumors:
– Combine with other immunotherapies, like CTLA-4 blockade
– Combine with targeted therapies
– Create tumor-specific T cells for TCR or CAR ACT
Charles G. Drake, MD, PhDProfessor, Immunology, Urology, and OncologyCo-Director, Multidisciplinary Prostate Cancer ClinicJohns Hopkins UniversityBaltimore, Maryland
What Are the Expected Benefits of Immune Checkpoint Inhibitors
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The Immunoediting Hypothesis: Shaping Tumor Development
Dunn GP, et al. Nat Immunol. 2002;3:991-998. Schreiber R, et al. Science. 2011;331:1565-1570.Mittal D, et al. Curr Opin Immunol. 2014;27:16-25.
Elimination Equilibrium Escape
Genetic instability/tumor heterogeneity
Immune selection
CTL
NK
CTL
T reg
T cyto
NKTT reg T reg
CTLNK T reg
CTL
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Pembrolizumab Antitumor Activity
1. Robert C, et al. Lancet. 2014;384:1109-1117. 2. Garon EB, et al. ESMO 2014. LBA43. 3. Chow LQ, et al. ESMO 2014. LBA31. 4. O’Donnell P, et al. ASCO GU 2015. Abstract 296. 5. Muro K, et al. ASCO GI 2015. Abstract 03. 6. Nanda R, et al. SABCS 2014. Abstract S1-09. 7. Moskowitz C, et al. ASH 2014. Abstract 290.
100806040200
-20-40-60-80
-100Ch
an
ge
Fro
m B
as
eli
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in
Su
m o
f L
arg
es
t D
iam
ete
r o
f T
arg
et
Le
sio
ns
(%
) Melanoma[1] (N = 411)KEYNOTE-001
100806040200
-20-40-60-80
-100
NSCLC[2] (N = 262)KEYNOTE-001
100806040200
-20-40-60-80
-100
HNSCC[3] (N = 61)KEYNOTE-012
100806040200
-20-40-60-80
-100Ch
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Fro
m B
as
eli
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Su
m o
f L
arg
es
t D
iam
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f T
arg
et
Le
sio
ns
(%
)
Urothelial Cancer[4] (N = 33)
KEYNOTE-012
100806040200
-20-40-60-80
-100
Gastric Cancer[5] (N = 39)
KEYNOTE-012100806040200
-20-40-60-80
-100
TNBC[6] (N = 32)KEYNOTE-012 100
806040200
-20-40-60-80
-100
cHL[7] (N = 29)KEYNOTE-013
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Pembrolizumab Antitumor Activity
1. Robert C, et al. Lancet. 2014;384:1109-1117. 2. Garon EB, et al. ESMO 2014. LBA43. 3. Chow LQ, et al. ESMO 2014. LBA31. 4. O’Donnell P, et al. ASCO GU 2015. Abstract 296. 5. Muro K, et al. ASCO GI 2015. Abstract 03. 6. Nanda R, et al. SABCS 2014. Abstract S1-09. 7. Moskowitz C, et al. ASH 2014. Abstract 290.
100806040200
-20-40-60-80
-100Ch
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Fro
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as
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in
Su
m o
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arg
es
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iam
ete
r o
f T
arg
et
Le
sio
ns
(%
) Melanoma[1] (N = 411)KEYNOTE-001
100806040200
-20-40-60-80
-100
NSCLC[2] (N = 262)KEYNOTE-001
100806040200
-20-40-60-80
-100
HNSCC[3] (N = 61)KEYNOTE-012
100806040200
-20-40-60-80
-100Ch
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Fro
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as
eli
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Su
m o
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arg
es
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arg
et
Le
sio
ns
(%
)
Urothelial Cancer[4] (N = 33)
KEYNOTE-012
100806040200
-20-40-60-80
-100
Gastric Cancer[5] (N = 39)
KEYNOTE-012100806040200
-20-40-60-80
-100
TNBC[6] (N = 32)KEYNOTE-012 100
806040200
-20-40-60-80
-100
cHL[7] (N = 29)KEYNOTE-013
Pembrolizumab is FDA approved in unresectable or metastatic melanoma with disease progression following ipilimumab
(and BRAF inhibitor if BRAF V600+) and received Breakthrough Therapy designation for
EGFR/ALK-negative NSCLC and disease progression following platinum-based chemotherapy
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Nivolumab Antitumor ActivityMelanoma (n = 272)[1]
1. Weber JS, et al. Lancet Oncol. 2015;16:375-384. 2. Rizvi NA, et al. Lancet Oncol. 2015;16:257-265 3. McDermott DF, et al. J Clin Oncol. 2015;[Epub ahead of print]. 4.Ansell SM, et al. N Engl J Med. 2015;372:311-319.
Advanced NSCLC(N = 117)[2]
Advanced RCC (N = 34)[3]
Hodgkin’s Lymphoma(N = 23)[4]
125100
7550250
-25-50-75
-100Ma
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ha
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e i
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arg
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Le
sio
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Fro
m B
L (
%)
Pts
100755025
0-25-50-75
-100 Ma
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ha
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e i
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et
Le
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Fro
m B
L (
%)
Pts
AliveDeadConfirmed responders
100
50
0
-59
-100 Ma
x C
ha
ng
e i
n T
um
or
Bu
rde
n F
rom
BL
(%
) 150
1 mg/kg nivolumab10 mg/kg nivolumab
Pts
100
-50-60
-40
-70-80-90
-100 Ma
x C
ha
ng
e i
n T
um
or
Bu
rde
n F
rom
BL
(%
)-30-20-10
Pts
StableDisease
Partial Response
Complete Response
clinicaloptions.com/oncologyImmune Checkpoint Inhibitors
Nivolumab Antitumor ActivityMelanoma (n = 272)[1]
1. Weber JS, et al. Lancet Oncol. 2015;16:375-384. 2. Rizvi NA, et al. Lancet Oncol. 2015;16:257-265 3. McDermott DF, et al. J Clin Oncol. 2015;[Epub ahead of print]. 4.Ansell SM, et al. N Engl J Med. 2015;372:311-319.
Advanced NSCLC(N = 117)[2]
Advanced RCC (N = 34)[3]
Hodgkin’s Lymphoma(N = 23)[4]
125100
7550250
-25-50-75
-100Ma
x C
ha
ng
e i
n T
arg
et
Le
sio
ns
Fro
m B
L (
%)
Pts
100755025
0-25-50-75
-100 Ma
x C
ha
ng
e i
n T
arg
et
Le
sio
ns
Fro
m B
L (
%)
Pts
AliveDeadConfirmed responders
100
50
0
-59
-100 Ma
x C
ha
ng
e i
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um
or
Bu
rde
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rom
BL
(%
) 150
1 mg/kg nivolumab10 mg/kg nivolumab
Pts
100
-50-60
-40
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-100 Ma
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ha
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um
or
Bu
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rom
BL
(%
)-30-20-10
Pts
StableDisease
Partial Response
Complete Response
Nivolumab is FDA approved in unresectable or metastatic melanoma with disease progression following ipilimumab (and
BRAF inhibitor if BRAF V600+) and in metastatic squamous NSCLC on or after progression with platinum-based chemotherapy and
received Breakthrough Therapy Designation for Hodgkin’s Lymphoma
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Median time to first response was 42 days (range: 38-85)
Median duration of response: not reached
– IHC (IC) 2 or 3: 0.1+ to 30.3+ wks; IHC (IC) 0 or 1: 0.1+ to 6.0+ wks
Median follow-up: 4.2 mos (1.1+ to 8.5) for IHC 2/3 tumors and 2.7 mos (0.7+ to 3.6) for IHC 0/1 tumors
MPDL3280A: Tumor Burden Over Time in UBC
Powles T, et al. Nature. 2014;515:558-562.
clinicaloptions.com/oncologyImmune Checkpoint Inhibitors
Median time to first response was 42 days (range: 38-85)
Median duration of response: not reached
– IHC (IC) 2 or 3: 0.1+ to 30.3+ wks; IHC (IC) 0 or 1: 0.1+ to 6.0+ wks
Median follow-up: 4.2 mos (1.1+ to 8.5) for IHC 2/3 tumors and 2.7 mos (0.7+ to 3.6) for IHC 0/1 tumors
MPDL3280A: Tumor Burden Over Time in UBC
Powles T, et al. Nature. 2014;515:558-562.
MPDL3280A has received Breakthrough Therapy designation for previously treated metastatic PD-L1–positive urothelial bladder
cancer and PD-L1–positive NSCLC with progression during or after platinum-based CT (and targeted therapy if EGFR or ALK positive)
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MEDI4736: Phase I Dose Expansion Preliminary Activity in Multiple Tumor Types Overall grade 3/4 adverse event rate of 6%
Segal NH, et al. ASCO 2014. Abstract 3002.
NSCLCnonsquamous
Melanoma, cutaneous
Gastroesophageal
NSCLCsquamous
Melanoma, uveal
TNBC
Pancreatic adeno
HNSCC
CRCRCCHCC
0 6 12 18 24 30 36 42 48 54 60
Wks Since Treatment Initiation
On treatment
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Objective Response Rate to PD-1 Blockade ≈ 25% In KIDNEY Cancer
Drake CG, et al ASCO 2013. Abstract 4514.
Generally tolerable: fatigue, rash, pruritus, diarrhea
– 3 deaths: pneumonitis (non-RCC)
Durable Responses
Even Off Drug
All stopped therapy
Preliminary efficacy in heavily pre-treated patients
– 29% objective responses
– Median PFS 7.3 months
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Drake CG, et al ASCO 2013. Abstract 4514.
Case 3: Long-Term Follow-Up of Patients With Metastatic RCC on PD-1 Agent 12/30/2009: Week 32 Imaging = 80% reduction in SLD
On treatment x 2 years total
LT stable PR
clinicaloptions.com/oncologyImmune Checkpoint Inhibitors
Summary
4 patterns of response
– Progression
– Stable disease
– Response
– Psuedoprogression
All discernible in retrospect
NOT easily discernible during treatment
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PD-1/PD-L1 Therapy in Solid Tumors: Single-Agent TrialsTumor Type Phase III
Melanoma
Nivo vs chemo (NCT01721772, NCT01721746) Adjuvant nivo vs ipi (NCT02388906) Pembro (2 doses) vs ipi (NCT01866319) Adjuvant pembro vs placebo (high risk) (NCT02362594)
NSCLC
MEDI4736 following adj chemo/CRT (NCT02125461, NCT02273375) MPDL3280A vs chemo (NCT02409355, NCT02409342,
NCT02008227) Nivo vs docetaxel (squamous or nonsquamous) (NCT01642004,
NCT01673867) Nivo vs investigator’s choice chemo (NCT02041533) Nivo x 1 yr vs continuous (2nd line/beyond) (NCT02066636) Pembro vs chemo (PD-L1+) (NCT02142738, NCT02220894) Pembro (2 doses) vs docetaxel (NCT01905657)
Pts with known or suspected autoimmune disease are generally excluded from these trials Bold font = recruiting
Red font = not yet recruitingClinicalTrials.gov.
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PD-1/PD-L1 Therapy in Solid Tumors: Single-Agent TrialsTumor Type Phase III
RCC Nivo vs everolimus (TKI progression) (NCT01668784)
UBC
MPDL3280A vs chemo (NCT02302807) Pembro vs chemo (NCT02256436) Adjuvant MPDL3280A vs observation for MIBC
(NCT02450331)
Gastric/GEJ Nivo vs placebo (unresectable advanced/recurrent)
(NCT02267343) Pembro vs paclitaxel (NCT02370498)
HNSCC Nivo vs investigator’s choice (NCT02105636) Pembro vs standard therapy (NCT02252042)
Pts with known or suspected autoimmune disease are generally excluded from these trials
ClinicalTrials.gov.
Bold font = recruitingRed font = not yet recruiting
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Key Immune Checkpoint Inhibitor Studies Still to Come at ASCO 2015 (Monotherapy)
Abstract Time Disease Setting Study Design
8009Sunday4:30 pm
NSCLC, SQ (salvage)
Nivo vs doc
8010Sunday4:30 pm
NSCLC(salvage)
MPDL3280A vs doc
4500Monday9:45 am
RCC Nivo
4501Monday9:45 am
UBC MPDL3280A
4502Monday9:45 am
UBC Pembro
LBA6008Monday1:15 pm
HNSCC Pembro
Joaquim Bellmunt, MD, PhDDirector, Bladder Cancer CenterDana-Farber Cancer InstituteAssociate Professor, Harvard Medical SchoolBoston, Massachusetts
Recognition and Management of Immunotherapy Related Toxicities
clinicaloptions.com/oncologyImmune Checkpoint Inhibitors
Adverse Events Associated With Checkpoint Inhibitors Are Immune Related
irAE (All Grades), % Ipilimumab + Dacarbazine[1]
(n = 247)Ipilimumab + Placebo[2]
(n = 251)
Total 77.7 61.1 Grade 3/4 41.7 14.5
Dermatologic
Pruritus 26.7 24.4 Rash 22.3 19.1
Gastrointestinal
Diarrhea 32.8 27.5 Colitis 4.5 7.6
Hepatic
Increase in ALT 29.1 1.5 Increase in AST 26.7 0.8 Hepatitis 1.6 0.8
1. Robert C, et al. N Engl J Med. 2011;362:2517-2526. 2. Hodi FS, et al. N Engl J Med. 2010;363:711-723.
clinicaloptions.com/oncologyImmune Checkpoint Inhibitors
Summary of CTLA-4 Blockade Immune-Mediated Toxicities Toxicity related to ipilimumab appears to be dose related
Toxicity-related death occurred in < 1% of cases
Common (> 20%)
Rash, pruritus
Fevers, chills, lethargy
Diarrhea/colitis
Occasional (3% to 20%)
Hepatitis/liver enzyme abnormalities
Endocrinopathies: hypophysitis, thyroiditis, adrenal insufficiency
Rare (< 2%)
Episcleritis/uveitis
Pancreatitis
Nephritis
Neuropathies, Guillain-Barré, myasthenia gravis
Lymphadenopathy (sarcoid)
Thrombocytopenia
Toxic epidermal necrolysis, Stevens-Johnson syndrome
Weber JS, et al. J Clin Oncol. 2012;30:2691-2697. Weber JS, et al. J Clin Oncol. 2015;[Epub ahead of print].
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Summary of PD-1/PD-L1 Blockade Immune-Mediated Toxicities Toxicity less common than with anti–CTLA-4 but can be fatal
Occasional (5% to 20%)
Fatigue, headache, arthralgia, fevers, chills, lethargy
Rash: maculopapular, pruritus,vitiligo
– Topical treatments
Diarrhea/colitis
– Initiate steroids early, taper slowly
Hepatitis, liver/pancreatic enzyme abnormalities
Infusion reactions
Endocrinopathies: thyroid, adrenal, hypophysitis
Rare (< 5%)
Pneumonitis
– Grade 3/4 toxicities uncommon
– Low grade reversible with steroids and discontinuation
Anemia
Weber JS, et al. J Clin Oncol. 2012;30:2691-2697. Weber JS, et al. J Clin Oncol. 2015;[Epub ahead of print].
clinicaloptions.com/oncologyImmune Checkpoint Inhibitors
Ipilimumab Plus Nivolumab in Untreated Adv Melanoma: Adverse Events
Patients Reporting, % (Select AEs/Organ Category)
NIVO + IPI (n = 94) IPI (n =46)
Any Grade Grade 3–4 Any Grade Grade 3–4
Gastrointestinal select AEs 51 21 37 11Diarrhea 45 11 37 11Colitis 23 17 13 7
Hepatic select AEs 28 15 4 0ALT increased 22 11 4 0AST increased 21 7 4 0
Pulmonary select AEs 12 2 4 2Pneumonitis 11 2 4 2
Renal select AEs 3 1 2 0Creatine increased 2 1 0 0
Endocrine select AEs 34 5 17 4Thyroid disorder 23 1 15 0Hypothyroidism 16 0 15 0Hypophysitis 12 2 7 4
Skin select AEs 71 10 59 0Rash 41 5 26 0Pruritus 35 1 28 0Rash maculo-popular 16 3 17 0
Postow MA, et al. N Engl J Med. 2015;372:2006-2017.
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Combination Therapy With Ipilimumab and Nivolumab: Toxicity Summary
The safety profile of ipilimumab and nivolumab is characterized by immune related adverse events
There is the potential for increased frequency of drug related adverse events with nivolumab combined with ipilimumab over either agent as monotherapy, in particular for lipase / amylase, AST / ALT
Skin toxicity, uveitis, neurological, renal
No new toxicities have been identified with the combination treatment
Toxicities with the combination have been manageable and reversible following intervention with systemic steroids in alignment with established AE management algorithms
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0
Weber JS, et al. J Clin Oncol. 2012;30:2691-2697. Weber JS, et al. J Clin Oncol. 2015;[Epub ahead of print].
Kinetics of Appearance of irAEs With Checkpoint Blockade
Data from pts receiving anti–PD-1 antibodies q2w for ≥ 3 yrs show most irAEs occur by Wk 24 (6 mos)
Toxicities with PD-1/PD-L1 agents may take longer to resolve than with ipilimumab, so long-term surveillance is recommended
Rash, pruritusLiver toxicityDiarrhea, colitisHypophysitis
Wks142 4 6 8 10 12
To
xici
ty G
rad
e
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Immunotherapy-Related Dermatitis
Ipilimumab: skin toxicity most common irAE
– Rare severe rashes require hospitalization
– Sweet syndrome rarely described
PD-1 inhibitors: oral mucositis and dry mouth more frequent
– Oral corticosteroid rinses and topical lidocaine can be beneficial
Nivolumab: rash (36%) and pruritus (28%) most common skin toxicities; grade 3/4 rare
– Typically maculopapular and managed as outlined for ipilimumab
Howell M, et al. Lung Cancer. 2015;88:117-123.
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Skin Toxicity: Learnings!!!
If patient reports rash → visual exam!
High-dose IV steroids for grade 3/4 rash
Long taper upon improvement
Severe reactions are rarely seen. Recently, a case of toxic epidermal necrolysis (TENS) occurred in a nivolumab/ ipilimumab combination study
Educate pts regarding importance of immuno-suppression
Compliance with oral steroids!
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Colitis: Immune Checkpoint Inhibitor Toxicity Ulceration in descending colon
Focal active colitis
Alterations in crypt epithelium
Maker AV, et al. Ann Surg Oncol. 2005;12:1005-1016.
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Prompt Treatment of Colitis
A retrospective analysis of 836 trial pts showed that early initiation of steroid treatment for colitis led to faster resolution of symptoms than delayed steroid treatment[1]
Several case studies support use of infliximab to further blunt immune response in steroid-refractory colitis[2,3]
Bloody diarrhea uncommon but may indicate more severe colitis[4]
At colonoscopy, colitis typically affects the distal colon with sparing of rectum[4]
1. O’Day S, et al. ASCO 2011. Abstract 8554. 2. Pagès C, et al. Melanoma Res 2013;23:227-230. 3. Merrill SP, et al. Ann Pharmacother. 2014;48:806-810. 4. Howell M, et al. Lung Cancer. 2015;88:117-123.
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Pulmonary Toxicities related to Immunotherapy
Several pulmonary inflammatory complications reported with ipilimumab. (sarcoidosis and organizing inflammatory pneumonia)
Pneumonitis rarely in patients treated with PD-1 blocking agents, but with occasional fatal consequence in early trials. (< 3%)
Symptoms of an upper respiratory infection, new cough, or SOB, pneumonitis should be considered and imaging is warranted
In moderate to severe symptoms and/or radiographic findings, bronchoscopy should be considered to exclude infectious processes prior to starting immunosuppression.
In severe cases, treatment with 2 mg/kg of intravenous methylprednisone and consideration of additional immunosuppression including infliximab, mycophenolate mofetil, cyclophosphamide if necessary
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Endocrine Toxicities
Following ipilimumab therapy, incidence of hypophysitis 8% and hypothyroidism/thyroiditis 6%; primary adrenal dysfunction rare
Combination of ipilimumab and nivolumab associated with 22% incidence of thyroiditis or hypothyroidism and 9% incidence of hypophysitis
Symptomatic relief for hypophysitis achieved with hormone replacement, although endogenous hormone secretion rarely recovered
– Symptoms can include: headache, fatigue, weakness, memory loss, impotence, personality changes, and visual-field impairment
– Events can occur within wks of beginning treatment but also have been noted to occur many mos (while still on treatment)
Ryder M, et al. Endocr Relat Cancer. 2014;21:371-381.
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Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.
Symptom Management: Hypophysitis
Prompt therapy ameliorates symptoms and permits continued therapy
25% of pts with hypophysitis have normal pituitary MRI
Monitor ACTH and cortisol levels in pts receiving checkpoint inhibitors
Physiologic steroid replacement may be sufficient
– Higher-dose in symptomatic pts (headaches and vision changes)
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Less Common Immune-Related Adverse Events Hematologic (hemolytic anemia, thrombocytopenia)
Cardiovascular (myocarditis, pericarditis, vasculitis)
Ocular (blepharitis, conjunctivitis, iritis, scleritis, uveitis)
Renal (nephritis)
Several case reports of rare autoimmune-based toxicities in pts treated with ipilimumab
– Lupus nephritis
– Inflammatory enteric neuropathy
– Tolsosa-Hunt syndrome
Ipilimumab adverse reaction management guide.
– Myocardial fibrosis
– Acquired hemophilia A
– Autoimmune polymyositis
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Ipilimumab-Associated Uveitis
Uveitis and episcleritis have been reported in < 1% of pts treated with ipilimumab or anti–PD-1 antibodies
Symptoms typically occur ~ 2 mos following treatment: photophobia, pain, dryness of the eyes, blurred vision
Treatment: topical steroids for grade 1/2 toxicity
For grade ≥ 3 toxicity systemic corticosteroids and discontinuation of immunotherapy is required
Attia P, et al. J Clin Oncol. 2005;23:6043-6053. Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.
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irAE Management With Immunomodulatory Medication
Nivolumab + Ipilimumab (n = 94) Ipilimumab (n = 46)
Tx With IMM, %
(n/N)
Resolution After IMM, %
Resolution, Wks
Tx With IMM, %
(n/N)
Resolution After IMM,
%
Resolution, Wks
Skin (any gr)Skin (gr 3/4)
61 (41/67)100 (9/9)
6989
18.66.1
50 (13/26)0
850
8.6NE
GI (any gr)GI (gr 3/4)
65 (31/48)85 (17/20)
9388
4.74.3
65 (11/17)100 (5/5)
7880
5.03.6
Endo (any gr)Endo (gr 3/4)
44 (14/32)80 (4/5)
1425
NENE
38 (3/8)100 (2/2)
3350
NENE
Hep (any gr)Hep (gr 3/4)
50 (13/26)86 (12/14)
8583
14.18.3
00
00
NENE
Pul (any gr)Pul (gr 3/4)
73 (8/11)100 (3/3)
7567
6.19.0
100 (2/2)100 (1/1)
100100
3.23.6
Renal (any gr)Renal (gr 3/4)
67 (2/3)100 (1/1)
100100
0.40.6
00
00
NENE
Postow MA, et al. N Engl J Med. 2015;372:2006-2017.
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Toxicity Guidelines
TFTs, CBCs, LFTs and metabolic panels should be obtained at each treatment and q6-12 wks for 6 mos posttreatment in all pts receiving checkpoint protein antibodies
ACTH, cortisol should also be checked in pts with fatigue and nonspecific symptoms, plus testosterone in men
Frequency of follow-up testing should be adjusted to individual response and AEs that occur
Corticosteroids can reverse nearly all toxicities associated with these agents, but should be reserved for grade 3/4, or prolonged grade 2, irAEs
Weber JS, et al. J Clin Oncol. 2015;[Epub ahead of print].
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Management of Drug-Related AEs
The majority of both nivolumab- and ipilimumab-related AEs to date have been reversible and manageable by delaying study drug ± administration of corticosteroids; other immunosuppressants may also be needed
The following categories of AEs, requiring greater vigilance and early intervention:
– Pulmonary
– Hepatic
– Renal
– GI
– Endocrine
– Neurological
– Skin
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Summary
Toxicity is mostly low grade and can be managed with supportive treatment
A concerted effort to educate the whole multidisciplinary team needs to take place and development of accessible algorithms to ensure minimized risk with toxicity
The key to successful management of checkpoint protein antibody toxicities is early diagnosis, high suspicion, excellent patient–provider communication, and rapid and aggressive use of corticosteroids and other immune suppressants for irAEs
The majority of both nivolumab and ipilimumab related AEs to date have been reversible and manageable by delaying study drug ± administration of corticosteroids; other immunosuppressants may also be needed
The following categories of AEs, requiring greater vigilance and early intervention: pulmonary, hepatic, renal, GI, endocrine, neurological, skin
Leora Horn, MD, MSc, FRCPCAssociate Professor of MedicineClinical Director, Thoracic Oncology Research ProgramAssistant Director, Education Development ProgramVanderbilt Ingram Cancer CenterNashville, Tennessee
Immune Checkpoint Inhibitors: Who Will Benefit?
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Things to Consider
What is the best marker?
– What is the best assay?
What stage of disease?
– What line of therapy?
In what sequence?
What type of pt?
Image courtesy of Cliparts.co.
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What Is a Marker?
Predictive marker
– Provide information on the likely benefit from therapy
Prognostic marker
– Provide information on outcome regardless of therapy
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PD-L1 Testing Is Controversial
Different assays have not been compared
Each assay has a different cut point that defines PD-L1 positive
What is better – archival or fresh tissue?
Where do you biopsy – the primary tumor or a metastatic site?
Is tissue from a core biopsy the only way to evaluate for PD-L1 expression?
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PD-L1 as a Prognostic Marker
PD-L1 expression has been identified as a negative prognostic marker
– More aggressive phenotype in melanoma[1]
– Increased risk of metastasis and death in RCC and lung cancer[2,3]
– Increased risk of metastatic disease in gastric cancer [4]
1. Massi D, et al. Ann Oncol. 2014;25:2433-2442. 2. Thompson RH, et al. Proc Natl Acad Sci USA. 2004;101:17174-17179. 3. Mu CY, et al. Med Oncol. 2011;28:682-688. 4. Zheng Z, et al. Chin J Cancer Res. 2014;26:104-111.
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Topalian SL, et al. N Engl J Med. 2012;366:2443-2454.
PD-L1 as a Predictive Marker: Response Based on PD-L1 Expression
P = .006 for association by Fisher’s exact test
9 (21)33 (79)
42
Total
Objective responseNo objective responseAll
9 (36)16 (64)
25
017 (100)
17
PD-L1Positive
PD-L1Negative
Response Status, n (%)
PD-L1 Status
1.0
0.8
0.6
0.4
0.2
0Positive(n = 25)
Negative(n = 17)
9/25
16/25
17/17
0/17
Objective responseNo objective response
n/N =
Pro
po
rtio
n o
f P
ts
Association Between Pretreatment Tumor PD-L1 Expression and Clinical Response
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PD-L1 Prevalence and Expression
Herbst RS, et al. Nature. 2014;515:563-567.
PD-L1 Prevalence Determined With Anti–PD-L1 IHC Assay
Indication NPD-L1 Positive
(IC), %PD-L1 Positive
(TC), %
NSCLC 184 26 24
RCC 88 25 10
Melanoma 58 36 5
HNSCC 101 28 19
Gastric cancer 141 18 5
Colorectal cancer 77 35 1
Pancreatic cancer 83 12 4
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Herbst RS, et al. Nature. 2014;515:563-567.
IHC 3
IHC 2
IHC 1
IHC 0
All
IHC 3
IHC 2
IHC 1
IHC 0
All
0 20 40 60 80 100
0 20 40 60 80 100
020406080100
020406080100
Pts (%)
Pts (%)
IHC 3, n = 8; IHC 2, n = 1; IHC 1, n = 3; IHC 0, n = 34; Unknown, n = 7; All, n = 53
IHC 3, n = 15; IHC 2, n = 3; IHC 1, n = 11; IHC 0, n = 121; Unknown, n = 25; All, n = 175
All
Tu
mo
r T
ype
P
ts –
IH
C (
TC
)P
ts W
ith
NS
CL
C –
IH
C (
TC
)
All T
um
or T
ype
P
ts – IHC
(TC
)P
ts With
NS
CL
C –
IHC
(TC
)
IHC 3
IHC 2
IHC 1
IHC 0
All
IHC 3
IHC 2
IHC 1
IHC 0
All
CR/PR SD PD
Association of MPDL3280A Response With PD-L1 IHC (Tumor Cell) Status
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Association of MPDL3280A Response With PD-L1 IHC (Immune Cell) Status
Herbst RS, et al. Nature. 2014;515:563-567.
IHC 3
IHC 2
IHC 1
IHC 0
All
IHC 3
IHC 2
IHC 1
IHC 0
All
0 20 40 60 80 100
0 20 40 60 80 100
020406080100
020406080100
Pts (%)
Pts (%)
IHC 3, n = 6; IHC 2, n = 7; IHC 1, n = 13; IHC 0, n = 20; Unknown, n = 7; All, n = 53
IHC 3, n = 33; IHC 2, n = 23; IHC 1, n = 34; IHC 0, n = 60; Unknown, n = 25; All, n = 175
All
Tu
mo
r T
ype
P
ts –
IH
C (
IC)
Pts
Wit
h N
SC
LC
–
IHC
(IC
)
All T
um
or T
ype
P
ts – IHC
(IC)
Pts W
ith N
SC
LC
– IH
C (IC
)
CR/PR SD PD
IHC 3
IHC 2
IHC 1
IHC 0
All
IHC 3
IHC 2
IHC 1
IHC 0
All
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KEYNOTE-001: Pembrolizumab Efficacy By PD-L1 StatusCohort N ORR*, %
All patients 495 19.4
Percent PD-L1 tumor cell staining≥ 50%1% - 49%< 1%
7310328
45.216.510.7
Garon EB, et al. N Engl J Med. 2015; 372:2018-2028.
*per RECIST
Proportion score (PS): membranous PD-L1 expression of tumor cells
0 4 8 28242016120
20
40
60
80
100
Mos
11916176
9211955
565833
000
300
440
560
22158
PS ≥50%PS 1-49%PS <1%
No. at RiskO
vera
ll S
urv
ival
(%
)
PS 1-49%
PS ≥50%
PS <1%
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Intratumoral PD-L1 as a Predictive Marker
Mahoney KM, et al. Oncology. 2014;28:39-48.
Setting TreatmentObjective Response Rate, %
Assay (mAb)Unselected PD-L1+ PD-L1–
Solid tumors (n = 42) Nivo 21 36 0 Tumor (5H1)
Melanoma (n = 44) Nivo 32 67 19 Tumor (28-8)
Tumor (28-8)Melanoma (n = 34) Nivo 29 44 17
Melanoma (n = 113) Pembro 40 49 13 Tumor (22C3)
NSCLC (n = 129) Pembro 19 37 11 Tumor (22C3)
HNSCC (n = 55) Pembro 18 46 11 Tumor (22C3)
Melanoma (n = 411) Pembro 40 49 13 Tumor (22C3)
Solid tumors (n = 94) MPDL 21 36 13 TIL
Melanoma (n = 30) MPDL 29 27 20 TIL
NSCLC (n = 53) MPDL 23 46 15 TIL
Bladder (n = 65) MPDL 26 43 11 TIL
Solid tumors (n = 179) MEDI 11 22 4 NR (SP263)
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Mutational Burden in Human Cancers
National Cancer Informatics Program.
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Frequency of Driver Mutations in NSCLC, %
AKT1 1
ALK 3-7
BRAF 1-3
EGFR 10-35
HER2 2-4
KRAS 15-25
MEK1 1
NRAS 1
PIK3CA 1-3
RET 1
ROS1 1
BRAFHER2
MEK1
AKT1
ALK
PIK3CA
NRAS
ROS1
RET
www.mycancergenome.org.
Molecular Subsets of Lung Cancer Defined by Driver Mutations
UnknownKRAS
EGFR
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*ORR includes investigator-assessed u/c PR by RECIST 1.1. Patients first dosed at 1-20 mg/kg by October 1, 2012.
Former/ Current Smokers
Never Smokers
Response by Smoking Status (ORR*)Smoking Status (NSCLC; n = 53)
Pts
Wit
h P
R (
%)
EGFR Mutant
EGFR Status (NSCLC; n = 53)
Unknown
Response by EGFR Status (ORR*)
Pts
Wit
h P
R (
%)
KRAS Status (NSCLC; n = 53) Response by KRAS Status (ORR*)P
ts W
ith
PR
(%
)
KRAS Mutant
Unknown
EGFR WT EGFR Mutant
KRAS WT KRAS Mutant
11/43 1/10
9/40 1/6
8/27 1/10
MPDL3280A Phase Ia: Response by Smoking and Mutational Status
Horn L, et al. WCLC 2013. Abstract MO18.01.
5040302010
0
5040302010
0
5040302010
0
Former/Current Smokers Never Smokers
26%
10%
23%17%
30%
10%51%
30%
19%
76%13%
11%
81%
19%
KRAS WT
EGFR WT
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Immune Therapy in NRAS Melanoma
Johnson DB, et al. Cancer Immunol Res. 2015;3:288-295.
*Pearson χ2 test P value for NRAS-mutant vs non-NRAS-mutant pts.
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Immune Therapy in NRAS Melanoma
Response, n (%) NRAS Mutant BRAF Mutant Wild Type
Anti–PD-1/PD-L1 (n = 11) (n = 14) (n = 23)
Objective response 7 (64) 3 (21) 8 (35)
Clinical benefit 8 (73) 3 (21) 10 (43)
Ipilimumab (n = 43) (n = 31) (n = 95)
Objective response 8 (19) 4 (13) 10 (11)
Clinical benefit 18 (42) 5 (16) 19 (20)
IL-2 (n = 15) (n = 29) (n = 19)
Objective response 5 (33) 6 (21) 5 (26)
Clinical benefit 5 (33) 11 (34) 7 (37)Owing to many pts receiving multiple lines of therapy, no formal analysis to compare ORR between groups was performed
Johnson DB, et al. Cancer Immunol Res. 2015;3:288-295.
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In What Sequence?
Severe cutaneous and neurologic toxicity in melanoma pts during vemurafenib administration following anti–PD-1 therapy
Johnson DB, et al. Cancer Immunol Res. 2013;1:373-377.
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What Line of Therapy?
Tumor Type Line of Therapy
Melanoma Phase I: heavily treated; second line; first line (BRAF mutation negative); adjuvant
Renal cell Phase I: heavily treated; second line
Lung cancer Phase I: heavily treated; second line, PD-L1 positive or unknown; first line, PD-L1 positive (EGFR and ALK negative); adjuvant
Bladder Phase I: second line
Breast cancer Phase I: second line or beyond
Pancreatic cancer Phase I: first line; adjuvant, neoadjuvant
HCC Phase I
Ovarian cancer Phase I: platinum refractory
Gastric cancer Phase I
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What Line of Therapy?
Tumor Type Line of Therapy
Melanoma Phase I: heavily treated; second line; first line (BRAF mutation negative); adjuvant
Renal cell Phase I: heavily treated; second line
Lung cancer Phase I: heavily treated; second line, PD-L1 positive or unknown; first line, PD-L1 positive (EGFR and ALK negative); adjuvant
Bladder Phase I: second line
Breast cancer Phase I: second line or beyond
Pancreatic cancer Phase I: first line; adjuvant, neoadjuvant
HCC Phase I
Ovarian cancer Phase I: platinum refractory
Gastric cancer Phase I
All Lines of Therapy
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Which Pts Do We Avoid?
Exclusion criteria in previous studies:
– Performance status ≥ 2
– Autoimmune disease
– Recent data suggest ipilimumab can be given safely
– Hepatitis, HIV
– Recent data suggest ipilimumab can be given safely
– Brain metastases
– PD-L1 negative
– Interstitial lung disease
– On “higher dose” steroids
Extreme caution should be taken in treating pts with recent or ongoing autoimmune conditions
– Particularly inflammatory bowel disease
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Summary
PD-L1 is a negative prognostic marker in multiple tumor types
PD-L1 expression is associated with an increased response rate to therapy with PD-1/PD-L1 inhibitors
Response to immune checkpoint inhibitors has not been associated with current known mutations
Increased mutation burden is associated with response to immune checkpoint inhibitors
PD-1/PD-L1 inhibitors are active and being explored in all lines of therapy
The safety of PD-1/PD-L1 inhibitors in select clinical cohorts needs to be explored
Antoni Ribas, MD, PhDProfessorDepartment of Medicine and Hematology-OncologyUniversity of California, Los AngelesLos Angeles, California
Future Directions: Combinations and Resistance
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Management of Cancer in the Post Anti–PD-1/PD-L1 Era
Anti–PD-1/anti–PD-L1
Generate T cells:
+ Anti–CTLA-4+ Immune-activating antibodies or cytokines+ TLR agonists or oncolytic viruses+ IDO or macrophage inhibitors+ Targeted therapies
Bring T cells into tumors:
VaccinesTCR-engineered ACTCAR-engineered ACT
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Ipilimumab ± Nivolumab in Previously Untreated Metastatic Melanoma
Postow MA, et al. N Engl J Med. 2015;372:2006-2017.
100908070605040302010
0
PF
S (
% o
f P
ts)
0 3 6 9 12 15 18Mos
Nivolumab plus ipilimumab (n = 72)
Ipilimumab (n = 37)
Death or DiseaseProgression, n/N
30/7225/37
Median PFS, Mos (95% CI)
NR4.4 (2.8-5.7)
Nivolumab plus ipilimumabIpilimumab
HR: 0.40 (95% CI: 0.23-0.68; P < .001)
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Immunotherapy Effects of BRAF Inhibitors
↑ CD8+ TILs[1]
↑ Melanoma antigen expression[1]
Antitumor activity of combined BRAFi + MEKi plus anti–PD-1[2]
↑ MHC and melanoma antigen expression[2]
1. Frederick DT, et al. Clin Cancer Res. 2013;19:1225-1231. 2. Hu-Lieskovan S, et al. Sci Transl Med. 2015;7:279ra41.
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Immune Checkpoint Therapy: What Is Next?
Anti–PD-1/PD-L1
Your favorite
treatmentThe future of cancer therapy
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Checkpoint Inhibitor Therapy: Select Phase III Combination TrialsTumor Type Phase III (Unless Otherwise Indicated)
Melanoma Nivo vs ipi vs ipi/nivo (NCT01844505) Nivo/ipi + GM-CSF vs nivo/Ipi (NCT02339571)
RCC Nivo/ipi vs sunitinib (NCT02231749) MPDL + bev vs sunitinib (NCT02420821)
NSCLC Ipi + pac/carbo vs pac/carbo (NCT02279732) MPDL + CT (± bev) vs CT (+ bev) (NCT02367794,
NCT02367781, NCT02366143)
HNSCC MEDI4736 + treme vs SOC (NCT02369874)
GBM Nivo/Ipi vs nivo vs bev (NCT02017717)
TNBC MPDL/nab-pac vs nab-pac (NCT02425891)
Pts with known or suspected autoimmune disease are generally excluded from these trials
ClinicalTrials.gov.
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Conclusions
PD-1 blockade induces responses by releasing a checkpoint (brake) that limits immune responses to melanoma and other tumors
When CD8+ T cells blocked by PD-1 are not present in tumors
– Combine with other immunotherapies, like ipilimumab
– Combine with targeted therapies
– Create tumor-specific T cells for TCR or CAR ACT
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Select Checkpoint Inhibitor Combination Studies Still to Come at ASCO 2015
Abstract Time Disease Setting Study Design
LBA1Sunday1:00 PM
Melanoma(first line)
Nivo ± ipi vs ipi
3003Monday1:15 PM
MelanomaMEDI4736 ± dabrafenib ±
trametinib
8011Sunday4:30 PM
NSCLC(second line)
Pembro + ipi
8030Monday8:00 AM
NSCLC(first line)
MPDL3280A + doublet CT
8031Monday8:00 AM
NSCLC(first line)
Pembro + doublet CT
Go Online for More CCO Coverage of Cancer Immunotherapy!
Downloadable slidesets of key studies from ASCO 2015 selected by expert faculty
Expert Analysis of key ASCO 2015 abstracts
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