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.

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Immune Checkpoint Inhibitors
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Faculty
Program Director:
Antoni Ribas, MD, PhD
Professor
Department of Medicine and
Hematology-Oncology
University of California, Los
Angeles
Los Angeles, California
Joaquim Bellmunt, MD, PhD
Director, Bladder Cancer Center
Dana-Farber Cancer Institute
Associate Professor, Harvard
Medical School
Boston, Massachusetts
Charles G. Drake, MD, PhD
Professor, Immunology, Urology,
and Oncology
Co-Director, Multidisciplinary
Prostate Cancer Clinic
Johns Hopkins University
Baltimore, Maryland
Leora Horn, MD, MSc, FRCPC
Associate Professor of Medicine
Clinical Director, Thoracic
Oncology Research Program
Assistant Director, Education
Development Program
Vanderbilt Ingram Cancer Center
Nashville, Tennessee

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.

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.

Professor
Hematology-Oncology
University of California, Los Angeles
Overview of Immune Checkpoint
Blockade

Active immunotherapy
Adoptive cell transfer
immunotherapy
IL-2
IFN
IL-15
IL-21
Peptide vaccine
DC vaccine
Genetic vaccine
OX40
CD137
CD40
PD-1
CTLA-4
T cell cloning
TCR or CAR
genetic engineering
General Approaches for Cancer
Immunotherapy

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.

Pts at Risk, n
Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0
ProportionAlive
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)
Ipilimumab
Censored
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)

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
Cancer
cell
MHCTCR
PD-1
PD-L1
T cell
Cancer
cell
Dendritic
cell
T cell
B7

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 18
Mos
HR for death: 0.42 (99.79%
CI: 0.25-0.73; P < .001)
Nivolumab
Dacarbazine
Not reached
10.8 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 4
Mos
Ipilimumab
Pembrolizumab q2w
Pembrolizumab q3w
0 8 106 14 1612 18

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

Inhibiting PD-1–Mediated Adaptive
Immune Resistance
TCR
MHC
Melanoma cell
PD-1
PD-L1
Interferons
Taube JM, et al. Sci Transl Med. 2012;4:127ra37. Tumeh PC, et al. Nature. 2014;515:568-571.

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.
TCR
MHC
Melanoma cell
PD-1
PD-L1
Interferons
Anti–PD-1
Anti–PD-L1

TCRMHC
Melanoma cell
PD-1 PD-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

Predicting Responses in a Validation Set
From Gustave Roussy
Pt CD8+ Density, Invasive
Margin Before Treatment
Predicted Probability
of Response
Blinded
Prediction
Clinical Response
(RECIST 1.1)
1 58 0.35 Progression Progression
5 2120 0.75 Response Stable
6 5466 0.98 Response Progression
7 2211 0.76 Response Response
13 5951 0.99 Response Complete response
Tumeh PC, et al. Nature. 2014;515:568-571.

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 CT
Phase 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-224
Fc-PD-L2 fusion
protein
Phase I

Clinical Development of Anti–PD-L1
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)

Clinical Development of Other Immune
Target Antibody Molecule Development Stage
CTLA-4
Ipilimumab Humanized IgG1
Approved: advanced melanoma
Phase III multiple tumors
(melanoma, NSCLC, SCLC,
CRPC, GBM, RCC)
Tremelimumab Fully human IgG2
Phase III multiple tumors
(HNSCC, NSCLC)
IDO
INCB024360
Small-molecule
inhibitor
Phase II multiple tumors
(ovarian, melanoma)
NLG919
Small-molecule
inhibitor
Phase I
B7-H3 MGA271
Humanized
IgG1kappa
Phase I
LAG-3 BMS-986016 --- Phase I

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:
Vaccines
TCR-engineered ACT
CAR-engineered ACT
Management of Cancer in the Post Anti–
PD-1/L1 Era

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, PhD
Professor, Immunology, Urology, and
Oncology
Co-Director, Multidisciplinary Prostate
Cancer Clinic
Johns Hopkins University
Baltimore, Maryland
What Are the Expected Benefits of

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
NKT
T reg T reg
CTL
NK T reg
CTL

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.
100
80
60
40
20
0
-20
-40
-60
-80
-100
ChangeFromBaseline
inSumofLargestDiameter
ofTargetLesions(%)
Melanoma[1]
(N = 411)
KEYNOTE-001
100
80
60
40
20
0
-20
-40
-60
-80
-100
NSCLC[2]
(N = 262)
KEYNOTE-001
100
80
60
40
20
0
-20
-40
-60
-80
-100
HNSCC[3]
(N = 61)
KEYNOTE-012
100
80
60
40
20
0
-20
-40
-60
-80
-100
ChangeFromBaseline
ofTargetLesions(%)
Urothelial Cancer[4]
(N = 33)
KEYNOTE-012
100
80
60
40
20
0
-20
-40
-60
-80
-100
Gastric Cancer[5]
(N = 39)
KEYNOTE-012
100
80
60
40
20
0
-20
-40
-60
-80
-100
TNBC[6]
(N = 32)
KEYNOTE-012 100
80
60
40
20
0
-20
-40
-60
-80
-100
cHL[7]
(N = 29)
KEYNOTE-013

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.
100
80
60
40
20
0
-20
-40
-60
-80
-100
ChangeFromBaseline
ofTargetLesions(%)
Melanoma[1]
(N = 411)
KEYNOTE-001
100
80
60
40
20
0
-20
-40
-60
-80
-100
NSCLC[2]
(N = 262)
KEYNOTE-001
100
80
60
40
20
0
-20
-40
-60
-80
-100
HNSCC[3]
(N = 61)
KEYNOTE-012
100
80
60
40
20
0
-20
-40
-60
-80
-100
ChangeFromBaseline
ofTargetLesions(%)
Urothelial Cancer[4]
(N = 33)
KEYNOTE-012
100
80
60
40
20
0
-20
-40
-60
-80
-100
Gastric Cancer[5]
(N = 39)
KEYNOTE-012
100
80
60
40
20
0
-20
-40
-60
-80
-100
TNBC[6]
(N = 32)
KEYNOTE-012 100
80
60
40
20
0
-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

Nivolumab Antitumor Activity
Melanoma
(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]
125
100
75
50
25
0
-25
-50
-75
-100
MaxChangeinTarget
LesionsFromBL(%)
Pts
100
75
50
25
0
-25
-50
-75
-100
MaxChangeinTarget
LesionsFromBL(%)
Pts
Alive
Dead
Confirmed responders
100
50
0
-59
-100
MaxChangeinTumor
BurdenFromBL(%)
150
1 mg/kg nivolumab
10 mg/kg nivolumab
Pts
10
0
-50
-60
-40
-70
-80
-90
-100
MaxChangeinTumor
BurdenFromBL(%) -30
-20
-10
Pts
Stable
Disease
Partial Response
Complete
Response

Nivolumab Antitumor Activity
Melanoma
(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]
125
100
75
50
25
0
-25
-50
-75
-100
MaxChangeinTarget
LesionsFromBL(%)
Pts
100
75
50
25
0
-25
-50
-75
-100
MaxChangeinTarget
LesionsFromBL(%)
Pts
Alive
Dead
Confirmed responders
100
50
0
-59
-100
MaxChangeinTumor
BurdenFromBL(%)
150
1 mg/kg nivolumab
10 mg/kg nivolumab
Pts
10
0
-50
-60
-40
-70
-80
-90
-100
MaxChangeinTumor
BurdenFromBL(%) -30
-20
-10
Pts
Stable
Disease
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

 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.

 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)

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.
NSCLC
nonsquamous
Melanoma, cutaneous
Gastroesophageal
NSCLC
squamous
Melanoma, uveal
TNBC
Pancreatic
adeno
HNSCC
CRC
RCC
HCC
0 6 12 18 24 30 36 42 48 54 60
Wks Since Treatment Initiation
On treatment

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

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

Summary
 4 patterns of response
– Progression
– Stable disease
– Response
– Psuedoprogression
 All discernible in retrospect
 NOT easily discernible during treatment

PD-1/PD-L1 Therapy in Solid Tumors:
Single-Agent Trials
Tumor 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 recruiting
ClinicalTrials.gov.

PD-1/PD-L1 Therapy in Solid Tumors:
Single-Agent Trials
Tumor 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 = recruiting
Red font = not yet recruiting

Key Immune Checkpoint Inhibitor Studies
Still to Come at ASCO 2015 (Monotherapy)
Abstract Time Disease Setting Study Design
8009
Sunday
4:30 pm
NSCLC, SQ
(salvage)
Nivo vs doc
8010
Sunday
4:30 pm
NSCLC
(salvage)
MPDL3280A vs doc
4500
Monday
9:45 am
RCC Nivo
4501
Monday
9:45 am
UBC MPDL3280A
4502
Monday
9:45 am
UBC Pembro
LBA6008
Monday
1:15 pm
HNSCC Pembro

Joaquim Bellmunt, MD, PhD
Director, Bladder Cancer Center
Dana-Farber Cancer Institute
Associate Professor, Harvard
Medical School
Boston, Massachusetts
Recognition and Management of
Immunotherapy Related Toxicities

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.

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].

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].

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 11
Diarrhea 45 11 37 11
Colitis 23 17 13 7
Hepatic select AEs 28 15 4 0
ALT increased 22 11 4 0
AST increased 21 7 4 0
Pulmonary select AEs 12 2 4 2
Pneumonitis 11 2 4 2
Renal select AEs 3 1 2 0
Creatine increased 2 1 0 0
Endocrine select AEs 34 5 17 4
Thyroid disorder 23 1 15 0
Hypothyroidism 16 0 15 0
Hypophysitis 12 2 7 4
Skin select AEs 71 10 59 0
Rash 41 5 26 0
Pruritus 35 1 28 0
Rash maculo-popular 16 3 17 0
Postow MA, et al. N Engl J Med. 2015;372:2006-2017.

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

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, pruritus
Liver toxicity
Diarrhea, colitis
Hypophysitis
Wks
142 4 6 8 10 12
ToxicityGrade

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.

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!

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.

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.

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

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.

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)

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

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.

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)
69
89
18.6
6.1
50 (13/26)
0
85
0
8.6
NE
GI (any gr)
GI (gr 3/4)
65 (31/48)
85 (17/20)
93
88
4.7
4.3
65 (11/17)
100 (5/5)
78
80
5.0
3.6
Endo (any gr)
Endo (gr 3/4)
44 (14/32)
80 (4/5)
14
25
NE
NE
38 (3/8)
100 (2/2)
33
50
NE
NE
Hep (any gr)
Hep (gr 3/4)
50 (13/26)
86 (12/14)
85
83
14.1
8.3
0
0
0
0
NE
NE
Pul (any gr)
Pul (gr 3/4)
73 (8/11)
100 (3/3)
75
67
6.1
9.0
100 (2/2)
100 (1/1)
100
100
3.2
3.6
Renal (any gr)
Renal (gr 3/4)
67 (2/3)
100 (1/1)
100
100
0.4
0.6
0
0
0
0
NE
NE

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].

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

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, FRCPC
Associate Professor of Medicine
Clinical Director, Thoracic Oncology
Research Program
Assistant Director, Education
Development Program
Vanderbilt Ingram Cancer Center
Nashville, Tennessee
Immune Checkpoint Inhibitors:
Who Will Benefit?

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.

What Is a Marker?
 Predictive marker
– Provide information on the likely benefit from therapy
 Prognostic marker
– Provide information on outcome regardless of therapy

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?

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.

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 response
No objective response
All
9 (36)
16 (64)
25
0
17 (100)
17
PD-L1
Positive
PD-L1
Negative
Response Status, n
(%)
PD-L1 Status
1.0
0.8
0.6
0.4
0.2
0
Positive
(n = 25)
Negative
(n = 17)
9/
25
16/
25
17/
17
0/
17
Objective response
No objective response
n/N =
ProportionofPts
Association Between Pretreatment Tumor
PD-L1 Expression and Clinical Response

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 N
PD-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

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
AllTumorType
Pts–IHC(TC)
PtsWithNSCLC–
IHC(TC)
AllTumorType
Pts–IHC(TC)
PtsWithNSCLC–
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

Association of MPDL3280A Response
With PD-L1 IHC (Immune Cell) Status
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 (%)
AllTumorType
Pts–IHC(IC)
PtsWithNSCLC–
IHC(IC)
AllTumorType
Pts–IHC(IC)
PtsWithNSCLC–
IHC(IC)
CR/PR SD PD
IHC 3
IHC 2
IHC 1
IHC 0
All
IHC 3
IHC 2
IHC 1
IHC 0
All

KEYNOTE-001: Pembrolizumab Efficacy
By PD-L1 Status
Cohort N ORR*, %
All patients 495 19.4
Percent PD-L1
tumor cell staining
≥ 50%
1% - 49%
< 1%
73
103
28
45.2
16.5
10.7
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 2824201612
0
20
40
60
80
100
Mos
119
161
76
92
119
55
56
58
33
0
0
0
3
0
0
4
4
0
5
6
0
22
15
8
PS ≥50%
PS 1-49%
PS <1%
No. at RiskOverallSurvival(%)
PS 1-49%
PS ≥50%
PS <1%

Intratumoral PD-L1 as a Predictive Marker
Mahoney KM, et al. Oncology. 2014;28:39-48.
Setting Treatment
Objective 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)

Mutational Burden in Human Cancers
National Cancer Informatics Program.

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
BRAF
HER2
MEK1
AKT1
ALK
PIK3CA
NRAS
ROS1
RET
www.mycancergenome.org.
Molecular Subsets of Lung Cancer
Defined
by Driver Mutations
UnknownKRAS
EGFR

*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)
PtsWithPR(%)
EGFR
Mutant
EGFR Status (NSCLC; n = 53)
Unknown
Response by EGFR Status (ORR*)
PtsWithPR(%)
KRAS Status (NSCLC; n = 53) Response by KRAS Status (ORR*)
PtsWithPR(%)
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.
50
40
30
20
10
0
50
40
30
20
10
0
50
40
30
20
10
0
Former/Current Smokers Never Smokers
26%
10%
23%
17%
30%
10%51%
30%
19%
76%
13%
11%
81%
19%
KRAS WT
EGFR WT

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.

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)
IL-2 (n = 15) (n = 29) (n = 19)
Owing to many pts receiving multiple lines of therapy, no formal analysis to compare ORR
between groups was performed

In What Sequence?
 Severe cutaneous and neurologic toxicity in melanoma pts
during vemurafenib administration following anti–PD-1
therapy

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

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

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

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

Professor
Hematology-Oncology
University of California, Los Angeles
Future Directions:
Combinations and Resistance

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:
Vaccines
TCR-engineered ACT
CAR-engineered ACT

Ipilimumab ± Nivolumab in Previously
Untreated Metastatic Melanoma
100
90
80
70
60
50
40
30
20
10
0
PFS(%ofPts)
0 3 6 9 12 15 18
Mos
Nivolumab plus ipilimumab (n = 72)
Ipilimumab (n = 37)
Death or Disease
Progression, n/N
30/72
25/37
Median PFS,
Mos (95% CI)
NR
4.4 (2.8-5.7)
Nivolumab plus ipilimumab
Ipilimumab
HR: 0.40 (95% CI: 0.23-0.68; P < .001)

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.

Immune Checkpoint Therapy: What Is
Next?
Anti–PD-1/PD-L1
Your
favorite
treatment
The future
of cancer
therapy

Checkpoint Inhibitor Therapy: Select
Phase III Combination Trials
Tumor 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.

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

Select Checkpoint Inhibitor Combination
Studies Still to Come at ASCO 2015
Abstract Time Disease Setting Study Design
LBA1
Sunday
1:00 PM
Melanoma
(first line)
Nivo ± ipi vs ipi
3003
Monday
1:15 PM
Melanoma
MEDI4736 ± dabrafenib ±
trametinib
8011
Sunday
4:30 PM
NSCLC
(second line)
Pembro + ipi
8030
Monday
8:00 AM
NSCLC
(first line)
MPDL3280A + doublet CT
8031
Monday
8:00 AM
NSCLC
(first line)
Pembro + doublet CT

Go Online for More CCO Coverage
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Downloadable slidesets of key studies from ASCO 2015 selected by
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Expert Analysis of key ASCO 2015 abstracts

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