1. 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.
2. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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3. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
4. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
5. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
6. Antoni Ribas, MD, PhD
Professor
Department of Medicine and
Hematology-Oncology
University of California, Los Angeles
Los Angeles, California
Overview of Immune Checkpoint
Blockade
7. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
17. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
18. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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)
19. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
Clinical Development of Other Immune
Checkpoint Inhibitors in Solid Tumors
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
20. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
21. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
22. 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
Immune Checkpoint Inhibitors
23. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
27. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
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Immune 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.
29. clinicaloptions.com/oncology
Immune 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)
31. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
32. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
34. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
35. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
36. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
37. 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
38. clinicaloptions.com/oncology
Immune 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.
39. clinicaloptions.com/oncology
Immune 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].
40. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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].
42. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
43. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
44. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
45. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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!
47. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
48. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
49. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
50. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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)
51. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
52. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
53. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
Postow MA, et al. N Engl J Med. 2015;372:2006-2017.
54. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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].
55. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
56. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
57. 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?
60. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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?
61. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
62. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
63. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
64. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
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
65. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
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
72. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
73. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
74. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
75. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
76. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
77. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
78. Antoni Ribas, MD, PhD
Professor
Department of Medicine and
Hematology-Oncology
University of California, Los Angeles
Los Angeles, California
Future Directions:
Combinations and Resistance
79. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
80. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
Ipilimumab ± Nivolumab in Previously
Untreated Metastatic Melanoma
Postow MA, et al. N Engl J Med. 2015;372:2006-2017.
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)
81. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
83. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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.
84. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
85. clinicaloptions.com/oncology
Immune Checkpoint Inhibitors
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
86. 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
clinicaloptions.com/oncology
Notes de l'éditeur
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IL, interleukin; IFN, interferon; TCR, T-cell receptor; CAR, chimeric antigen receptor; PD1, programmed death 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4.
CTLA-4, cytotoxic T-lymphocyte-associated protein 4; MHC, major histocompatibility complex; TCR, T-cell receptor.
CI, confidence interval; OS, overall survival.
MHC, major histocompatibility complex; TCR, T-cell receptor; PD-1, programmed death 1; PD-L1 programmed death ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4.
OS, overall survival; PFS, progression-free survival; DTIC, dacarbazine; HR, hazard ratio; mOS, median overall survival; Q3W, every 3 weeks; Q2W, every 2 weeks; CI, confidence interval.
HD, high dose; IL-2, interleukin-2.
PD-1, programmed death 1; PD-L1, programmed death ligand 1; TCR, T-cell receptor; MCH, major histocompatibility complex.
PD-1, programmed death 1; PD-L1, programmed death ligand 1; TCR, T-cell receptor; MCH, major histocompatibility complex.
PD-1, programmed death 1; PD-L1, programmed death ligand 1; TCR, T-cell receptor; MCH, major histocompatibility complex.
RECIST, Response Evaluation Criteria in Solid Tumors.
CRC, colorectal cancer; CT, chemotherapy; HCC, hepatocellular carcinoma; HNCC, head and neck squamous cell carcinoma; NSCLC, non-small cell carcinoma; PD, programmed death; PD-L, programmed death ligand; RCC, renal cell carcinoma.
CRC, colorectal cancer; HCC, hepatocellular carcinoma; HNCC, head and neck squamous cell carcinoma; NSCLC, non-small cell carcinoma; PD, programmed death; PD-L, programmed death ligand; RCC, renal cell carcinoma.
HNSCC, head and neck squamous cell carcinoma.
PD-1, programmed death 1; PD-L1, programmed death ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; TLR, toll-like receptor; IDO, indoleamine-pyrrole 2,3-dioxygenase; CAR, chimeric antigen receptor; ACT, adoptive cell transfer.
PD-1, programmed death 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; TCR, T-cell receptor; CAR, chimeric antigen receptor; ACT, adoptive cell transfer.
CTL, cytotoxic T cell lymphocyte; NK, natural killer cell; NKT, natural killer T cell; T reg, T regulatory cell
NSCLC, non-small cell lung cancer; HNSCC, head and neck squamous cell carcinoma; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; TNBC, triple negative breast cancer; cHL, classical Hodgkin’s lymphoma.
NSCLC, non-small cell lung cancer; HNSCC, head and neck squamous cell carcinoma; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; TNBC, triple negative breast cancer; cHL, classical Hodgkin’s lymphoma.
The safety profile of NIVO + IPI was consistent with previous reports
Treatment-related AEs were reported more frequently with the NIVO + IPI combination than with IPI
Adverse events were generally manageable using established guidelines and the majority resolved with the use of immunosuppressants
irAEs, immune-related adverse events; q2w, every 2 weeks.
irAEs, immune-related adverse events
IV, intravenous.
ACTH, adrenocorticotropic hormone; MRI, magnetic resonance imaging.