April 18 2018 ImmunoOncology Activating the immunesystem to fight the cancer via the use of antibodies We have many tumours that form in our body throughout our lifetime Most tumours removed by immune response ID: 777305
Download The PPT/PDF document "Immuno-Oncology Dr. Michael Palumbo" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Immuno-Oncology
Dr. Michael Palumbo
April 18, 2018
Slide2Immuno-OncologyActivating the immune-system to fight the cancer (via the use of antibodies)
We have many
tumours
that form in our body throughout our lifetimeMost tumours removed by immune responseOnce a tumour learns to evade the immune system….we’re in trouble!
Slide3CTLA-4 and PD-1: Priming vs Effector
[
Ribas
A., N
Engl
J Med, 2012]
CD: Cluster of Differentiation; CTLA4: Cytotoxic T‑lymphocyte-Associated Antigen 4; DC: Dendritic Cell; MHC: Major Histocompatibility Complex;
PD-1:
Programmed Death-1; PD-L: Programmed Death Ligand; TCR: T-Cell Receptor.
Anti-PD1
Nivolumab
Pembrolizumab
Anti-CTLA4
Ipilimumab
Slide4Metastatic Melanoma
Treatment
Dacarbazine (DTIC)
In large randomized trials, Response rate (RR) of <15%
Temozolomide
Similar to DTIC
IL-2
RR of 15-20%A minority are durable responsesHighly toxic treatment
Survival
1
Median OS: 6.2 monthsOne year OS: 25.5% (95% CI, 23.6% to 27.4%)
OS=overall survival.
1. Korn, JCO. 2008 Feb 1; 26(4)
Slide5Study CheckMate 066:
Overall Survival in Patients Receiving
Nivolumab
(Anti-PD1) or Dacarbazine
Database lock was on July 15, 2015.
CI = confidence interval; HR = hazard ratio; NR = not reached; OS = overall survival.
Atkinson V, et al. Presented at: Society for Melanoma Research; November 18-21, 2015; San Francisco, CA.
46.3%
26.7%
70.7%
57.7%
Dacarbazine
Nivolumab
Months
30
0
27
24
21
18
15
12
9
6
3
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Probability of Survival
Nivolumab
(N = 210)
Dacarbazine
(N = 208)
Median OS,
month
(95% CI)
NR
(23.1, NR)
11.2
(9.6, 13.0)
HR (95% CI)
0.43 (0.33, 0.57);
P
< 0.001
5+ year survival ~30%!
Slide6Summary of Nivolumab-Related Immune-Mediated Adverse Events in Study
CheckMate
037
Immune-Mediated AE Organ Category, %
CheckMate
037
Melanoma
N = 268
Any Grade
Grade 3/4
Skin
29.1
0.4
Gastrointestinal
11.6
1.1
Endocrine
7.8
0
Hepatic
4.5
0.7
Pulmonary
2.2
0
Hypersensitivity/Infusion reaction
1.9
0.4
Renal
1.5
0.4
AE = adverse event; NA = not available.
Weber JS, et al
. Lancet Oncol.
2015;16(4):375
‒
384.
Slide7CHECKMATE 004: Long-term Survival Data with Concurrent Nivolumab
(Anti-PD1) & Ipilimumab (Anti-CTLA4)
7
Cohorts 1–3
Cohort 8
All concurrent cohorts
63
60
57
54
51
48
45
42
39
36
33
30
27
24
21
18
15
12
9
6
3
0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months
Probability of Survival
a
Median duration of follow-up was 32.7 months (range: 2.5–61.4), 19.9 months (range: 0.9–24.0), and 23.0 months (range 0.9–61.4) for cohorts 1–3, cohort 8, and all concurrent cohorts, respectively
Died/treated,
n/N
Median OS
a
,
mo (95% CI)
Cohorts 1–3
18/53
NR (39.8–NR)
Cohort 8
14/41
NR (20.0–NR)
All concurrent cohorts
32/94
43.9 (39.8–NR)
Cohorts 1–3: 85%
Cohorts 1–3: 68%
Sznol M, et al: Presented at SMR 2015.
Slide8Ipilimumab +
Nivolumab
- Safety Profile
62% Grade 3-4
AEs
;
1/94 G5 (i.e.
colitis);23%
discontinued treatment due to treatment-related AEs.
AE
[
%]
Concurrent
Cohorts
1-3 N=53
Cohort
8
N=41
All Concurrent N=94
All
Grade
3-4
All
Grade 3-4
All
Grade 3-4
All
Related
AEs
96
62
95
61
96
62
Selected
AEs
Gastrointestinal
43
9
34
20
39
14
Hepatic
30
15
1212
22
14Skin
79
473
1577
9
Endocrine17
422
219
3
Renal6
6
00
33
Others
Uveitis64
2243Pneumonitis6
22242Lipase
261915102115
Amylase 216127176
[Adapted from Sznol M. et al., ASCO, 2014]
Slide9Overall Survival at 2 Years of Follow-up: Effect of AE
9
Percentage of Overall Survival
Time (months)
0
10
20
30
40
50
60
70
80
90
100
0
3
6
9
12
15
18
27
24
21
30
Median and 95% CI
All Randomized NIVO+IPI
NR
Discontinued Due to AEs NIVO+IPI
NR
All Randomized IPI
NR (11.9, NR)
83%
71%
73%
64%
65%
54%
Database lock February 2016
Slide10irAE = immune-realted adverse events
Harmankaya K,
et al.
Presented at the World Meeting of Interdisciplinary Melanoma/Skin Cancer Centers: November 19 - 21, 2009; Berlin, Germany.
Example of Evolution of Response
to CTLA-4 Inhibition (Pseudo-progression)
Screening
Week 96:
Durable and ongoing response
without signs of irAEs
Week 12:
Initial increase in
total tumour burden
(mWHO PD)
Week 16:
Responding
Slide11Non-Small Cell Lung Cancer
Metastatic Non-Small Cell Lung Cancer
Chemotherapy: Carboplatin + Pemetrexed,
Taxotere, TarcevaMedian Survival:~ 6 months5 year survival ~1%
Slide12Slide13Slide14Slide15Slide1616
Slide1717
Slide18Hepatic 4%
Colitis 1-2%
Diarrhoea 13%
Neurological <1%
Hypothyroid 5-10%
Renal <3%
Hypophysitis 0.2%
Pneumonitis 2-4%
Auto-immune Side Effects:
Anti-PD1
1. Weber et al JCO 2016 in press; 2. Robert C et al ASCO 2016
All Grade = 70-85%
Grade 3/4 = 10-20%
Discontinuation 5-10%
Fatigue
~20-30%
Vitiligo ~10%
Lichenoid Rash
~15-20%
©Georgina V Long
Slide1919
General Approach
If Patient Presents with Specific Symptom
Early Identification
Evaluate differential diagnoses
Consider
noninflammatory etiologies
Consider all signs and symptoms
Patient education essential
Mild--> Symptom control
Systemic high-dose corticosteroids may be needed
Slide20Gastro-Intestinal Side Effects
Management
Mild:
<4 BMs/day over baseline
Loperamide
, Hydration
Moderate:
4-6BM/day over baseline or blood/mucus/dehydration for <24hrsHold ImmunotherapyImmodiumConsider steroids Prednisone 0.5mg/kg/daySevere : >7BM/day or >24hrs blood/mucus/need for IV Grade 4: Life threatening, perforationWill need steroids (Pred
1mg/kg/d), If worsens may require InfiliximabAdmit for supportive careIf Abdominal pain rule out perforation
Slide21Skin
Management
Mild
<10% BSA
Antipruritics
(
eg
, hydroxyzine, diphenhydramine), topical corticosteroid creams, hydrating creamsModerate: widespread, limiting ADL, 10-30% BSAHold Immunotherapy + give supportive therapyConsider Pred 0.5-1mg/kg/dSevere: Pruritis limiting self care/sleep. Rash covering >30% BSA. Grade 4: Steven JohnsonsDiscontinue therapy, consider admission, derm
consultPred 1-2mg/kg/dTaper when symptoms return to mild
Slide22Endocrinopathies
Hypophysitis
Adrenal
Insuffiency
Hyper-Hypo Thyroid
Cushings
Signs Symptoms
Headaches, Fever, Fatigue, Hypotension, ConfusionMonitorTSH, cortisol InvestigateACTH, TSH, FT3, FT4, Cortisol, Prolactin, Testosterone
Headache – consider MRI pituitaryTreatmentsynthroid, hormone replacement
Slide23Hepatic Side Effects
Signs/Symptoms
Icterus, Fatigue, Nausea, Abdominal pain
Elevation of ALT/AST, Elevation
Bili
Rule out: infectious causes, liver metastases
Management
Mild: ALT/AST <2.5xULN, Bili <1.5xULNContinue Immunotherapy + MonitorModerate: ALT/AST <5xULN, Bili <3.0xULNHold Immunotherapy + InvestigateIf persistent consider Pred
0.5-1mg/kg/daySevere: ALT/AST >5xULN, Bili >3xULNDiscontinue immunotherapy, consider admission to monitorPred 1-2mg/kg/dayIf no improvement day 3-5, consider MMF, ATG, (not Infliximab)
Slide24Pneumonitis
Symptoms
Cough, SOB, Fever
Radiographic changes
Investigate
Rule out cancer progression, infection, radiation effects
CXR
Resp consult, BronchTreatmentRadiographic changes + Symptoms consider Prednisone
Slide25Neurologic
Signs and Symptoms
Motor or Sensory Neuropathy
Unilateral or Bilateral Weakness
Parasthesias
Guillain-Barré Syndrome
Myasthenia Gravis
ApproachAs always, rule out alternative causes e.g. local tumor invasion, brain metsConsult Neurology, consider EMGs to diagnose and monitorTreat with immunosuppression (steroids, MMF, ?pheresis/IVIG/Rituximab)
Slide26Rare Immune mediate side effects
Nephritis (<1% Severe):
inc
Cr, Nephro consult, consider biopsy
Meningitis, Encephalitis, Myositis
Pericarditis, Myocarditis, Cardiomyopathy, Tamponade
Uveitis,
Iritis, Blepharitis, Episcleritis, Scleritis, Ocular myositisHemolytic anemia?AplasiaTemporal arteritis, Vasculitis, Polymyalgia rheumatica, Erythema multiforme, Psoriasis
Slide27Conclusions
Immuno-Oncology is demonstrating
Long term survival in some cancer types (and possible cure!)
Significantly reduced yet different side-effects with a significantly better quality of life!The side-effect profile however is very different from traditional anti-cancer therapies
27
Slide28The Future?
Anti-CTLA4 and Anti-PD1 therapies
In 1
st lineIn adjuvantIn combination with chemo
In combination with targeted therapy
Other indications
Bladder and head and neck
New antibodies to come!28
Slide29Car-T Therapy (Chimeric Antigen Receptor)
Slide30Thank you!
Questions?
Slide31Slide32Slide33Slide34Slide35Gastro-Intestinal Side Effects
Signs and Symptoms
Enterocolitis
Diarrhée
Douleur
abdominale
, nausées, vomissementsSang ou mucus dans les sellesPerforationPeritoneal signsIleusManagement
Rule out other causes infectious etiologies, tumor relatedUnless an alternative cause is identified, consider symptoms to be immune-mediatedIf mild hydration, immodiumIf moderate to severe consider admission, hydration, GI consult, consider endoscopy, Prednisone
Slide36Skin
Clinical Signs/Symptoms
Éruption
cutanée
,
Rougeur
PruritisDermatitisSteven-Johnsons syndrome/toxic epidermal necrolysis occurred in 2.5% of pts on Ipilumumab
Slide37Slide38