Immuno-Oncology Dr. Michael Palumbo - PowerPoint Presentation

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Immuno-Oncology

Dr. Michael Palumbo

April 18, 2018

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Immuno-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!

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CTLA-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

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Metastatic 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)

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Study 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%!

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Summary 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.

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CHECKMATE 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.

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Ipilimumab +

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]

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Overall 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

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irAE = 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

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Non-Small Cell Lung Cancer

Metastatic Non-Small Cell Lung Cancer

Chemotherapy: Carboplatin + Pemetrexed,

Taxotere, TarcevaMedian Survival:~ 6 months5 year survival ~1%

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Hepatic 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

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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

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Gastro-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

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Skin

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

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Endocrinopathies

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

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Hepatic 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)

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Pneumonitis

Symptoms

Cough, SOB, Fever

Radiographic changes

Investigate

Rule out cancer progression, infection, radiation effects

CXR

Resp consult, BronchTreatmentRadiographic changes + Symptoms  consider Prednisone

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Neurologic

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)

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Rare 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

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Conclusions

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

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The 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

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Car-T Therapy (Chimeric Antigen Receptor)

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Thank you!

Questions?

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Gastro-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

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Skin

Clinical Signs/Symptoms

Éruption

cutanée

,

Rougeur

PruritisDermatitisSteven-Johnsons syndrome/toxic epidermal necrolysis occurred in 2.5% of pts on Ipilumumab

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