imunoterapia: manejo de efeitos colaterais agudos e tardios · slide cedido dr carlos dos anjos....

Fernando Costa SantiniMédico Titular do Centro de Oncologia do Hospital Sirio Libanes

Médico Assistente do Instituto do Cancer do Estado de Sao Paulo

Especializado em Oncologia Torácica pelo Memorial Sloan Kettering Cancer Center

Oncologia Clínica pelo Hospital Sirio Libanes

Hematologia pela Universidade de São Paulo

Imunoterapia: Manejo de efeitos colaterais

agudos e tardios

• Pesquisa Clínica – Como investigador: Roche, BMS

• Apresentações científicas – Como palestrante convidado: MSD, Novartis, BMS e AstraZeneca

• Advisory Board – AstraZeneca, BMS

Conflitos de interesse

Mudança de Paradigma

Slide cedido Dr Carlos dos Anjos

Fisiopatologia – Eventos Adversos imuno relacionados (EAir)

Michot et al. European Journal of Cancer 2016Postow et al. NEJM 2018

Contextualizando…

J Clin Oncol 29: 2011 (suppl; abstr 8583)

EAir: 60 – 85%

Graus 3 e 4: 10 – 30%

Mortes: 2%

Anti-CTLA4

Contextualizando…

Pillai et al. Cancer 2017

Contextualizando…

Ramalingam et al. Cancer 2017 Soria et al. Clin Cancer Res; 21(10) May 15, 2015

❌❌

❌

❌

✅

✅Anti-PD-1

Anti-PD-L1

❌✅

PD-L2 – Manutenção tolerância periférica?

Nivo 3 Q2W+ Ipi 1 Q12W

(n = 38)

Nivo 3 Q2W+ Ipi 1 Q6W

(n = 39)Nivo 3 Q2W

(n = 52)

Any grade

Grade 3–4

Any grade

Grade 3–4

Any grade

Grade 3–4

Treatment-related AEs, % 82 37 72 33 71 19

Treatment-related AEs leading to discontinuation, %

11 5 13 8 10 10

Nivolumab Plus Ipilimumab in First-line NSCLC:Safety Summary

6

• There were no treatment-related deaths

• Treatment-related grade 3–4 AEs led to discontinuation at a third of the rate seen with older

combination arms using higher or more frequent doses of ipilimumab6

Hellmann et al. Checkmate 012 Presented at ASCO Annual Meeting 2016

Contextualizando…

Langer et al. Lancet Oncol 2016

KEYNOTE-021

Khoja et al. Annals of Oncology 2017

Cinética

Média de tempo para aparecimento

PeleTGIHepática

2 mesesPulmonar EndócrinoRenal

Manejo Adequado

Champiat et al. Annals of Oncology 2016

• Conhecer os EAir• Fatores de risco• Patógenos oportunistas• Medicação• Condições especiais

• Diagnósticos diferenciais• Progressão

Manejo Adequado

Monitorização clínica e

laboratorialComparação Diagnóstico

Creatinina

0.6 mg/dL 0.79 mg/dL 1.1 mg/dL Suspender tratamento+/- Corticoterapia

Common Terminology Criteria for Adverse Events (CTCAE)

Princípios Gerais do Manejo de Toxicidade

Munhoz R et al - Braz J Oncol. 2017; 13(43)

c

Fadiga

Pele

Alterações histológicas:• Desordens inflamatórias• Lesões de pele imuno-bolhosas• Alteração queratinócito• Reação imuno-mediada pela alteração no melanócito

Manifestações mais comuns:• Rash, prurido, vitiligo (melanoma)

Manifestações menos comuns:• Xerose, alopécia estomatite, urticária, fotossensibilidade,

erupção acneiforme, hiperidrose, alteração de coloração do cabelo e dificuldade de cicatrização.

• Stevens- Johnson, NET, DRESS, Síndrome Sweet

Cuidados de hidratação da pele e fotoproteção

Haanen et al. Annals of Oncology 2017

Pele

Grau I/II Grau IV

Endocrinopatias

Sznol et al. Cancer Treatment Reviews 2017

Anti-CTLA4

Anti-PD-1Anti-PD-L1

Anti-PD-1Anti-PD-L1

Anti-CTLA4

Endocrinopatias

Incidência no geral:472 casos (6,6%)

≥ G3: 0,12%

Hipotireoidismo Hipertireoidismo


≥ G3: 0,10%

Incidência no geral:85 casos (1,2%) ≥ G3: 0,5%

InsuficiênciaAdrenal 1ª


Terapia combinada: 4,2%

≥ G3: 0,3%


≥ G3: 0,1%DM1

Romualdo Barroso-Sousa et al, JAMA Oncol.,September 28, 2017

Tireoidopatias

Monitorização

TSH e T4 livre mensal

Sintomas suspeitos

Recomendações

TSH e T4l ↓• Hipofisite(hipotireoidismo

secundário)

Manifestações

Cukier P, Santini FC, Scaranti M, Hoff AO, Endocr Relat Cancer 2017

TSH ↑ e T4l ↓• Hipotireoidismo

primário

TSH ↓ ou nle T4l e T3l ↑ Anti-TPO Anti-Tg TRAB

• Tireoidite• Dç Graves*

Diagnóstico & Manejo

• Hipotireoidismo central

• Hipotireoidismo primário

Tireoidite não dolorosa

Tireotoxicose transitória

Hipotireoidismo

Oftalmopatia

Tempestade tireoidiana FadigaAsteniaConstipaçãoIntolerância frioXerodermiaGanho de peso

FADiarréia

Intolerância calorSudorese

Perda de peso

Mecanismo ?

Assintomático e TSH <10:- ObservarSintomático- Levotiroxina

Tireotoxicose- Beta-bloqueadorDoença Graves- Beta-bloqueador- Anti-tireoidianos

Imunoterapia deve ser mantida

Hipofisite

• Tempo para início dos sintomas: 4 a 16 semanas

CefaléiaFadigaFraqueza muscular

NáuseaAnorexiaEmagrecimentoAlterações visuaisAlt. estado mentalInt. temperaturaArtralgiasHiponatremia

Crise AdrenalHipotensãoDesidrataçãoDist. Hidroeletrolíticos

• Recuperação do eixo hipofisário é rara

Byun et al. Nat Rev Endoc 2017

From: Ipilimumab-Induced Hypophysitis: A Detailed Longitudinal Analysis in a Large Cohort of Patients With

Metastatic MelanomaJ Clin Endocrinol Metab. 2014;99(11):4078-4085. doi:10.1210/jc.2014-2306

J Clin Endocrinol Metab | Copyright © 2014 by the Endocrine Society

RM de sela normal não exclui o diagnóstico!

Hipofisite

Monitorização

TSH

T4 livre

ACTH

Cortisol

Mensal por 6 meses

2-3m por 1 ano

6 meses por 2 anos

Sintomas suspeitos

Confirmado Hipopituitarismo?

RNM

Sela túrcica

FSH, LH, estradiol, testosterona,

prolactina

Insuficiência adrenal 2ária:

• ACTH nl ou ↓ Cortisol ↓

Hipotireoidismo secundário:

TSH nl ou ↓ T4l ↓

Recomendações

Cukier P, Santini FC, Scaranti M, Hoff AO, Endocr Relat Cancer. 2017 Oct 12

Munhoz R. Rodrigo, Diretrizes brasileiras de manejo de toxicidades imunomediadas, Braz J Oncol;2017

matinal

Sintomas severos:• Prednisolona 0.5 a 1 mg/kg/dia

ou equivalente• Considerar adiar tratamento

Sintomas moderados:• hidrocortisona 20-30mg/dia • prednisona 5-7,5mg/dia

Sem necessidade de reposição de mineralocorticóide

• Levotiroxina (monitorizar após 4-6s)

Corticoterapia não reverte

hipopituitarismo

Crise Adrenal

Insuficiência Adrenal Primária

• Incidência menor que 1% (aumenta na terapia combinada).

• Tempo até inicio dos sintomas 2 a 4 meses.

• Crise adrenal é a endocrinopatia mais ameaçadora de vida importante descartar sepse grave.

Diagnóstico

Distúrbios hidroeletroliticos

Cortisol basal supresso

ACTH elevado

Depleção volume

Tratamento

Glicocorticoide

Encaminhar endocrinologista

Manutenção da imunoterapia

Mineralocorticoide

Cukier P, Santini FC, Scaranti M, Hoff AO, Endocr Relat Cancer. 2017 Oct 12.

Diabetes Mellitus Autoimune

Sznol et al. Cancer Treatment Reviews 2017

Anti-PD-1Anti-PD-L1

• Cetoacidose diabética

• Anti - GAD65 (ácido glutâmico decarboxilase 65)


≥ G3: 0,1%DM1

Romualdo Barroso-Sousa et al, JAMA Oncol.,September 28, 2017

Colite

Grau 1 – Leve• < 4 evacuações líquidas/dia• Clinicamente bem

Ambulatorial:Segue ImunoterapiaSintomáticos: fluidos, loperamida, dieta

LaboratórioClostridiumParasitosesCMV

Grau 2 – Moderado• 4 a 6 evacuações líquidas/dia• Dor abdominal• Sangue nas fezes• Náuseas• Episódios noturnos

Prednisona 0.5 a 1 mg/kg/dia

Ambulatorial:Reavaliar a cada 48-72hRepetir laboratórioConsiderar colonoscopia

Grau 3/4 – Severa• > 6 evacuações líquidas/dia• Episódios logo após

alimentação

Metilprednisolona 1-2mg/kg IVSuspender ImunoterapiaAvaliação gastroenterologia

Hospitalização: Considerar TC AbdomenLaboratório diárioRever dietaChecar complicações

Sintomas Manejo Investigação

Persistir por mais de 2 semanas

Sem melhora em 72h


Colite

Grau 3/4 – Severa• > 6 evacuações líquidas/dia• Episódios logo após

alimentação

Metilprednisolona 1-2mg/kg IVSuspender ImunoterapiaAvaliação gastroenterologia

Hospitalização: Considerar TC AbdomenLaboratório diárioRever dietaChecar complicações

Desmame de corticóide:• Moderada: 4 semanas• Grave: 4-8 semanas

Considerar:• Profilaxia PJP• Proteção gástrica• Profilaxia estrongiloidíase

disseminada• Glicemica

Infliximab 5mg/kg(se não perfuração/sepse/TB/hepatite/ICC)

Pode ser repetido em 2 semanas

Micofenolato MofetilTacrolimus


• Reconhecimento rápido• Afastar outras causas

Fígado


Pneumonite

Naidoo et al. J Clin Oncol 2016

• MSKCC• Insituto de Melanoma da Austrália• 915 pacientes• Incidência: 5%• Tempo mediano: 2.8 meses• 72% Graus 1 e 2

Pulmão

Grau 1Alteração radiológica

Considerar atraso no ttoMonitorizar a cada 2-3 diasSe piora: tratar como grau 2 ou 3

Laboratório Considerar infecção viral, bacteriana ou oportunista

Grau 2 Sintomas

leves/moderadosDispnéia, tosse, dor

torácica

Adiar tratamentoPrednisona 1mg/kg/dia VOTC Tórax +/- broncoscopiaConsiderar ATB

Se não melhorar em 48h: tratar como Grau 3

Se ambulatorial, monitorar os sintomas diariamente

Grau 3 ou 4Sintomas gravesHipoxia em pioraDispnéia repouso

Suspender tratamentoHospitalizaçãoMetilprednisolona 1-2 mg/kg/diaTC Tórax +/- broncoscopiaATB empírico

Infliximab 5mg/kgMMF

G2: Desmame 6 semG3/4: Desmame 8 sem


Ocular immune-related adverse events following PD-1 based therapy:

Case report and seriesFernando C. Santini M.D.1, Jasmine H. Francis M.D.2, Matthew D. Hellmann M.D.1

1 Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine 2 Ophthalmic Oncology Service, Department of Surgery.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Introduction

Case presentation

We report a 70-year-old former smoker male with an advanced

squamous cell carcinoma of the lung who presented with a right

hilar lung mass, bilateral mediastinal and supraclavicular

lymphadenopathy. His past medical history was significant for

benign prostatic hypertrophy and abdominal aortic aneurism. He

denied any personal or family history of autoimmune

predisposition. He started first-line treatment with PD-1 base

therapy.

Ten days after two doses of treatment, he developed symmetrical

periorbital swelling, ptosis and diplopia. After comprehensive

ophthalmologic evaluation a diagnosis of orbital inflammatory

disease was made. Thyroid function tests and thyroid auto

antibodies were negative. MRI of the brain showed bilateral

symmetric proptosis with a proliferation of intraorbital fat and

bilateral enhancement of nasolacrimal ducts and lacrimal sacs. He

started on prednisone 60mg followed by a rapid symptomatic

improvement and complete recovery. Prednisone was then tapered

off slowly over 10 weeks and he received the third dose 12 weeks

after the adverse event. Of note, he achieved continued partial

response with 47% reduction of the target lesions on his second

follow-up scans.

The orbital inflammatory disease represents a diagnostic and therapeutic

challenge for ophthalmologists. Differential diagnosis ranges from

inflammatory conditions to infection, metastasis, ocular tumor, trauma or

thyroid ophthalmopathy. Inflammation of the orbit may diffusely involve

multiple orbital structures or may be localized to a specific orbital tissue.

Our case report consists of a bilateral pseudotumor with concomitant

dacryocystitis. To the authors’ knowledge this is the first case reported of a

dacryocystitis as an adverse event of immunotherapy. These ocular

symptoms can be the first manifestation of systemic diseases like thyroid

disease, sarcoidosis, Wegner granulomatosis, tuberculosis or even more rare

conditions like IgG4-related disease. The adequate detection and treatment

of these conditions are of utmost importance as several of these diseases can

mimic cancer progression.

Our review of the literature highlighted interesting findings, such as: most

of the adverse events occurred after the third infusion of ipilimumab; there

is a high prevalence of hypophysitis co-occurrence; and there is a possible

relation of the ophthalmic immune-related adverse event with tumor

response in these population. Medical oncologists should be aware of these

associations and rapidly trigger appropriate work-up should any signs or

symptoms of eye or central nervous system toxicity appear.

ConclusionGiven the breath of potential targets in the immune system and the

promising field of immunotherapy combination therapies in lung cancer

patients, clinicians should be aware of the less common immune related

adverse events like the ocular toxicity reported. Determining the safety and

feasibility of immunotherapy retreatment after an ocular toxicity remains a

future challenge.

References1. J Clin Oncol. 2012 Nov 20;30(33):e356-72. Retin Cases Brief Rep. 2012 Fall;6(4):423-6.3. Ann Dermatol Venereol. 2013 Jun-Jul;140(6-

7):448-514. Cutan Ocul Toxicol. 2013 Oct;32(4):341-35. J Natl Compr Canc Netw. 2014 Aug;12(8):1077-816. Ophthalmic Surg Lasers Imaging Retina. 2015

Jun;46(6):658-607. J Immunother. 2015 Feb-Mar;38(2):80-48. Ophthal Plast Reconstr Surg. 2015 May;31(3):e68-

709. JAMA Ophthalmol. 2015;133(8):965-96710. Can J Ophthalmol. 2015 Feb;50(1):e2-411. Ophthal Plast Reconstr Surg. 2015 Jun 11.12. J Neuroophthalmol. 2015 Jun;35(2):144-7

13. Retinal cases & brief reports 0:1–4, 201614. Eur J Ophthalmol. 2016 Apr 12;26(3):e46-815. J Dermatol. 2016 Sep 2116. Can J Ophthalmol. 2016 Feb;51(1):e4-617. Arthritis Rheumatol. 2016 Feb;68(2):556-718. J Immunother. 2016 Nov/Dec;39(9):379-382.19. Klin Monbl Augenheilkd. 2016 Apr;233(4):540-420. J Ophthalmic Inflamm Infect. 2016 Dec;6(1):1421. Pharmacotherapy. 2016 Nov;36(11):e183-e18822. Ocul Immunol Inflamm. 2016 Sep 6:1-323. Case Rep Ophthalmol. 2016 Sep 9;7(3):126-131.24. Dermatoendocrinol. 2016 Jun 30;8(1):e119930725. Ocul Immunol Inflamm. 2016;24(2):140-626. J Immunother Cancer. 2016 Oct 18;4:6627. Nat Rev Immunol. 2003 Nov; 3, 879-889

Methods

We searched case reports and clinical trials using the following terms

for each drug (ipilimumab, nivolumab, pembrolizumab, atezolizumab,

anti-CTLA4, anti-PD-1, anti-PD-L1): ”orbitopathy”, ”orbital disease”,

”eye disease”, ”ocular disease”, ”orbital pseudotumor”, ”uveal diseases”,

”uveitis”, ”keratitis”, ”scleritis”, ”conjunctivitis”, ”blepharitis”, ”optic

neuritis”, ”retinal disease”, ”vision loss”, ”choroid disease”, ”choroiditis”.

We retrieved 101 articles and we manually selected 29 that fitted the

characteristics of the review. We excluded all the cases involving Graves

ophthalmopathy. In total, 33 cases were retrieved. Table 1 summarizes

the demographics of all the patients with ocular/orbital disease

associated with immunotherapy treatment, found in this review.

Discussion

Table1. Immunotherapy-associated ocular adverse events in the literature Ocular immune privilege

As the eye has limited capacity of regeneration, immune-mediated

inflammation is greatly reduced. Ocular immune privilege is highly

complex and is the product of multiple anatomic, physiologic and

immuno-regulatory mechanisms. The last is mostly driven by the

inhibitory ocular microenvironment represented by innumerous

immunosuppressive soluble factors (e.g. TGF-β2, ⍺-MSH, CD95L).

Finally, the eye actively regulates systemic immune responses,

represented by the anterior chamber associated immune deviation

(ACAID). Briefly, the camero-splenic axis leads to activation of antigen-

specific CD4+ and CD8+ T cells that differentiate into the antigen-

specific regulatory T cells.27

39%

26%

35%

Malignancy Outcome

ORR

SD

PD

3

5

11

6 6

2

1 2 3 4 ≥ 5 NR

Nº o

f p

ati

en

ts

Nº of infusions before toxicity

Cases n %

Median age, years range 59, (34-82)

Total 33 100

Sex

Female 19 58

Male 14 42

Type of malignancy

Melanoma 29 88

Uveal Melanoma 2 6

Renal Cell Carcinoma 1 3

Non-Small Cell Lung Cancer 1 3

Eye diseases (few pts with > 1 disorder)

Uveal diseases 20 61

Anterior uveitis 13

Posterior uveitis 2

Panuveitis 2

Choroidal diseases 12

Orbital inflammatory syndrome 8 24

Vogt-Koyanagi-Harada syndrome like 2 6

Retinal diseases 1 3

PUK (Peripheral Ulcerative Keratitis) 1 3

Optic Neuritis 2

Retinal vasculitis 1

Hypophysitis

Yes 8 24

No 21 63

Not reported 4 13

Nasolacrimalduct

A

B

C

D

E F G

H I J

(A) External photograph of the patient at

presentation with periorbital swelling and ptosis

(B) External photograph of the patient off steroids

and with complete recovery of the toxicity

(C) MRI of the orbit (Axial T1) showing enhancement

of nasolacrinal ducts and lacrimal sacs.

(D) MRI of the orbit (Coronal T1) showing symmetric

proliferation of intraorbital fat

(E,H ) Baseline CT scan with 5.5 x 4.6 cm right hilar

node and 5.0 x 3.7 cm infracarinal node

(F,I ) First follow-up with 37% reduction of the target

lesions compared to baseline

(G,J) Second follow-up with 47% reduction of the

target lesions, continued partial response

Figure 1

n %

Outcome of malignancy

Complete Response 5 15

Partial Response 4 12

Stable Disease 6 18

Progressive Disease 8 24

Adjuvant therapy 2 6

Not reported 8 25

Immunotherapy

Continued 10 30

Discontinued 17 52

Last dose 5 15

Not reported 1 3

Management of eye disease

Systemic steroid

Yes 16 50

No 16 50

Topical/Intra ocular steroid

Yes 20 61

No 12 39

Long taper or chronic eye therapy

Yes 14 44

No 18 56

Outcome of eye disease

Complete recovery

Yes 26 81

No 6 19

Literature ReviewA broad range of new auto-immune toxicities are emerging among

patients treated with immunotherapy. Nearly all organs can be

affected; the eyes are among the least frequently affected but can be

clinically severe. Ophthalmic immune-related adverse events have been

reported in less than 1% of patients, including uveitis as the most

common. Herein we report the first case of orbital inflammatory

disease in a patient with advanced NSCLC who developed orbital

inflammation, including bilateral dacriocystitis, following treatment

with anti-PD-1 based therapy. We also made a comprehensive review of

the literature covering all the cases published in the literature in which

immune-related ocular adverse event occurred.

Patients who continued therapy after eye disorder n=10

Recurrence of the eye toxicity n=4

Sustained recovery n=6

70%

30%

Treatment received

Anti-CTLA4

Anti-PD-1

Eventos Adversos Incomuns

Eventos Adversos Incomuns

Restituição da terapia imune

Munhoz R et al - Braz J Oncol. 2017; 13(43)

Safety of retreatment with immunotherapy after immune-

related toxicity in patients with lung cancers treated with anti-

PD-(L)1 therapy

Fernando C. Santini, Hira Rizvi, Olivia Wilkins, Martine van Voorthuysen, Elizabeth Panora, Darragh

Halpenny, Mark G. Kris, Charles M. Rudin, Jamie E. Chaft, Matthew D. Hellmann;

Memorial Sloan Kettering Cancer Center, New York, NY

Abstract #9012

Lung Cancer—Non-Small Cell Metastatic

Em revisão pela Cancer Immunology Research

Overview of cohort – retrospectively identified patients who had treatment delay or discontinuation due to irAE*

Dados não publicados

CR/PR before irAE

No CR/PR before irAE

Response eligible

HR 0.4595% CI, 0.21 to 1.0

p=0.049

P=0.28


Conclusões:

• Nos pacientes após EAIR, retratamento com terapia anti-PD-(L)1 resultou

em novos/recorrentes EAIR em metare dos pacientes

• Entre os pacientes retratados, necessidade de hospitalização está

associado com maior risco de recorrência ou nova toxicidade

• Maioria das toxicidades foi resolvida, porém dois óbitos ocorreram

• Algumas respostas ocorreram após o retratamento

• No grupo de pacientes que atingiram RC/RP antes da detecção do evento

adverso imuno relacionado, SLP e SG são iguais quando retratado ou

discontinuados

Santini et al, 2017

Safety of retreatment with immunotherapy after immune-related toxicity in patients with lung cancers treated with anti-PD-(L)1 therapy


Uso de corticosteróide altera eficácia do tratamento?

Horvat et al. J Clin Oncol 2015

• 2011 e 2013• 254/298 (85%) tiveram

algum IrAE. • 19% descontinuaram • 35% corticoide• 10% infliximabe

Não afetou eficácia da

imunoterapia

Suspender precocemente altera eficácia do tratamento?

Schadendorf et al. J Clin Oncol 2017

Evento adverso imuno-relacionado v Eficácia

Haratami et al. Jama Oncol 2017

Take home messages

• Monitorização e orientação do paciente

• Uso do corticosteróide quando indicado

• Desmame lento e cuidadoso!

• Suspender/adiar tratamento se > grau 2

• Retratamento?

• Consultar guias de manejo

Take home messages

Obrigado!

Brahmer et al. J Clin Oncol 2018

[email protected]

imunoterapia: manejo de efeitos colaterais agudos e tardios · slide cedido dr carlos dos anjos....

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