La gestione della tossicità

Laura Bonanno Oncologia Medica 2

Istituto Oncologico Veneto IRCCS

Torino, 5-6 Settembre 2018

Gestione della tossicità

Ernstoff M et al, ASCO 2018

irAE: far from tradition

Postow M et al, NEJM

WHY: potential mechanisms

▪ Development of autoimmunity - release of autoreactive T cells

- increase of pre-existing antibodies - shared tumor antigens on normal

tissue

▪ Target tissue expression of checkpoint

▪ Inflammatory cytokine release

WHAT: Immune-Related Adverse Events (irAEs

)

Anti CTLA-4

- 10% → Hypophysitis and hypothyroidism

Anti PD-1

- <10% → Hypothyroidism

Anti CTLA-4

- 50% → Rash and pruritus (trunk and extremities) Anti PD-1

- 37% → skin toxicity of all grades

- 6,5% → dry mouth

Anti CTLA-4

- 30% → Diarrhoea (only 10% G3-4)

- 5% → Colitis G3-4 Anti PD-1

- 1-2% → Diarrhoea G3-4 Anti CTLA-4

- 2.5% → Hepatotoxicity G2 - 2% → Hepatotoxicity G3-4 Anti PD-1

- <5% → Hepatotoxicity

Less frequent irAEs:

• Pneumonitis

• Asymptomatic pancreatitis

• Hematologic syndromes

• Ophthalmologic disorders

• Renal insufficiency

• Neurologic syndromes

Champiat S. et al, Annals of Oncology 2015

The majority of AE occur within 3 months (but not only)

With the exception of treatment-related endocrine AEs (often requiring continued hormone replacement

therapy) most irAEs resolve (within some weeks)

irAEs may happen also after discontinuation of drugs

WHEN

Haanen JBAG et al, Annals of Oncology 2017

Champiat S. et al, Annals of Oncology 2015

TREATMENT

1- PREVENT Baseline:

✓ Educate: patients, care givers, nurse team

✓ Baseline assessment:

history of autoimmune diseases, endocrinopathies, infectious disease, bowel habits

✓ Baseline labs

2-ANTICIPATE:

MONITOR AND INFORM

✓ LISTEN TO SYMPTOMS (and not only…)

✓ MONITOR LAB TEST

(remember glycemia, serume electrolytes and TSH and……)

✓ VISIT

✓ WATCH CT-SCAN

Baseline test Anti-CTLA Anti-PD-1/PD-L1 Anti-CTLA4 + anti-PD-1/PD-L1

Hb Y Y Y

L Y Y Y

ANC Y Y Y

ALC Y Y Y

Thr Y Y Y

Bilirubin Y Y Y

AST Y Y Y

ALT Y Y Y

Creatinine Y Y Y

Na Y Y Y

K Y Y Y

TSH Y Y Y

FT4 Y Y Y

T3 Y^a Y^a Y^a

ACTH Y N Y

Cortisol Y N Y

Lipase N N Y

Amylase N N Y

Glucose N Y Y

LH Y N Y

FSH Y N Y

Testosterone Y N Y

ESR Y Y Y

LDH Y Y Y

ESMO

- Baseline

- Every 3 weeks (or at every infusion) until 3 months after the last infusion - later: every 3 months

Haanen JBAG et al, Ann Oncol 2017

3-DETECT:

ANY NEW SYMPTOM AND LAB ABNORMALITIES MAY BE IMMUNORELATED

✓ STUDY AND MONITOR

✓ CONSIDER OTHER CAUSES (1^st PROGRESSION)

✓ CONSIDER TIMING

4-TREAT:

Boutros C et al, Nat Rev Clin Onc 2016 Champiat S et al, Ann Oncol 2015 Haanen JBAG et al, Ann Oncol 2017 Brahmer J R et al, JCO 2018

NO PANIC,

DELAY (AND USE STEROIDS)

AFTER RESOLUTION

GRADUAL STEROID TAPERING At least 1 month

Temporary suspension Permanent discontinuation - IrAEs stabilized < G1

- Steroid dose reduced to <

10 mg/d prednisone

- IrAEs G4

- IrAEs G3 and recurring - IrAEs G2 not resolutive in

3 months

✓ Immunotherapy dose reduction not recommended

✓ No clear correlation between dose density and efficacy of immunecheckpoints inhibitors:

→ not influenced by delaying immunotherapy

PNEUMONITIS:ESMO-ASCO

Haanen JBAG et al, Ann Oncol 2017

FIRST:

RECOGNIZE AND EDUCATE

Elements affecting irAE

1- Treatment-related:

ICI and other anti-cancer treatment

2- Disease-related

3- Patient-related

Elements affecting irAE 1-ICIs

El Osta E et al, CROH 2017

All-grade irAE: 53.8% (anti-CTLA4) vs 26.5% (ant-PD1) and 17.1% (anti-PDL1) p<0.001

El Osta E et al, CROH 2017

Elements affecting irAE

1- ICIs

Elements affecting irAE

1-Combination treatment-CT

Gandhi L et al, NEJM 2018

Attili I et al, CROH 2017

Elements affecting irAE

1- combination treatment-targeted agents

CHECKMATE 370: closed for toxicity

Spigel et al, JTO 2018

Shaw AT et al, ASCO 2018

JAVELIN lung 101

Elements affecting irAE

1- combination treatment-targeted agents

Oshima Y et al, JAMA Oncology 2018

15: NIVOLUMAB→ EGFR TKIs

Elements affecting irAE

1- combination treatment-RT

Bonanno L et al, JTO in press

Bonanno L et al, JTO in press

Elements affecting irAE

1- combination treatment-RT

Elements affecting irAE 2- Disease

Antonia S et al, Lancet Oncol 2016 Maddison P et al, Lancet 1999

Elements affecting irAE

3-Patient: pre-existing conditions

Danlos F-X et al, EJC 2018

20/45: irAE

11/45: AID flare

Elements affecting irAE

3-Patient: non-pathological immune-related factors

Pavan A et al, submitted

Univariate Multivariate

IrAE/N % OR 95%CI p-value OR 95%CI p-value

L-NLR 32/74 43.2% 2.2 1.1-4.1 0.018 1.7 0.8-3.3 0.160

H-NLR 26/100 26.0% 1 1

L-PLR 42/98 42.9% 2.8 1.4-5.5 0.003 2.3 1.1-4.8 0.027

H-PLR 16/75 21.3% 1 1

WAITING FOR DISCUSSION…..

GRAZIE