SAMPLE TEMPLATE STYLESTKIs, mTORIs AND IMMUNOTHERAPY: SIDE EFFECTS

Camillo PortaDepartment of Internal Medicine and Medical Therapeutics, University of Pavia

& Division of Translational Oncology, I.R.C.C.S. Istituti Clinici Scientifici

Maugeri, Pavia, Italy

C. PORTA: DISCLOSURE OF INTEREST

CONSULTANCY SPEAKER STEERING COMMITTEES EXPERT TESTIMONY

BMS BMS BMS Pfizer (EMA)

MSD MSD Eisai EUSA Pharma (AIFA)

Pfizer Pfizer EUSA Pharma

Novartis Novartis

Eisai Eisai

EUSA Pharma EUSA Pharma

Ipsen Ipsen

Janssen Astra Zeneca

Astra Zeneca General Electrics

General Electrics

RCC PROGNOSIS HAS MARKEDLY IMPROVED WITH TARGETED AGENTS

Patil S, et al. Cancer 2010;116:347-54.

0

Years From Treatment Start

1 2 3 4 5 6 7 8 9 10

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

nS

urv

ivin

g1975–1980

1981–1985

1986–1990

1991–1995

1996–2000

2001–2007

2005

to

dat

e

NEWS AGENTS, NEW TOXICITIES

“OPENING PANDORA’S VASE”

Historical cytotoxic drugs have toxicities familiar to most involved Physicians

Prompt and correct treatment of these AEs has improved QoL for patients

Newer targeted agents have resulted in new and ill-defined AEs

These toxicities must be recognized and appropriate management initiated

Porta C, et al. Clin Exp Med 2007;7:127-34.

TOXICITIES MAY SIGNIFICANTLY AFFECT TREATMENT SCHEDULE …

Treatment

Treatment

Discontinuations, %

Dose

Reductions, %

Treatment

Interruptions, %

Bevacizumab1* 19 40** N/A

Sorafenib2 10 13 (35)8† 21 (61)8†

Sunitinib3 19 50 N/A

Pazopanib4 14 36 428

Axitinib5 35 45 73

Tivozanib6 4 12 18

Temsirolimus7 7% 23% 66%

Everolimus8 7% 7% 38%

*Combined with interferon-a; **Relative just to interferon-a; †US-ARCCS study (EAP)

1. Escudier B, et al. Lancet 2007;370:2103-11; 2. Escudier B, et al. N Engl J Med 2007;356:125-34; 3. Motzer RJ, et al. J Clin Oncol 2009;27:3584-90; 4.

Sternberg CN, et al. J Clin Oncol 2010;28:1061-8; 5. Rini BI, et al. J Clin Oncol 2009;27:4462-8; 6. Motzer RJ, et al. J Clin Oncol 2013;31:3791-9; 7. Hudes G,

et al. N Engl J Med 2007;356:2271-81; 8. Motzer RJ, et al. Lancet 2008;372:449-56.

… POSSIBLY LEADING TO REDUCED TREATMENT EFFICACY …

0.5 1.0 1.5 2.00.0

Mean

95% CI

Sunitinib AUC, mghr/mL

Pro

bab

ility

of

resp

on

se

0.2

0.4

0.6

0.8

1.0

• The probability of obtaining an

objective response increases as a

function of the mean daily Sunitinib

exposure

• This could be true also for the other

TKIs we use in RCC

Houk BE, et al. Cancer Chemother Pharmacol 2010;66:357-71.

AEs ARE RELATED TO THE FACTORS/RECEPTORS

INHIBITED

“ON TARGET” vs “OFF TARGET” AEs

Porta C, et al. Cancer Treat Rev 2009;35:297-307; Di Lorenzo G, et al. Eur Urol 2011;59:526-40; Rudman DG. Toxicologic Pathology 2013;41:310-4.

Agent Main target(s) inhibited

Bevacizumab VEGF

SorafenibVEGFR-2, VEGFR-3, PDGFR, c-KIT,

Flt-3, RET, RAF-1

Sunitinib VEGFR, PDGFR, c-KIT, Flt-3

Pazopanib VEGFR, PDGFR, c-KIT

Axitinib VEGFR, PDGFR, c-KIT, Flt-3

Tivozanib VEGFR-1, VEGFR-2, VEGFR-3

Temsirolimus mTORC-1

Everolimus mTORC-1

CabozantinibVEGFR-2, MET, Axl, KIT, RET, Flt-3,

Tie-2, RON

On-target toxicity is commonly due

to the interaction of the drug with

its intended target

The inhibition of targets other than

those desired for drug’s antitumor

activity leads to off-target AEs

VEGFR TKIs and mTOR inhibitors

Porta C, et al. Cancer Treat Rev 2009;35:297-307; Di Lorenzo G, et al. Eur Urol 2011;59:526-40.

VEGF(Rs)-Related AEs Non-VEGF(Rs)-Related AEs

Hypertension Cardiotoxicity

Bleeding/haemorrhage Hand-foot skin reaction

Wound healing impairment Diarrhea

Thromboembolic events Stomatitis

Proteinuria Fatigue

mTOR-Related AEs Myelosuppression

Dyslipidemia and hyperglycemia Hypothyroidism

Noninfectious pneumonitis Rash

Stomatitis Hepatotoxicity

SELECTED TARGETED THERAPIES-RELATED AEs

VEGFR TKIs and mTOR inhibitors

Porta C, et al. Cancer Treat Rev 2009;35:297-307; Di Lorenzo G, et al. Eur Urol 2011;59:526-40.

VEGF(Rs)-Related AEs Non-VEGF(Rs)-Related AEs

Hypertension Cardiotoxicity

Bleeding/haemorrhage Hand-foot skin reaction

Wound healing impairment Diarrhea

Thromboembolic events Stomatitis

Proteinuria Fatigue

mTOR-Related AEs Myelosuppression

Dyslipidemia and hyperglycemia Hypothyroidism

Noninfectious pneumonitis Rash

Stomatitis Hepatotoxicity

SELECTED TARGETED THERAPIES-RELATED AEs

SELECTED AEs FROM mRCC TREATMENTVEGF/VEGFRs TKIs

HYPERTENSION

One of the most common AEs associated with anti-VEGF/VEGFRs pathway

inhibitors (across different tumor types)

Impaired angiogenesis, through the decrease of vascular surface and the

increase of peripheral resistances, contribute to its development1

Possible biomarker of treatment activity for many VEGFR-TKIs2,3

1. Porta C, et al. Clin Exp Med 2007;7:127-34; 2. Rini BI, et al. Target Oncol 2015;10:45-53; 3. Rautiola J, et al. BJU Int 2016;117:110-7.

HYPERTENSION: MANAGEMENT

CONSIDER

• Non-adherence

• Secondary HTN

• Interfering drugs or

lifestyle

• White coat effect

Dual combination

Triple or quadruple therapy

Lifestyle modifications

Thiazidediuretic

ACEI Long-acting

CCBBeta-

blocker*

Target <140/90 mm Hg

ARB

Initial therapy

ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; *Not indicated as first-

line therapy over 60 years

A combination of 2 first-line

drugs may be considered as

initial therapy if the blood

pressure is ≥ 20 mm Hg sys-

tolic, or ≥ 10 mm Hg diastolic

above target

2012 Canadian Hypertension Education program Recommendations. Available at: http://www.hypertension.ca

HYPERTENSION: MANAGEMENT IN PATIENTS WITH

KIDNEY IMPAIRMENT

In patients with some degree of kidney impairment, anti-hypertensives that

prevent progression of hypertension-related CKD could be considered

ACE-inhibitors and ARB can lower intraglomerular pressure, independent of changes

in systemic blood pressure; they have also antiproteinuric effects, which may

contribute to protection of renal function

Wolf S, et al. Herz 2004;29:248-54.

Chronic kidney disease

and proteinuria*ACEI or ARB (if ACEI tolerated)

Combination with other agents

Additive therapy: Thiazide diuretic.

Alternate: If volume overload: loop diuretic

• Monitor serum potassium and creatinine carefully in patients with CKD prescribed an

ACEI or ARB

• Combinations of a ACEI and a ARB are specifically not recommended in the absence of

proteinuria

ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers

*Albumin:creatinine ratio (ACR) > 30 mg/mmol or urinary proteins > 500 mg/24 hours

2012 Canadian Hypertension Education program Recommendations. Available at: http://www.hypertension.ca

HYPERTENSION: MANAGEMENT IN PATIENTS WITH

KIDNEY IMPAIRMENT

Condition Target

Systolic BP and Diastolic BP (mm Hg)

Isolated systolic hypertension <140

Systolic / diastolic hypertension

• Systolic BP

• Diastolic BP

<140

<90

Diabetes

• Systolic BP

• Diastolic BP

<130

<80

Non-DM CKD

• Systolic BP

• Diastolic BP

<140

<90

HYPERTENSION: GOALS OF TREATMENT

HAND-FOOT SKIN REACTION

Painful, symmetrical, erythematous and edematous areas on the palms and soles

Commonly preceded or accompanied by paresthesias

Aggravated by warm environments

Hyperkeratosis and desquamation, often associated with bullous lesions

At histology: alterations in cell maturation, modifications of keratinocyte diffe-

rentiation (apoptosis), inflammation

Greatly affects patients’ QoL

1. Robert C, et al. Lancet Oncol 2005;6:491-500; 2. Manchen E, et al. J Support Oncol 2011;9:13-23; Bracarda S, et al. Crit Rev Oncol Hematol 2011;82:378-86.

HAND-FOOT SKIN REACTION

Porta C, et al. Clin Exp Med 2007;7:127-34.

MANAGEMENT OF HAND-FOOT SKIN REACTION

Sec

on

d o

r T

hir

d

•Continue preventive strategies plus:

–Soak hands or feet in cold water

–Apply petroleum jelly to moisten skin

–Continue MKI treatment; maintain dose level for

current and next cycle

–In the case of hyperkeratitic lesions, exfoliate the

hands or feet and apply moisturizing cream

immediately afterwards

Grade 1 Grade 2 Grade 3

OC

CU

RR

EN

CE

Fo

urt

hF

irst

•Institute supportive measures such as

topical therapy for relief of symptoms

•Consider a dose reduction for 7-28 days (sorafenib, 400 mg

qd; 4 wks on/2 wks off cycles)

-If toxicity resolves to grade 0/1 after dose reduction, increase

to recommended dose (sorafenib, 400 mg bid; sunitinb, 50 mg

qd; 4 wks on/2 wks off cycles)

-If toxicity does not resolve to grade 0/1, interrupt MKI

treatment for at least 7 days and until toxicity has resolved to

grade 0 or 1

-When resuming treatment after dose interruption, begin at

reduced dose (sorafenib, 400 mg qd; sunitinib, 25 mg qd; 4

wks on/2 wks off cycles)

-If toxicity is maintained at grade 0/1 at reduced dose for a

minimum of 7 days, increase to recommended dose

•Institute supportive measures such as

topical therapy for relief of symptoms

•Interrupt MKI treatment for at least 7 days and until

toxicity has resolved to grade 0/1

-When resuming treatment after dose interruption,

decrease by one dose level (sorafenib 400 mg qd or

qod; sunitinib 25 mg or 37.5 mg qd or qod)

-If toxicity is maintained at grade 0/1 at reduced dose

for a miinimum of 7 days, increase by one dose

level (sorafenib, 400 mg bid or qd; sunitinib, 50 mg

qd or 37.5 mg qod)

•Manage as for 1st occurrence but decrease dose by

one dose level (sorafenib, 400 mg qd or qod;

sunitinib, 25 mg or 37.5 mg qd or qod)

•Decision whether or not to re-escalate dose should

be based on clinical judgment and patient preference

•For 2nd occurrence of grade 3 HFSR, manage as for

first occurrence

-Upon resuming treatment, decrease dose by one

level (sorafenib, 400 mg qd or qod; sunitinib, 25 mg

or 37.5 mg qd or qod)

-Decision whether or not to re-escalate dose should

be based on clinical judgment and patient preference

•For 3rd occurrence of grade 3 HFSR, decision

whether or not to re-escalate dose should be based

on clinical judgment and patient preference

•Decision whether or not to re-escalate dose should

be based on clinical judgment and patient preference

Manchen E, et al. J Support Oncol 2011;9:13-23.

FATIGUE

An extremely common, and clinically relevant, complaint of patients receiving

anticancer Tx, and targeted agents in particular

Although in some studies asthenia and fatigue are reported separately, G3-4

fatigue may be observed in as much as 12% of mRCC patients treated with

targeted agents; when added with asthenia, these figures increase up to 20%

Pay attention! May be associated with: hypothyroidism, hypomagnesemia, and

hypophosphatemia

Greatly affects patients’ QoL; probably the main complaint from patients’ perspective

Larkin JM, et al. Oncologist 2010;15:1135-46.

FATIGUE: MANAGEMENT

Correction of hypothyroidism and/or hypomagnesemia and hypophosphatemia

(when present) is mandatory

Nutritional intake is key; thus, anorexia, cachexia, and weight loss should be

monitored closely

Progestational anabolic agents, e.g. MPA1,2, and/or steroids3 may be useful (low

level of evidence)

In severe cases, Tx interruptions or dose modifications may be necessary

1. Maltoni M, et al. Ann Oncol 2001;12:289-300; 2. Taylor JK, Pendleton N. BMJ Support Palliat Care 2016;6:276-86; Yennurajalingam S, Bruera E. Cancer J 2014;20:319-24.

SELECTED AEs FROM mRCC TREATMENTmTOR inhibitors

NONINFECTIOUS PNEUMONITIS

Symptomatic cases usually are mild to moderate and reversible

Often asymptomatic, or presents with non-specific respiratory symptoms, e.g. dry

cough, dyspnoea on exertion, malaise, fever, hypoxia, and pleural effusion

High risk in abnormal pre-treatment pulmonary functions or history of lung disease

Should be considered in patients presenting with non-specific respiratory symptoms

and in whom other causes have been excluded

Differential diagnosis between noninfectious pneumonitis, bacterial pneumonitis, and

interstitial lung involvement from the tumor is often difficult

Porta C, et al. Eur J Cancer 2011;47:1287-98.

NONINFECTIOUS PNEUMONITIS

Endo M, et al. Lung Cancer 2006;52:135-43.

Ground-glass opacity

(often vasal)

Airspace

consolidation

Patchy distribution of

ground-glass opacity

Extensive ground-glass

opacity/consolidation

NONINFECTIOUS PNEUMONITIS: PATHOGENESIS

Cell-mediated autoimmune response based on the analysis of broncho-alveolar lavage

(BAL)

BAL often reveals lymphocytic alveolitis with a majority of CD4+ cells and a

significantly increased number of eosinophils and mast cells

mTOR inhibitors may expose cryptic antigens to induce such an autoimmune response

T cell-mediated delayed-type hypersensivity

BAL is often essential for a correct differential diagnosis

Porta C, et al. Eur J Cancer 2011;47:1287-98.

NONINFECTIOUS PNEUMONITIS: MANAGEMENT

Porta C, et al. Eur J Cancer 2011;47:1287-98.

Grade Symptoms Management Dose Modification

1 Asymptomatic ⚫ No specific therapy ⚫ No change

2 Symptomatic, not interfering with ADL

Depending on severity of

Symptoms:

⚫ consider consulting a pulmonologist

⚫ consider diagnostics to exclude infectious causes

⚫ consider steroids

⚫ Decrease dose until G ≤1 and restart at initial dose

⚫ Hold dose if symptoms are troublesome

⚫ If no recovery to G ≤1 within 3 wks, discontinue

3 Symptomatic, interfering with ADL, O2 indicated

⚫ Consult a pulmonologist

⚫ Consider diagnostics to exclude infectious causes

⚫ consider antibiotics/steroids based on clinical evidence

⚫ Hold dose until recovery to G1

⚫ Restart dose within 3 wks at reduced dose if evidence of clinical benefit

4 Life-threatening, ventilatory support indicated

⚫ Discontinue

STOMATITIS

An inflammation of the mucous membranes in mouth, which appears

as ulcerated areas in the oral cavity, inner surface of the lips, or

tongue

Usually, 1-3 round ulcers, similar to aphtous ulcers, are present; they

appear as oval lesions with greyish-white necrotic centres surround-

ded by a ring of erythematous ulceration, without pseudomembranes

Everolimus-induced stomatitis

RT-induced stomatitis

STOMATITIS IN mRCC AND OTHER TUMORS

Everolimus (n/N=120/274; Kaplan-Meier Median: 10.78 mo)

Placebo (n/N=11/137; Kaplan-Meier Median: NA)

100

0

80

60

40

20

Inci

de

nce

, %

15

0 2 3 4 5 6 7 8 9 10

11

12

13

14

1

Time, mo

Porta C, et al. Eur J Cancer 2011;47:1287-98; Motzer RJ, et al. Ann Oncol 2016;27:519-25.

STOMATITIS: MANAGEMENT

Porta C, et al. Eur J Cancer 2011;47:1287-98.

Grade Symptoms Management Dose Modification

1 Minimal (normal diet) ⚫ Good oral hygiene

⚫ Non-alcoholic mouthwash or 0.9% salt water

⚫ Avoid agents containing hydrogen peroxide, iodine, and thyme derivatives

⚫ No change

2 Symptomatic, but can eat and swallow modified diet

⚫ Topical analgesic mouth treatments

⚫ Topical corticosteroids

⚫ Avoid agents containing hydrogen peroxide, iodine, and thyme derivatives

⚫ Maintain dose if tolerable

⚫ Hold dose if intolerable until recovery to grade ≤1, then restart at same dose

3 Symptomatic and unable to adequately aliment or hydrate orally

⚫ Hold dose until recovery to grade ≤1, then restart at reduced dose

4 Severe ⚫ Discontinue treatment

SELECTED AEs FROM mRCC TREATMENTImmune Checkpoint Inhibitors

BEWARE OF irAEs!

Activation of the immune system against tumors can result

in a novel spectrum of irAEs1

• May be due to cytokine release

by activated T cells1

• May be unfamiliar to clinicians

• Requires a multidisciplinary

approach

• Can be serious2

• Requires prompt recognition and

treatment2

• Requires patient and HCP

education

irAEs occur in almost all organs

and systems:1

• Skin

• Endocrine system

• Liver

• Gastrointestinal tract

• Nervous system

• Eyes

• Respiratory system

• Hematopoietic cells

1. Amos SM, et al. Blood 2011;118:499‒509; 2. Chin K, et al. ESMO 2008 (abstr. 787P).

DATA MINING FROM THE US FOOD AND DRUG ADMINISTRATION

(FDA) AEs REPORTING SYSTEM (FAERS) DATABASE

AEs of CTLA-4 and PD-1 mAbs were most commonly observed in the skin, gastrointestinal tract,

endocrine systems, liver, and lung, and they included rash, diarrhea, colitis, and thyroid dysfunction

Thyroid dysfunction, type 1 diabetes mellitus, and pneumonitis were more closely associated with the

use of anti-PD-1, whereas colitis, diarrhea, hypophysitis, and adrenal insufficiency were more closely

associated with anti-CTLA-4; rash and hepatitis occurred similarly in both

Disproportionality signals for less common AEs in other organ systems, including the renal,

neurological, cardiac, ocular, musculoskeletal, and hematologic systems, were also detected

Nivolumab and pembrolizumab have very similar safety profiles, but the signal strength of AEs

increased when combined with ipilimumab.

Ji HH, et al. Clin Drug Invest 2019;39:319-30.

KINETICS OF irAEs

Time (weeks)

Toxi

city

gra

de

Rash, pruritus

Liver toxicity

Diarrhea, colitis

Hyphophysitis

NIVOLUMAB MONOTHERAPY SAFETYNivolumab

N = 406

Everolimus

N = 397

Any grade Grade 3 Grade 4a Any grade Grade 3 Grade 4b

Treatment-related AEs, % 79 18 1 88 33 4Fatigue 33 2 0 34 3 0

Nausea 14 <1 0 17 1 0

Pruritus 14 0 0 10 0 0

Diarrhea 12 1 0 21 1 0

Decreased appetite 12 <1 0 21 1 0

Rash 10 <1 0 20 1 0

Cough 9 0 0 19 0 0

Anemia 8 2 0 24 8 <1

Dyspnea 7 1 0 13 <1 0

Edema peripheral 4 0 0 14 <1 0

Pneumonitis 4 1 <1 15 3 0

Mucosal inflammation 3 0 0 19 3 0

Dysgeusia 3 0 0 13 0 0

Hyperglycemia 2 1 <1 12 3 <1

Stomatitis 2 0 0 29 4 0

Hypertriglyceridemia 1 0 0 16 4 1

Epistaxis 1 0 0 10 0 0

aGrade 4 AEs not listed in

table: increased blood

creatinine (1), acute kidney

injury (1), anaphylactic

reaction (1)

bGrade 4 AEs not listed in

table: increased blood

triglycerides (2), acute

kidney injury (1), sepsis (1),

chronic obstructive

pulmonary disorder (1),

increased blood

cholesterol (1), neutropenia

(1), pneumonia (1)

Motzer RJ, et al. N Engl J Med 2015;373:1803-13.

CheckMate 025

AEs FROM IPI-NIVO COMBO INCREASE

Motzer RJ, et al. N Engl J Med 2018;378:1277–90.

Treatment-related adverse events (TRAEs)

NIVO + IPI (n=547) SUN (n=535)

Any Gradeb Grade 3 or 4 Any Gradec Grade 3 or 4

≥15% of patients, % 93 46 97 63

Leading to discontinuation, % 22 15 12 7

Treatment-related deaths, no. n=8 n=4

Immune-mediated AEs

• 436 patients treated with NIVO + IPI had an immune-mediated TRAE, including skin,

endocrine, gastrointestinal, pulmonary, hepatic, and renal categories

• 152 (35%) received high-dose glucocorticoids (≥40 mg of prednisone per day or

equivalent)

CheckMate 214

DIFFERENT COMBOS, DIFFERENT SAFETY PROFILES

Treatment-Related AEs (ITT Population)

Diarrhoea

PPE

Hypertension

Fatigue

Nausea

Dysgeusia

Decreased appetite

Mucosal Inflammation

Stomatitis

Asthenia

Vomiting

Proteinuria

60 50 40 30 1020 0 10 20 30 40 50 60

Atezolizumab + Bevacizumab Sunitinib

All-Grade AEs

Grade 3/4 AEs

All-Grade AEs

Grade 3/4 AEs

IMmotion 151

Rini BI, et al. Lancet 2019;393:2404-15.

DIFFERENT COMBOS, DIFFERENT SAFETY PROFILES

Javelin Renal 101Avelumab + Axitinib

(N = 434)

Sunitinib

(N = 439)

All grades Grade 3 (4) All grades Grade 3 (4)

All TRAEs, % 95 51 (4) 96 48 (7)

Diarrhea

Hypertension

Fatigue

Hand-foot syndrome

Dysphonia

Nausea

Hypothyroidism

Stomatitis

Decreased appetite

Dysgeusia

Increased alanine aminotransferase

54

48

36

33

27

25

24

22

20

13

13

5 (0)

24 (0)

3 (0)

6 (0)

1 (0)

1 (0)

< 1 (0)

2 (0)

2 (0)

0 (0)

4 (1)

45

32

36

34

3

34

13

23

26

32

10

3 (0)

15 (0)

4 (0)

4 (0)

0 (0)

1 (0)

< 1 (0)

1 (0)

1 (0)

0 (0)

2 (0)

TRAEs leading to discontinuation of all study drugs, % 4 8

TRAEs leading to death, % 1 < 1

Motzer RJ, et al. N Engl J Med 2019;380:1103-15.

irAEs: PNEUMONITIS

Nishino MJ, et al. N Engl J Med 2015;73:288-90.

irAEs: COLITIS

Gupta A, et al. Aliment Pharmacol Ther 2015;42:406-17.

Endoscopic image depicting the

presence of granularity, loss of

vascular pattern, and ulcers

Histopathological finding from colonic

biopsies revealing the presence of ulcers,

inflammation, and granulation tissue

OTHER UNEXPECTEDLY FREQUENT irAEs: OCULAR

MANIFESTATIONS

Fang T, et al. J Curr Opthalmol 2019;31:319-22.

KEY PRINCIPLES OF irAEs MANAGEMENT

40

Early identification

Timely intervention

Stay alert: continuous monitoring

• Most imARs occur during treatment

• Monitor after the last dose; imARs can occur week to months later

Evaluate differential diagnoses per standard practice

• Consider non-inflammatory etiologies

• Consider all signs and symptoms

Patients must report new,

persistent orworseningsymptoms

Robust, provenmanagement

guidelines available

Patient education first

Individualized patient

follow-up and counseling

Systemic high-dose

corticosteroids may be

needed for severe events

Consider other immune

suppressants if no

resolution

Multidisciplinary

management is key

irAEs MANAGEMENT: ESMO GUIDELINES

• Skin toxicity

• Endocrinopathies (including hypophysitis)

• Hepatotoxicity

• Gastrointestinal toxicity

• Pneumonitis

• Neurological toxicity (including Guillame Barrè Syndrome)

• Cardiotoxicity

• Rheumatological toxicity

• Renal toxicity

Haanen JBA, et al. Ann Oncol 2017;28(Suppl. 4):i119-i142.

IN CONCLUSION …

TAKE HOME MESSAGES (I)

AEs associated with novel anticancer agents are often difficult to recognize; therapeutic drug

monitoring is thus essential1 – “You cannot find what You’re not looking for” …

Patient education, in order to recognize AEs quickly and seek medical advice before symptoms

worsen, is key

Education and training of healthcare professionals, other than Oncologists is also important, in

order to recognize as soon as they do appear common AEs

Specialist Nurses are in a unique position to understand patient concerns and offer advice, as

they are often the first point of contact

Healthcare teams must work closely with patients and caregivers to facilitate early detection and

effective management of AEs2

1. Hon YY, et al. Clin Chem 1998;44:388-400; 2. Escudier B, et al. Cancer Treat Rev 2012;38:127-32.

TAKE HOME MESSAGES (II)

Multidisciplinary evaluation of these toxicities is key, but non-Oncologist Specialists should

have a specific competence, which is often difficult to achieve

The treatment of many of these AEs is often empirical … or relies on steroids (for irAEs)

Preventive measures – whenever applicable, prompt recognition of these AEs, and appropriate

treatment, will increase the likelihood that:

- patients are maintained on therapy as long as possible

- antitumor effects are thus maximized

Specific trials of supportive measures/agents are warranted, together with the development of

more tolerable agents

1. Hon YY, et al. Clin Chem 1998;44:388-400; 2. Escudier B, et al. Cancer Treat Rev 2012;38:127-32.

THANK YOU VERY MUCH FOR YOUR KIND

ATTENTION!!!

T

camillo.porta@unipv.it