tkis, mtoris and immunotherapy: side …...hypophosphatemia greatly affects patients’ qol;...
TRANSCRIPT
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.