ESMO Preceptorship Programme

Immuno-Oncology
Siena, July 04-05, 2016

MANAGEMENT OF TOXICITY

Luana Calabr
Medical Oncology and Immunotherapy, Department of Oncology
University Hospital of Siena, Istituto Toscano Tumori
SIENA, ITALY
 Therapeutic Options for Cancer

Chemotherapy/
Surgery
Target therapy

Radiotherapy Immunotherapy

Maio et al, Seminars Oncol 2015

 T-cell Checkpoint and Co-stimulatory Pathways

APC/ T cell
Tumor

CD40 CD40L Activation

CD137L CD137 Activation These pathways can be

activated via I-O agents to
OX40L OX40 Activation counteract tumor-mediated
inhibition
B7-2 (CD86) CD28 Activation

B7-1 (CD80) CTLA-4 Inhibition

These pathways can be
PD-L1 PD-1 Inhibition
blocked via I-O agents to
PD-L2 B7-1 (CD80) Inhibition counteract tumor-
mediated inhibition
LAG-3 Inhibition
MHC
TCR

Adapted from Pardoll DM 2012.

APC=antigen-presenting cell; CTLA-4=cytotoxic T-lymphocyte antigen-4; LAG-3=lymphocyte activation gene-3; MHC=major

histocompatibility complex;
PD-1=programmed death-1; PD-L1=PD ligand-1; PD-L2=PD ligand-2; TCR=T-cell receptor.
Pardoll DM. Nat Rev Cancer. 2012;12:252-264.

3
Immunotherapy in solid tumors with
immunomodulating antibodies

www.ImmunOncologia.it
 Immunotherapy of cancer:

A challenge for clinicians within (and outside) clinical trials?

Likely YES, being a totally new therapeutic strategy!

Major challenges:

Oncologists have utilized chemo/targeted therapies for decades

Treating physician education
Patient education on side effects and mechanisms of action of IO at variance with
chemo/target therapies
Multidisciplinary management

Respose evaluation criteria that are different from chemo/targeted therapies

 Immunotherapies are associated with novel
immune-related toxicities
Immunotherapies

Breaking peripheral tolerance

to self

Expansion of
Tumour infiltration
self-reactive T cells/
of lymphocytes
inflammatory T-cell infiltration

Antitumour
Immune-related side effects immune response
Champiat S, et al, Annal Oncol 2016
Most common immune-related Adverse Events
 Kinetics of appearance of immune-related adverse event

Weber J S et al. JCO 2012;30:2691-2697

2012 by American Society of Clinical Oncology

 Time to Resolution of Grade 24 irAEs
Monotherapy 10mg/kg treated patients
1.0 1.0
Censored
0.9 0.9 Liver
GI
Proportion not resolved

0.8 0.8
0.7 0.7
0.6 0.6
Median: 2.3 weeks Median: 4.0 weeks
0.5 0.5
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
0 0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Weeks Weeks

1.0 1.0
0.9 0.9
Endocrine Skin
Proportion not resolved

0.8 0.8
0.7 0.7
Median: 20.1 weeks Median: 6.1 weeks
0.6 0.6
0.5 0.5
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
0 0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Lebb, C et al. Perspectives in Melanoma XII 2008; Abstract O-015.

 Frequency of adverse events with I-O agents

Vaccines
Anti-idiotypic vaccine-induced local reaction
 Frequency of adverse events with I-O agents

Vaccines

CTLA-4
 Gastrointestinal irAEs
Diarrhoea/colitis during anti-CTLA-4: 30% (G3-4: 10%)
Diarrhoea/colitis during anti-PD-1/PD-L1: 7.4% (G3-4: 0.5%)

Grade 3 Immune colitis in a mesothelioma patient treated with tremelimumab (MESOT-TREM-2008)

a b
B

Colonoscopic view of bowel Histological signs:

edema the descending colon
a. erosion, increased number of inflammatory cells, and decreased
or loss of gland globet cells H&E; x 50 magnification);
b. isolated cryptic micro-abscesses (H&E; x 100 magnification)
 Frequency of adverse events with I-O agents

Vaccines

CTLA-4

PD1/PDL1
 Dermatologic irAEs
Dermatoligic toxicity is the the most frequent Ir-AE for both anti-CTLA-4/PD-1/PD-L1 mAb
They are usually mild-moderate (Grade 2-3), case of Steven-Johson syndrome and toxic
epidermal necrosis have been only sporadically reported.

Ipilimumab-associated rash in a
patient with advanced melanoma
resolved after steroids
Exacerbation of psoriasis after the 15
dose of
nivolumab. Treated with retinoid and fototherapy
 Anti-PD1-induced pneumonitis
3-5% of patients treated with anti-PD-1/PD-L1 (rarely observed with anti-CTLA-4).
This toxicity can be severe and life threatening.
Median time to onset is around 11 weeks, and median time to resolution is around 4 weeks.

W 12 W 16 W 38 (therapy resumed)
 Frequency of adverse events with I-O agents

Vaccines

CTLA-4

PD1/PDL1

PD1/PDL1
+
CTLA-4
 CHECKMATE 067

Safety Summary

Updated safety information with 9 additional months of follow-up were

consistent with the initial report

NIVO+IPI NIVO IPI

(N = 313) (N = 313) (N = 311)

Patients reporting event, % Any grade Grade 3-4 Any grade Grade 3-4 Any grade Grade 3-4

Treatment-related adverse event

95.8 56.5 84.0 19.8 85.9 27.0
(AE)

Treatment-related AE leading to
38.7 30.7 10.5 7.3 15.4 13.5
discontinuation

Treatment-related deatha 0 0.3 0.3

68.8% of patients who discontinued NIVO+IPI due to treatment-related AEs

achieved a response

aOne reported in the NIVO group (neutropenia) and one in the IPI group (colon perforation)
Database lock Nov 2015
ASCO 2016
 General Management Guidelines for irAEs
Signs and Symptoms Determine Cause Adverse Event
Present and Severity Management

Rule out
Provide appropriate symptomatic treatment, and continue
alternative
ipilimumab dosing as clinically appropriate
etiologies
no

Suspect
irAE? Grade 1 Manage with symptomatic therapy
Determine
yes

Improvement to grade 1
severity using
NCI CTCAE
grading
Administer oral steroid therapy, such as prednisone
scale Any grade 2 or 1 mg/kg daily or equivalent
grade 3 skin toxicities If symptoms improve, gradually taper over a
minimum of 4 weeks
If no improvement to grade 1 after 1
week, manage as high-grade event
If symptoms have a GI,
liver, or endocrine Treat with high-dose steroid therapy, such as
etiology, refer to their Grade 3 non-skin toxicity methylprednisolone 2 mg/kg IV once or twice daily
specific treatment or any grade 4 toxicity or equivalent
guidelines If symptoms improve, gradually taper over 4 weeks

If no improvement

Please refer to specific GI, liver, or endocrine

guidelines
Administer antimicrobial prophylactics as
appropriate for patients on long-term
immunosuppressive therapy, per institutional
Chin K et al. ESMO 2008, poster presentation Abstract #787P guidelines
 Rare irAEs: neurological toxicity

Neurological irAEs may occur as mild symptoms or more severe and life-threatening
impairmnets that require immediated diagnosis and treatement, notably in progressing
cases (role of skilled neurologist!);

Although oncological immunotherapy discontinuation and appropriate treatment, the

neurological damage could be irreversible, or partially and transiently reversible;

CNS and PNS irAEs can concurrently arise;

Whether neurological irAEs are paraneoplastic syndromes rather than true irAEs may in
some cases debatable, taking also in account that the one does not necessarily exclude the
other;

Late onset and long duration of irAEs are peculiar features of checkpoint blockade
therapy and emphasize the need for long-term follow-up of patients, during treatment
and also after its discontinuation.
 Neurological irAEs in our casistics

More than one thousand patients treated with anti-CTLA-4 (ipilimumab,

tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1
(atezolizumab, duvalumab, avelumab) mAb and combos.

Seven cases of diverse neurological toxicities have been observed in

different tumor types treated with different I-O and their combos:
1 case with limbic encephalitis,
2 cases with limbic encephalitis and Guillaine-Barr-like syndrome,
4 cases with acute inflammatory demyelinating polyneuropathy (AIDP).
Male, 66 yrs, with pleural mesothelioma
Dec 2015 started treatement with tremelimumab+durvalumab x 6 doses with PR
May 2016 memory desorders (anterograde amnesia)multidisciplinary management with neurologist
diagnosis of limbic encephalitis

Start treatment with IVIg high doses of steroids

 Oncologist

Dermatologist
Gatroenterologist irAE
Pneumologist Patient
mangement
Endocrinologist
Neurologist
..

Radiologist

Melero I. et al Nat rev cancer (2007) modified

 irAE management

t say!
What patients don
 Clinical Case
M, 48-year-old, PS=0, affected by pleural mesothelioma stage IV

BRIEF PATIENTS ONCOLOGICAL HISTORY

February 2015: First line CT with Cisplatin/Pemetrexed

December 2015: Second line therapy within the NIBIT-MESO-1

 NIBIT-MESO-1: Study Design

Screening Treatment FU

Tremelimumab +
Durvalumab Dose Durvalumab Dose Q4W (9 doses)
Q4W (4 doses)

Cycle 1 2 3 4 5 6 7 8 9 10 11 12 13

Week 0 4 8 12 16 20 24 28 32 36 40 44 48
TA TA TA TA TA

Re-treatment in case of PD after induction phase or follow-up

FU= follow-up; TA= tumor assessment

 Clinical Case

23 Feb 2016 1st dose with treme+durvalumab

08 Mar 2016 lab tests showed increase levels of Bilirubin total and direct,
transaminases (G3 CTC)

No deterioration of clinical condition (PS=0)

No significant abnormalities showed at liver ultrasound and liver MRI
Viral test negatives
Autoimmunity test negatives

21 Mar 2016 Liver biopsy with histology mild flogosis, severe necrosis
morphologically signs of acute cholestatic liver toxic injury
25 Mar 2016 the patient had taken homeopathy compound (Ganoderma/Coriulus,
chinese mushroom) hospitalization for worsening of lab tests

Bilirubin

25

High doses of steroids

20

15
mg/dl

10

0
8 9 11 14 15 16 17 25 28 30 1 3 30

Complete resolution of liver injury in 8 weeks

 KEY TAKEAWAYS
The immunotherapeutic agents have a different mechanism of action
from cytotoxic agents, as such, they have a different adverse event profile;
To prevent irAEs: select patients, identify dysimmunity risk factor;
Perform baseline assessment; monitor patients for signs/symptoms and lab
changes that may indicate irAEs at every visit, as well as monitor their onset also
off treatment;
In case of AEs: rule out other etiologies, initiate prompt and appropriate treatment
and eventually interrupt immunotherapy based on irAE grade; while many of the
irAEs are mild-moderate in nature, severe and life-threatening irAEs do occurr;
through a prompt identification and appropriate management, many of these irAEs
can be reversed and may allow patients to resume immunotherapy after irAEs
resolution;
To educate patients and caregivers on signs and symptoms of irAEs, to stress the
importance of early identification and reporting, and to report every non
conventional coumpounds they are taking.
ENJOY SIENA
BACK UP SLIDES
Analyses of the impact of steroid use on
ipilimumab responses
Steroids prior to response
No steroids prior to response

100
74.6% 75.7%
80 (85/114) (103/136)
Percent of patients

60

40 25.4% 24.3%
(29/114) (33/136)
20

0
CR/PR/SD PD or Unknown*

*Including patients who had SD followed by PD

CR= complete response; PR= partial response; SD= stable disease; PD= progressive disease
37
 Endocrine irAEs
Endocrine irAEs of any grade are observed in around 5-10% of patients receiving anti-CTLA4 and/ir
PD-1/PD-L1 mAb

Thyroid dysfunction: hypothiroidism is the most frequently

observed, and usually required hormone replacement;
hyperthiroidism is rarely reported, can be treated with non-selected
beta-blockers, althou in almost all cases resolves spontaneously with
subsequent appearance of hypothiroidism.

Hypophysitis:is mainly observed with anti-CTLA-4 therapy qand can

affect up to 10% of patietnts; it is difficult to diagnose because often
symptoms are non-specific (headache, fatigue, muscle weakness,
weight loss, anorexia, nausea); serum hormonal levels is required, as
well as pituitary MRI imagin that can showes enlargement or
heterogeneity of the gland. Treatment is based on the replacement of
appropriate hormon deficiency.
 Gastrointestinal irAEs

Diarrhoea/colitis is more common during CTLA-4 blockade treatment

than during PD-1/PD-L1 blockade 30% vs 7.4%, respectively).
Diarrhoea occurr in around 10% at severe grade (grade 3-4), in
patients receiving anti-CTLA4 mAb, while only 0.5% receiving anti-
PD1/PD-L1.
Colitis during CTLA4 blockade treatment shares some features with
Chron disease (erithema, ulcerations in colonoscopic imaging;
histological signs include neutrophil inflammation with criptis and in
some cases cryptic abscesses and granuloma).
Ruled-out infections by microbiological testes, abdominal CT scan +/-
colonscopic evaluation is useful for establishing the severity and extent
of any digestive lesions.
Treatment is based on symptomatically or steroids for persistent grade
1-2 or severe diarrhoea/colitis; anti-TNF is required for refractory irAE.
 Lung irAEs

irAEs pneumonitis (including sarcoidosis) occurr in aroud 3-5% of

patients treated with anti-PD-1/PD-L1 or CTLA4 (rarely).
This toxicity can be severe and life threatening.
Median time to onset is around 11 weeks, and median time to
resolution is around 4 weeks.
CT scan can shows ground glass lesions and/ or disseminated nodular
infiltrates, predominantly in the lower lobes. A broncoscopy with BAL
should be considered to exclude infections.
Treatment is based on steroids, and immunosoppressor could be
considered if cases steroid-refractory.
 Take home message (Case 1)

Beware of non-conventional
concurrent medications
 Case study liver toxicity
1800
*
1600
1400
1200 ALT
1000
AST
800
600
SD Clincal
benefit
400 PR
200
0
W1 W12 W24 W48 W70 W71 W72 W73 W84

* Dexamethasone 8 mg i.v. BID x 7 days slow tapering