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Gestion des toxicités
Cas Particuliers
Benjamin Besse, MD., PhD.
Thoracic Unit, Head
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 2
Disclosures
No personal financial disclosures
Institutional grants for clinical and translational
research
Abbott, Amgen, AstraZeneca, BMS, Boehringer-
Ingelheim, Lilly, Pfizer, Roche-Genentech, Sanofi-
Aventis, Clovis, GSK, Servier, EOS
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Welcome to my world
3Schiller et. al., NEJM 02
Median OS
8 months
Advanced Non Small Cell Lung Cancer, 1st line
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 4
Disease segmentation based
on oncogenic events
« Druggable » genomic alterations
From an organ-based disease to a molecular classifications
of rare diseases
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 5
Disease segmentation based
on oncogenic events
« Druggable » genomic alterations
From an organ-based disease to a molecular classifications
of rare diseases
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
EGFR mutations in lung cancer
Sharma SV, et al. Nat Rev Cancer 2007;7;169–81Sharma SV, et al. Nat Rev Cancer 2007;7:169–81
ACTIVATINGMUTATIONS
mostlyexon 19 del
&exon 21 L858R
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 7Rosell et al, NEJM 2009
A unique disease history
Median OS: 27 months
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 8
IPASS PFS in EGFRmut patients
Gefitinib
(250 mg / day)
Carboplatin
(AUC 5 or 6) /
paclitaxel
(200 mg / m2)
3 weekly cycle
6 cycles
1:1 randomisation
Patients
• Chemonaïve
• Age ≥18 years
• Adenocarcinoma histology
• Never or light ex-smokers*
• Life expectancy≥12 weeks
• PS 0-2
• Measurable stage IIIB / IV disease
Mok NEJM 2009
EGFR mut patients (60%)
HR = 0.48
p<0.001
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 9Fukuoka JCO 2011
IPASS OS in EGFRmut patients
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 10
Studypatients (n)
EGFRmDrugs PFS
IPASS 261 gefitinib vs
carboplatine-paclitaxel
HR 0.48
(95% CI 0.36–0.64), p=0.001
FIRST-SIGNAL 42gefitinib vs
gemcitabine-cisplatine
HR = 0.544
(95% CI 0,269-1,1), p=0.086
WJTOG 172
gefitinib vs cisplatine-
docetaxel
HR 0,33
(95% CI 0,21-0,54), p<0,0001
NEJ 002 228gefitinib vs
carboplatine-placitaxel
HR 0,32
(95% CI 0,24-0,44), p<0,001
OPTIMAL154
erlotinib vs
carboplatine-
gemcitabine
HR 0,16
(95% CI 0,10-0,26), p<0,0001
EURTAC
173erlotinib vs doublet à
base de platine
HR 0,37
(95% CI 0,25-0,54), p<0,0001
LUX-LUNG 3 345 afatinib vs cisplatine-
pemetrexed
HR 0,58
(95% CI 0,43-0,78) p=0,001
LUX-LUNG 6 364afatinib vs cisplatine-
gemcitabine
HR 0,28
(95% CI 0,19-0,36), p<0,001
ENSURE 217erlotinib vs cisplatine-
gemcitabine
HR 0,34
(95% CI 0,22-0,51), p<0,0001
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 11
Studypatients (n)
EGFRmDrugs PFS OS
IPASS 261 gefitinib vs
carboplatine-paclitaxel
HR 0.48
(95% CI 0.36–0.64), p=0.001
HR 1,00
(95% CI 0.76–1.33), p=0,990
FIRST-SIGNAL 42gefitinib vs
gemcitabine-cisplatine
HR = 0.544
(95% CI 0,269-1,1), p=0.086
HR = 1.043
(95% CI 0,498-2,182)
WJTOG 172
gefitinib vs cisplatine-
docetaxel
HR 0,33
(95% CI 0,21-0,54), p<0,0001
HR 1,19
(95% CI 0,77-1,83), p=0,443
NEJ 002 228gefitinib vs
carboplatine-placitaxel
HR 0,32
(95% CI 0,24-0,44), p<0,001
HR 0,89
(95% CI 0,63-1,24), p=0,483
OPTIMAL154
erlotinib vs
carboplatine-
gemcitabine
HR 0,16
(95% CI 0,10-0,26), p<0,0001
HR 1,04
(95% CI 0,69-1,58), p=0,69
(immature)
EURTAC
173erlotinib vs doublet à
base de platine
HR 0,37
(95% CI 0,25-0,54), p<0,0001
HR 1,04
(95% CI 0,65-1,68), p=0,87
LUX-LUNG 3 345 afatinib vs cisplatine-
pemetrexed
HR 0,58
(95% CI 0,43-0,78) p=0,001
HR 0,91
(95% CI 0,66-1,25), p=0,55
(immature)
LUX-LUNG 6 364afatinib vs cisplatine-
gemcitabine
HR 0,28
(95% CI 0,19-0,36), p<0,001Immature
ENSURE 217erlotinib vs cisplatine-
gemcitabine
HR 0,34
(95% CI 0,22-0,51), p<0,0001Immature
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Patient #1
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 13
Clinical Case #1
Female 65 years old. Never-Smoker
Not pathological disease
Oncological history:
March 2006: M1 right humerus
Biopsy: Poorly differentiated ADC CK7+, CK20-, TTF1+,
HR+.
PET-scan:
Right superior lobe nodule + peribronquial nodule.
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical Case #1
14
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical Case #1
Initially: NSCLC (TTF1 IHC +) vs. Breast Cancer (HR+,
HER2 -, Ca15.3: 80):
No humerus radiotherapy because patient asymptomatic.
Taxol 175 mg/m2 d1 + Gemzar 1250 mg/m2 d1,8 / 21d
After 6 cycles: PARTIAL RESPONSE
January 2007: Lung nodules progression.
15
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical Case #1
Screen failure in neratinib (pan-HER2) protocol (not
enough tissue for EGFR mutation testing , < 5% cells
in humerus biopsy).
Erlotinib 150 mg/d 07.02.2007
16
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical Case #1
Tarceva prescription form in Gustave Roussy
17
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical Case #1
After 1 month on treatment:
Rash grade 1
Dry skin grade 1
Not diarrhea.
CT scan March 2007: Partial Response.
The patient continued treatment in unchanged doses.
18
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical Case #1
On December 2009 some pigmented lesions in scalp
Alopecia
19
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical case #1
On February 2010, 3 years on Tarceva….
Tarceva 100mg/d + Diprosone + Erytromicine gel
Tetracyclines 2 cp/d
20
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical Case #1
After that episode, Doxicycline 100 mg/d continuous
during 12 months.
Last control:
Dermatology Unit 24.03.2015: Rash grade 1
Oncology Unit 06.10.2015: CT-scan, PR
21
8.5 years of tarceva…
Should we stop?
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 22
Disease segmentation based
on oncogenic events
« Druggable » genomic alterations
From an organ-based disease to a molecular classifications
of rare diseases
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 23
Melanoma : V600E BRAF mut & Vemurafenib
Flaherty, NEJM 10
PFS : 1.6 vs 5.3 months
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 24
Men, 68
Smoker
Active surgeon
Mutation BRAF V600E
Jan to Oct 2010
Pemetrexed Cisplatine
Bevacizumab 6 cycles
Pemetrexed Bevacizumab
maintenance
31/05/12
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 25
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 26
31/05/12 19/06/12
Ve
mu
rafe
nib
sta
rted
03/0
6/1
2
+ 4 kg
SaO2
89%
to
96%
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 27
Disease segmentation based
on oncogenic events
« Druggable » genomic alterations
From an organ-based disease to a molecular classifications
of rare diseases
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
ALK kinase activityCoiled coil domain of EML4
(facilitates protein–protein interaction)
EML4
promoter
first exonkinase region
ALK 3’/EML4 5’
EML4 EML4 promoterALK
p23.2 p21 short arm long arm
Chromosome 2
Oncogenic EML4–ALK gene product results from
a genomic translocation
Adapted from Soda M, et al. Nature 2007;448:561–6
FISH
separate
red/green signals
Definition of ALK
positivity: ≥15% of cells
with positive pattern
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Crizotinib
(250 mgX2 /
day)
Cisplatin
(75 mg/m²) /
pemetrexed
(500 mg / m2)
q3w
6 cycles
1:1 randomisation
Patients
• Chemonaïve
• Measurable stage IIIB / IV disease
• WHO performance status 0–2
•ALK + (FISH)
PROFILE 1014 : ALK+ patients
Primary objective : PFS
HR 0.45 (95% CI 0.35−0.60)
p<0.001
Solomon NEHM 14
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 30Solomon NEHM 14
PROFILE 1014 - OS
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Resistance to ALK TKI ?
Crizotinib (C) - ORR 61%
% t
um
or
shri
nka
ge
N=47 - All C pretreated
N=114 - 69% C pretreated
Be
st %
ch
an
ge
fro
m b
ase
line
–100
–80
–60
–40
–20
0
60
40
20
80
100
PFS event
Ceritinib - ORR 58%
Alectinib - ORR 54.5%
Shaw N Engl J Med 2013, Shaw ASCO 2013, Ou ECC 2013, Camridge, ECC 2013
Be
st
Ch
an
ge
fro
m B
as
elin
e in
Ta
rg
et
Le
sio
n (
%)
-100
-80
-60
-40
-20
0
20
40
Progressive Disease Stable Disease Partial Response Complete ResponseBest Overall Response:
c
b
b
a
a
a
d
N=34 - 91% C pretreated
AP26113 - ORR 65%
N=116 - All « C untreated »
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Patient #2
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 33
« Docteur : j’étouffe aussi».
67 ans
Antécédents
Péritonite à 12 ans.
Glaucome
Mode de vie
Mariée, 2 enfants, une fille en Australie, enceinte.
Secrétaire retraitée.
Non fumeuse
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Janvier 2013
Embolie pulmonaire au retour d’Australie
Nodule 5 mm LSD
Récidive EP en sept. 2014
Adénocarcinome cT4N2M1a (plèvre)
Diagnostic par endoscopie bronchique
Pas de mutation EGFR (mais faible % de cellules)
Pemetrexed-cisplatine 3 cycles
Du 10 oct au 21 nov 2014 :
PD thoracique + lésions osseuses lytiques
Nouvelle endoscopie : % de cell trop faible pour
biologie moléculaire
34
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
20 janvier 2015
Talcage + biopsies
Erlotinib commencé le 25 janvier avant bio.mol.
Aspect de lymphangite, profil non réalisable (% de
cellules trop faible), IHC ALK non faisable.
15/04 : progression thoracique
Paclitaxel/avastin debuté le 22/04
A J15, hospitalisée pour détresse respiratoire sur
progression de la maladie
Crizotinib à l’aveugle le 6/05
Beaucoup mieux à J15
35
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Cytolyse
ALAT 53N le 17 juin
TP et bilirubine Nx
36
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Cytolyse
ALAT 53N le 17 juin
TP et bilirubine Nx
Arrêt crizotinib
04/07 : ALAT 3N
Toux et majoration dyspnée et AEG
Ceritinib 750 mg /j
Disparition de la toux mais pas de la dyspnée
Nausées G2 et douleurs abdominales G1
37
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Hépatotoxicité
Pas de facteurs de risque
Dans les 2 premiers mois souvent
Arrêt crizotinib
Reprendre si transaminases <G1 (<2,5 N)
200 mg X 2 ou 250 mg X1 /j
Arrêt définitif si bilirubine a été G2 ou plus
38
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 39
06/05/15 20/08/15
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Septembre
Tolérance toujours limite
Majoration lente de la dyspnée
LBA : 85% macrophages, 5% lymphocyes, 10% PNN
IF pneumocystose -
4040
20/08/15 01/10/15
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Crizotinib recommencé le
11/10/15…
41
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 42
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
CheckMate 017 (NCT01642004) - Study Design
• One pre-planned interim analysis for OS
• At time of DBL (December 15, 2014), 199 deaths were reported (86% of deaths required for final analysis)
• The boundary for declaring superiority for OS at the pre-planned interim analysis was P <0.03
Patients stratified by region
and prior paclitaxel use
Nivolumab
3 mg/kg IV Q2W
until PD or
unacceptable toxicity
n = 135
Docetaxel
75 mg/m2 IV Q3W
until PD or
unacceptable toxicity
n = 137
Ra
nd
om
ize
1:1
• Primary Endpoint:
– OS
• Additional Endpoints:
Investigator-assessed ORR
Investigator-assessed PFS
Correlation between PD-L1
expression and efficacy
Safety
Quality of life (LCSS)
• Stage IIIb/IV SQ NSCLC
• 1 prior platinum doublet-based
chemotherapy
• ECOG PS 0–1
• Pre-treatment (archival or
fresh) tumor samples required
for PD-L1 analysis
N = 272
LCSS = Lung cancer symptom scale
David R. Spigel et al
Stage IIIb/IV SQ NSCLC
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Nivolumab
n = 135
Docetaxel
n = 137
ORR, %
(95% CI)
20
(14, 28)
9
(5, 15)
P-valuea 0.0083
Best overall response, %
Complete response
Partial response
Stable disease
Progressive disease
Unable to determine
1b
19
29
41
10
0
9
34
35
22
Median DOR,c mo
(range)
NR
(2.9, 21+)
8.4
(1.4+, 15+)
Median time to response,c mo
(range)
2.2
(1.6, 12)
2.1
(1.8, 9.5)
Objective Response Rate
• 28 patients in the nivolumab arm were treated beyond RECIST v1.1-defined progression
• Non-conventional benefit was observed in 9 patients (not included in ORR)
aBased on two-sided stratified Cochran–Mantel–Haenszel test on estimated odds ratio of 2.6 (95% CI: 1.3, 5.5). bOne pt experienced complete response.cValues are for all confirmed responders per RECIST v1.1 (nivolumab, n = 27; docetaxel, n = 12). Symbol + indicates a censored value.NR = not reached
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Progression-free Survival
90
80
70
60
50
40
30
10
0
20 Nivolumab
Docetaxel
Time (months)
1-yr PFS rate = 21%
1-yr PFS rate = 6.4%
PF
S (
%)
24211815129630
Number of Patients at Risk
Nivolumab
Docetaxel
135 68 48 33 21 15 6 2 0
137 62 26 9 6 2 1 0 0
Nivolumab
n = 135
Docetaxel
n = 137
mPFS, mo
(95% CI)3.5
(2.1, 4.9)
2.8
(2.1, 3.5)
HR = 0.62 (95% CI: 0.47, 0.81); P = 0.0004
100
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Overall Survival
Nivolumab
Docetaxel
135 113 86 69 52 31 15 7 0
137 103 68 45 30 14 7 2 0
Number of Patients at Risk
Time (months)
Nivolumab
Docetaxel
1-yr OS rate = 42%
1-yr OS rate = 24%
OS
(%
)Nivolumab
n = 135
Docetaxel
n = 137
mOS mo,
(95% CI)9.2
(7.3, 13.3)
6.0
(5.1, 7.3)
# events 86 113
HR = 0.59 (95% CI: 0.44, 0.79), P =
0.00025
24211815129630
100
90
80
70
60
50
40
30
10
0
20
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Treatment-related AEs (≥10% of patients)
Nivolumab
n = 131
Docetaxel
n = 129
Any Grade Grade 3–4 Any Grade Grade 3–4
Total patients with an
event, %58 7 86 55
Fatigue 16 1 33 8
Decreased appetite 11 1 19 1
Asthenia 10 0 14 4
Nausea 9 0 23 2
Diarrhea 8 0 20 2
Vomiting 3 0 11 1
Myalgia 2 0 10 0
Anemia 2 0 22 3
Peripheral neuropathy 1 0 12 2
Neutropenia 1 0 33 30
Febrile neutropenia 0 0 11 10
Alopecia 0 0 22 1
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Treatment-related Select AEs
• Select AEs: AEs with potential immunologic etiology that require frequent monitoring/intervention
a No cases of increased bilirubin occurred in the nivolumab arm. b Grade 5 event. c No cases of renal failure were reported in the nivolumab arm. d Includes rash, pruritus,
erythema, maculopapular rash, skin exfoliation, urticaria and palmar plantar erythrodysasthesia syndrome.
Nivolumabn = 131
Docetaxeln = 129
Any Grade Grade 3–4 Any Grade Grade 3–4
Endocrine, %Hypothyroidism
44
00
00
00
Gastrointestinal, %DiarrheaColitis
881
101
20200
220
Hepatic,a % ALT increasedAST increased
222
000
211
111
Pulmonary, %
Pneumonitis
Lung infiltrationInterstitial lung disease
5510
1100
1b
001b
0000
Renal,c % Blood creatinine increasedTubulointerstitial nephritis
331
101
220
000
Skin,d % 9 0 9 2
Hypersensitivity/Infusion reaction, % HypersensitivityInfusion-related reaction
101
000
221
110
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Patient #3
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical case #3
Male 52 years-old. Smoker 45 Paq/y
Lung Oncology History
2012 ADC T3 N0 M1b (right femur)
RT femur
Pemetrexed / CDDP + Bevacizumab x 6 cycles
Bevacizumab maintenance (last cycle 03/2013 because…
diagnosis of head and neck cancer!).
07/2013 Squamous carcinoma oropharynx T2 N1 M0
Cetuximab + RT 70 Gy (06.05.2013 to 02.07.2013): CR
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical case #3
On October 2014: Lung cancer progression on
superior right lobe
Taxol / Carboplatin 6 cycles
Thoracic RT “cloture” 30 Gy 17.03.15 to 31.03.2015
51
Before CT After 6 cycles
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical case #3
On July 2015:
Mediastinal nodules, bones and retro-pectoral progression,
IRM: M1 cerebrals symptomatic Whole brain RT (30
Gy, 13.07.15 to 24.07.15)
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical case #3
28.07.2015 D1C1 Nivolumab (mAb anti-PD1)
After 4 infusions (4th 08.09.2015): progressive dyspnoea
Angio-scanner 17.09.2015: no embolism. Interstitial pattern:
infection? (P carinii) / toxic for nivolumab
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GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical case #3
FBS 18.09.2015: Normal
250 cells, 58% lymphocytes.
No Pneumocystis carinii.
Betadeglucane negative. PCR pneumocystis negative.
Not bacterial report positive. Not candida.
Patient did not require oxygen with steroids and go
back home.
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GUSTAVE ROUSSY THÈME DU DIAPORAMA 55
Nouvelles thérapies
Traitements chroniques
Toxicités chroniques
When to stop?