Gestion des toxicités
Cas Particuliers
Benjamin Besse, MD., PhD.
Thoracic Unit, Head
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
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
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
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
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA 7Rosell et al, NEJM 2009
A unique disease history
Median OS: 27 months
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA 9Fukuoka JCO 2011
IPASS OS in EGFRmut patients
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
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA
Patient #1
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.
GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical Case #1
14
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
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical Case #1
Tarceva prescription form in Gustave Roussy
17
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA
Clinical Case #1
On December 2009 some pigmented lesions in scalp
Alopecia
19
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
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?
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA 23
Melanoma : V600E BRAF mut & Vemurafenib
Flaherty, NEJM 10
PFS : 1.6 vs 5.3 months
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA 25
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%
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
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
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA 30Solomon NEHM 14
PROFILE 1014 - OS
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 »
GUSTAVE ROUSSY THÈME DU DIAPORAMA
Patient #2
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
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
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA
Cytolyse
ALAT 53N le 17 juin
TP et bilirubine Nx
36
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
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA 39
06/05/15 20/08/15
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA
Crizotinib recommencé le
11/10/15…
41
GUSTAVE ROUSSY THÈME DU DIAPORAMA 42
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
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
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
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
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
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
GUSTAVE ROUSSY THÈME DU DIAPORAMA
Patient #3
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
50
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
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)
52
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
53
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.
54
GUSTAVE ROUSSY THÈME DU DIAPORAMA 55
Nouvelles thérapies
Traitements chroniques
Toxicités chroniques
When to stop?