Gestion des toxicités Cas Particuliers - Tao meeting · Gestion des toxicités Cas Particuliers Benjamin Besse, MD., PhD. Thoracic Unit, Head

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


Disease segmentation based

on oncogenic events

« Druggable » genomic alterations

From an organ-based disease to a molecular classifications

of rare diseases



on oncogenic events



of rare diseases


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


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


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


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


Patient #1


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.


Clinical Case #1

14


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


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


Clinical Case #1

Tarceva prescription form in Gustave Roussy

17


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


Clinical Case #1

On December 2009 some pigmented lesions in scalp

Alopecia

19


Clinical case #1

On February 2010, 3 years on Tarceva….

Tarceva 100mg/d + Diprosone + Erytromicine gel

Tetracyclines 2 cp/d

20


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?



on oncogenic events



of rare diseases


Melanoma : V600E BRAF mut & Vemurafenib

Flaherty, NEJM 10

PFS : 1.6 vs 5.3 months


Men, 68

Smoker

Active surgeon

Mutation BRAF V600E

Jan to Oct 2010

Pemetrexed Cisplatine

Bevacizumab 6 cycles

Pemetrexed Bevacizumab

maintenance

31/05/12



31/05/12 19/06/12

Ve

mu

rafe

nib

sta

rted

03/0

6/1

2

+ 4 kg

SaO2

89%

to

96%



on oncogenic events



of rare diseases


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


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


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 »


Patient #2


« 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


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


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


Cytolyse

ALAT 53N le 17 juin

TP et bilirubine Nx

36


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


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


06/05/15 20/08/15


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


Crizotinib recommencé le

11/10/15…

41



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


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


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


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


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


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


Patient #3


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


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


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


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


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


Nouvelles thérapies

Traitements chroniques

Toxicités chroniques

When to stop?

Documents

Gestion des toxicités Cas Particuliers - Tao meeting · Gestion des toxicités Cas Particuliers Benjamin Besse, MD., PhD. Thoracic Unit, Head